No full-text available
To read the full-text of this research,
you can request a copy directly from the authors.
The effects of short-term overfeeding on insulin action in lean and reduced-obese individuals
Abstract
Insulin resistance is clearly associated with obesity. However, the role of excess energy intake per se as opposed to increased fat mass in the development of insulin resistance has not been clearly defined. It may be that the nutrient load provided by short-term overfeeding is sufficient to induce measurable changes in insulin action in skeletal muscle and the liver. We examined the effects of 3 days of overfeeding on insulin action and glucose kinetics in 13 lean (body mass index, 20.9 +/- 2.4 kg/m(2); 6 men, 7 women) and 9 reduced-obese (RO) (body mass index, 29.1 +/- 2.2 kg/m(2); 4 men, 5 women) individuals. A two-step euglycemic hyperinsulinemic clamp study (5 and 40 mU m(-2) min(-1)) with a primed, constant infusion of [6,6-(2)H(2)]glucose was performed after 3 days of a weight-maintenance diet and again after 3 days of overfeeding by 50% (50% carbohydrate, 30% fat, 20% protein). At baseline, lean individuals were more insulin sensitive, as measured by glucose infusion rate, than RO individuals (12.08 +/- 0.8 vs 7.62 +/- 1.0 mg x kg(-1) x min(-1), P < .01) with lean women being more insulin sensitive than lean men (P < .01). Overfeeding resulted in a reduction in glucose infusion rate in lean women (13.37 +/- 1.3 to 11.42 +/- 1.0 mg x kg(-1) x min(-1), P < .05), but no change was noted in lean men or RO individuals. Basal and insulin-stimulated glucose disposal remained unchanged with overfeeding in all groups. Low-dose insulin suppression of endogenous glucose production was impaired after overfeeding in lean women (euenergetic, 1.92 +/- 0.36 to 0.36 +/- 0.16 mg x kg(-1) x min(-1); overfeeding: 2.13 +/- 0.17 to 0.86 +/- 0.12 mg x kg(-1) x min(-1); P = .04) but remained unchanged in the other groups. These findings demonstrate that insulin action is reduced in lean, obese-resistant women after short-term overfeeding primarily because of an inhibition of insulin-mediated suppression of endogenous glucose production, whereas short-term overfeeding does not appear to effect insulin action in lean men and RO individuals. This response may be indirectly involved in the ability of lean women to maintain weight in the face of an obesigenic environment.
... Beginning with the novel experiments of Sims et al (5,6) which demonstrated that long-term overfeeding increased fasting insulin and impaired glucose tolerance overfeeding has been used as a strategy to examine mechanisms for the adverse metabolic effects of weight gain and obesity. Impaired insulin sensitivity has been reported to be an untoward effect of overfeeding interventions (7)(8)(9)(10)(11)(12)(13)(14) with effects observed in as little as 3 days (10,(15)(16)(17). Insulin resistance during overfeeding is more readily demonstrated in individuals with a low birth weight (LBW) than normal birth weight (18) and in postsurgical bariatric patients (19). ...
... Beginning with the novel experiments of Sims et al (5,6) which demonstrated that long-term overfeeding increased fasting insulin and impaired glucose tolerance overfeeding has been used as a strategy to examine mechanisms for the adverse metabolic effects of weight gain and obesity. Impaired insulin sensitivity has been reported to be an untoward effect of overfeeding interventions (7)(8)(9)(10)(11)(12)(13)(14) with effects observed in as little as 3 days (10,(15)(16)(17). Insulin resistance during overfeeding is more readily demonstrated in individuals with a low birth weight (LBW) than normal birth weight (18) and in postsurgical bariatric patients (19). ...
... After an overnight fast 2 intravenous (IV) lines were placed and 3 baseline blood samples drawn. A glucose dose of 300 mg/kg was injected at Time 0, followed by collection of blood samples at 1, 3,4,5,6,7,8,10,12,14,16, and 20 minutes. Glucose and insulin concentrations measured in each sample were submitted for calculation of the AIRg using the Minimal Model method of Bergman and colleagues (22). ...
Context:
Obesity is associated with insulin resistance and other metabolic changes which might be modified by overfeeding diets with different protein levels.
Objective:
To determine the effect of overfeeding diets with 5%, 15% or 25% energy from protein on insulin sensitivity and compartments of body fat in healthy men and women.
Methods:
15 men and 5 women were overfed by∽40% for 56 days with 5% (LP), 15% (NP) or 25% (HP) protein diets. Insulin sensitivity was measured using a two-step insulin clamp at baseline and at 8 weeks. Body composition and fat distribution were measured by DXA and multi-slice CT scan and abdominal subcutaneous fat cell size was determined on osmium fixed fat cells.
Setting:
In-patient metabolic ward study Main Outcome Measures: Insulin sensitivity and free fatty acids during low and high levels of insulin infusion before and after 8 weeks after overfeeding and changes in body fat distribution from computed tomography.
Results:
Total body fat mass, fat free mass (FFM), visceral adipose tissue (VAT) and deep subcutaneous fat (DSAT) all increased with overfeeding. FFM and intrahepatic lipid increased more on the HP diet whereas%BF and fasting FFA increased more on the LP diet. Baseline fat cell size predicted the increase in VAT and the magnitude of FFA suppression during the high-dose insulin clamp. Acute release of insulin at baseline predicted the increase in DSAT, but not VAT. Fasting insulin and glucose increased with overfeeding, but glucose disposal as measured by the clamp was not changed. Suppression of FFA was less complete during the high dose insulin infusion after overfeeding.
Conclusion:
Eight weeks of overfeeding which increased fat mass including expansion of visceral and deep subcutaneous tissues and intrahepatic lipid, increased fasting insulin and glucose, impaired the suppression of FFA, but did not produce whole body insulin resistance.
... Previous studies have used intravenous lipid infusions to induce supraphysiological high levels of plasma FFA as a model to study the metabolic effects of high fat exposure, and thereby to mimic the state of overt type 2 diabetes commonly characterized by elevated FFA levels (Belfort et al. 2005;Bachmann et al. 2001). Other studies have used varying duration of either different types of overfeeding (Faeh et al. 2005;Clore et al. 1995;Cornier et al. 2006), or diets containing high amounts of fat (Bachmann et al. 2001;Westerbacka et al. 2005;Bisschop et al. 2001). However, these studies have mainly included rodents, obese human subjects and/or human subjects with a family history of diabetes with relatively small numbers (Westerbacka et al. 2005;Bachmann et al. 2001;Chanseaume et al. 2007;Chanseaume et al. 2006). ...
... Fasting plasma FFA, TG, LDL and VLDL concentrations were decreased, whereas HDL cholesterol was increased,after high-fat overfeeding, possibly caused by the fatty acid composition of the diet. Indeed, decreased FFA levels was previously reported in some short-term overfeeding studies (Clore et al. 1995;Cornier et al. 2006), and is most likely due to a suppression of lipolysis in adipose tissue in the fasting state mediated by the increased insulin level. The low plasma FFA could also be due to an increased uptake into the muscle tissue, possibly resulting in FFA being stored within the cell as IMCL (Bachmann et al. 2001;Schrauwen-Hinderling et al. 2005). ...
... Despite the observed hepatic insulin resistance, whole-body insulin-stimulated glucose disposal was not decreased after 5 days of fat overfeeding. Short-term fructose (Faeh et al. 2005) and carbohydrate (Cornier et al. 2006) overfeeding did not have an effect on whole-body insulin sensitivity in lean healthy subjects either. To ...
A high-fat, high-calorie diet is associated with obesity and type 2 diabetes. However, the relative contribution of metabolic defects to the development of hyperglycaemia and type 2 diabetes is controversial. Accumulation of excess fat in muscle and adipose tissue in insulin resistance and type 2 diabetes may be linked with defective mitochondrial oxidative phosphorylation. The aim of the current study was to investigate acute effects of short-term fat overfeeding on glucose and insulin metabolism in young men. We studied the effects of 5 days' high-fat (60% energy) overfeeding (+50%) versus a control diet on hepatic and peripheral insulin action by a hyperinsulinaemic euglycaemic clamp, muscle mitochondrial function by (31)P magnetic resonance spectroscopy, and gene expression by qrt-PCR and microarray in 26 young men. Hepatic glucose production and fasting glucose levels increased significantly in response to overfeeding. However, peripheral insulin action, muscle mitochondrial function, and general and specific oxidative phosphorylation gene expression were unaffected by high-fat feeding. Insulin secretion increased appropriately to compensate for hepatic, and not for peripheral, insulin resistance. High-fat feeding increased fasting levels of plasma adiponectin, leptin and gastric inhibitory peptide (GIP). High-fat overfeeding increases fasting glucose levels due to increased hepatic glucose production. The increased insulin secretion may compensate for hepatic insulin resistance possibly mediated by elevated GIP secretion. Increased insulin secretion precedes the development of peripheral insulin resistance, mitochondrial dysfunction and obesity in response to overfeeding, suggesting a role for insulin per se as well GIP, in the development of peripheral insulin resistance and obesity.
... Experimental studies that increased dietary intake of saturated fats (SFA) demonstrate reductions in whole-body insulin sensitivity (Bachmann et al., 2001;Hulston et al., 2015;Parry et al., 2017;Parry et al., 2019). However, studies using equal proportions of the three main classes of fats (SFA, monounsaturated (MUFA), and polyunsaturated (PUFA)) have failed to demonstrate an influence of overfeeding on whole-body measures of insulin sensitivity (Adochio et al., 2009;Brøns et al., 2009;Cornier et al., 2006). While a diet rich in SFA is typically related to the development of obesity and T2D (Van Dam et al., 2002), consuming long chain n-3 polyunsaturated fatty acids (n-3PUFAs) appears to have clinical benefit in reducing the development of insulin resistance (Fedor & Kelley, 2009). ...
... Despite the increases in skeletal muscle ceramide content with HFEE, we failed to detect a difference in whole-body glucose disposal or glucose kinetics during the OGTTs. While other studies have demonstrated an effect of short-term high-fat diets on glucose handling (Bachmann et al., 2001;Hulston et al., 2015;Parry et al., 2017Parry et al., , 2019, this outcome is not consistent across all studies (Adochio et al., 2009;Bakker et al., 2014;Brøns et al., 2009;Cornier et al., 2006). Studies reporting perturbed glucose handling following HFEE were of similar duration (6-7 d), and similar energy surplus (~50%) and fat content (~60%-65%) to the present study. ...
Abstract Understanding human physiological responses to high‐fat energy excess (HFEE) may help combat the development of metabolic disease. We aimed to investigate the impact of manipulating the n‐3PUFA content of HFEE diets on whole‐body and skeletal muscle markers of insulin sensitivity. Twenty healthy males were overfed (150% energy, 60% fat, 25% carbohydrate, 15% protein) for 6 d. One group (n = 10) received 10% of fat intake as n‐3PUFA rich fish oil (HF‐FO), and the other group consumed a mix of fats (HF‐C). Oral glucose tolerance tests with stable isotope tracer infusions were conducted before, and following, HFEE, with muscle biopsies obtained in basal and insulin‐stimulated states for measurement of membrane phospholipids, ceramides, mitochondrial enzyme activities, and PKB and AMPKα2 activity. Insulin sensitivity and glucose disposal did not change following HFEE, irrespective of group. Skeletal muscle ceramide content increased following HFEE (8.5 ± 1.2 to 12.1 ± 1.7 nmol/mg, p = .03), irrespective of group. No change in mitochondrial enzyme activity was observed following HFEE, but citrate synthase activity was inversely associated with the increase in the ceramide content (r=−0.52, p = .048). A time by group interaction was observed for PKB activity (p = .003), with increased activity following HFEE in HF‐C (4.5 ± 13.0mU/mg) and decreased activity in HF‐FO (−10.1 ± 20.7 mU/mg) following HFEE. Basal AMPKα2 activity increased in HF‐FO (4.1 ± 0.6 to 5.3 ± 0.7mU/mg, p = .049), but did not change in HF‐C (4.6 ± 0.7 to 3.8 ± 0.9mU/mg) following HFEE. We conclude that early skeletal muscle signaling responses to HFEE appear to be modified by dietary n‐3PUFA content, but the potential impact on future development of metabolic disease needs exploring.
... Intermittent and/or sustained periods of overfeeding and/or relative physical inactivity are necessarily responsible for net positive energy balance. Numerous studies have examined overfeeding of varied duration and composition, with the resultant positive energy balance associated with impaired insulin sensitivity (Wang et al. 2001;Cornier et al. 2006;Brons et al. 2009) and marked alterations in adipose tissue gene expression (Shea et al. 2009;Alligier et al. 2012). This in turn impacts the systemic concentration of key adipokines involved in the regulation of energy balance, such as leptin (Lammert et al. 2000;Wang et al. 2001;Brons et al. 2009), adiponectin (Brons et al. 2009) and visfatin (Sun et al. 2007). ...
... The greater insulin response to the OGTT reflects greater insulin secretion as indicated by the C-peptide response to the OGTT, which provides a more accurate assessment of β-cell function than peripheral insulin levels as it overcomes the issue of hepatic insulin clearance (Cobelli et al. 2007). Brief periods of positive energy balance have been shown to lead to impaired insulin sensitivity whether this is achieved through decreased physical activity (Vukovich et al. 1996;Arciero et al. 1998;Hamburg et al. 2007;Sonne et al. 2010), overfeeding (Wang et al. 2001;Cornier et al. 2006;Brons et al. 2009) 63 ± 53 119 ± 73# 57 (23 − 91) 60 ± 33 74 ± 33 14 ( − 9 to 37) * Insulin sensitivity index (comp) a 11.9 ± 4.2 6 .2 ± 2.5# 5.6 (3.4 − 7.8) 10.8 ± 5.9 8 .9 ...
Key points
Physical exercise significantly improves health but to what extent these benefits depend on altered energy balance remains unclear.
In a human experimental model, we investigated whether daily exercise could counteract the effects of short‐term overfeeding and under‐activity independent of its impact on energy imbalance in healthy young men.
Short‐term positive energy balance from overfeeding and under‐activity resulted in impaired metabolic outcomes and alterations in the expression of several key genes within adipose tissue involved in nutritional balance, metabolism and insulin action.
These changes were mostly prevented by the addition of a daily vigorous‐intensity exercise bout even in the face of a standardised energy surplus.
Abstract Physical activity can affect many aspects of metabolism but it is unclear to what extent this relies on manipulation of energy balance. Twenty‐six active men age 25 ± 7 years (mean ± SD) were randomly assigned either to consume 50% more energy than normal by over‐consuming their habitual diet for 7 days whilst simultaneously restricting their physical activity below 4000 steps day ⁻¹ to induce an energy surplus (SUR group; n = 14) or to the same regimen but with 45 min of daily treadmill running at 70% of maximum oxygen uptake (SUR+EX group; n = 12). Critically, the SUR+EX group received additional dietary energy intake to account for the energy expended by exercise, thus maintaining a matched energy surplus. At baseline and follow‐up, fasted blood samples and abdominal subcutaneous adipose tissue biopsies were obtained and oral glucose tolerance tests conducted. Insulinaemic responses to a standard glucose load increased 2‐fold from baseline to follow‐up in the SUR group (Δ17 ± 16 nmol (120 min) l ⁻¹ ; P = 0.002) whereas there was no change in the SUR+EX group (Δ1 ± 6 nmol (120 min) l ⁻¹ ). Seven of 17 genes within adipose tissue were differentially expressed in the SUR group; expression of SREBP‐1c , FAS and GLUT4 was significantly up‐regulated and expression of PDK4, IRS2, HSL and visfatin was significantly down‐regulated ( P ≤ 0.05). The pAMPK/AMPK protein ratio in adipose tissue was significantly down‐regulated in the SUR group ( P = 0.005). Vigorous‐intensity exercise counteracted most of the effects of short‐term overfeeding and under‐activity at the whole‐body level and in adipose tissue, even in the face of a standardised energy surplus.
... 9 By contrast, long-term CR has been shown to improve fasting and oral glucose tolerance test (OGTT)-derived indices of IS. 18 Similarly, the effects of short-term OF on IS remain unclear. In lean men, clamp-derived IS remained unchanged following 3 days OF at þ 50% energy, 13 whereas an increase in body mass index by two units has been shown to impair IS in the fasting state, in response to oral and intravenous glucose load, as well as during an euglycemic glucose clamp protocol. 14 A more recent study on lean men has shown that 5 days of high-fat OF at þ 50% energy needs induced a decline in hepatic IS as assessed by clamp, which was compensated by increased insulin secretion. ...
... 44,45 By contrast, previous studies in lean, healthy men have reported a selective decline in hepatic IS or even a completely sustained IS, as assessed by hyperinsulinemic euglycemic clamp. 12,13 Owing to the shorter study duration (o6 days), no significant weight changes occurred. A reduction in glycogen Table 4. Inter-and intra-individual variability in parameters of glucose metabolism during the different study periods (n ¼ 10) ...
Little is known about the effects of short-term caloric restriction (CR) and overfeeding (OF) on glucose homeostasis in healthy lean individuals. In addition, it remains unclear whether the effects of CR and OF are reversed by a complementary feeding period.
Ten healthy men participated in two cycles of controlled 7-day periods of CR and refeeding (RF; protocol A), and OF and CR (protocol B) at ±60% energy requirement. At baseline, insulin sensitivity (IS) was assessed by euglycemic clamp (M). Before and during each feeding cycle, fasting and oral glucose tolerance test-derived indices were used to estimate glucose tolerance, IS and glucose-stimulated insulin secretion.
Clamp tests revealed normal IS at baseline (M-values 9.4±2.1 mg kg⁻¹ min⁻¹, coefficient of variation (CV)(inter) 22%). M-values were significantly correlated with indices of IS. In protocol A, CR-induced weight loss (-3.0±0.4 kg) was associated with an increase in fasting IS. Postprandial IS and glucose-stimulated insulin secretion remained unchanged, but glucose tolerance decreased. RF decreased fasting and postprandial IS at increased glucose-stimulated insulin secretion. In protocol B, OF significantly increased the body weight (+1.6±0.9 kg). Concomitantly, fasting and postprandial IS decreased at increased glucose-stimulated insulin secretion. Subsequent CR reversed these effects. Inter-individual variability in indices of glucose metabolism was high with coefficients of variation ranging from 9 to 59%.
Significant changes in glucose metabolism are evident within 7-day periods of controlled OF and underfeeding. Although IS was impaired at the end of the CR-RF cycle, IS was normalized after the OF-CR cycle. At different feeding regimens, homeostatic responses of glucose metabolism were highly variable.
... After a meal containing carbohydrates, the liver not only disposes approximately one third of the glucose, but it also suppresses glucose production and release, together estimated to be responsible for approximately 60-65% of the disposed glucose load [23]. In healthy individuals, EGP was suppressed rapidly in response to glucose ingestion, regardless of the glucose dose (25,50, and 75 g) [24] and hypercaloric dietary interventions resulted in impairment in EGP suppression within days in healthy individuals [31]. ...
The liver, skeletal muscle, and adipose tissue are major insulin target tissues and key players in glucose homeostasis. We and others have described diverse insulin resistance (IR) phenotypes in people at risk of developing type 2 diabetes. It is postulated that identifying the IR phenotype in a patient may guide the treatment or the prevention strategy for better health outcomes in populations at risk. Here, we performed plasma metabolomics and lipidomics in a cohort of men and women living with obesity not complicated by diabetes (mean [SD] BMI 36.0 [4.5] kg/m2, n = 62) to identify plasma signatures of metabolites and lipids that align with phenotypes of IR (muscle, liver, or adipose tissue) and abdominal fat depots. We used 2-step hyperinsulinemic-euglycemic clamp with deuterated glucose, oral glucose tolerance test, dual-energy X-ray absorptiometry and abdominal magnetic resonance imaging to assess muscle-, liver- and adipose tissue- IR, beta cell function, body composition, abdominal fat distribution and liver fat, respectively. Spearman’s rank correlation analyses that passed the Benjamini–Hochberg statistical correction revealed that cytidine, gamma-aminobutyric acid, anandamide, and citrate corresponded uniquely with muscle IR, tryptophan, cAMP and phosphocholine corresponded uniquely with liver IR and phenylpyruvate and hydroxy-isocaproic acid corresponded uniquely with adipose tissue IR (p < 7.2 × 10−4). Plasma cholesteryl sulfate (p = 0.00029) and guanidinoacetic acid (p = 0.0001) differentiated between visceral and subcutaneous adiposity, while homogentisate correlated uniquely with liver fat (p = 0.00035). Our findings may help identify diverse insulin resistance and adiposity phenotypes and enable targeted treatments in people living with obesity.
... Diets such as high calorie (HC) and/or HFD present a valid model to study diet-induced insulin resistance [16][17][18][19]. In this review, we summarise what is known about the effects of shortterm HC and/or HFD on insulin action, glucose metabolism and on MBF in humans. ...
There is increasing evidence that skeletal muscle microvascular (capillary) blood flow plays an important role in glucose metabolism by increasing the delivery of glucose and insulin to the myocytes. This process is impaired in insulin-resistant individuals. Studies suggest that in diet-induced insulin-resistant rodents, insulin-mediated skeletal muscle microvascular blood flow is impaired post-short-term high fat feeding, and this occurs before the development of myocyte or whole-body insulin resistance. These data suggest that impaired skeletal muscle microvascular blood flow is an early vascular step before the onset of insulin resistance. However, evidence of this is still lacking in humans. In this review, we summarise what is known about short-term high-calorie and/or high-fat feeding in humans. We also explore selected animal studies to identify potential mechanisms. We discuss future directions aimed at better understanding the ‘early’ vascular mechanisms that lead to insulin resistance as this will provide the opportunity for much earlier screening and timing of intervention to assist in preventing type 2 diabetes.
... + 372, and multiplying by a correction factor of 1.4. This method has been used successfully by our group to maintain energy balance in a number of prior studies (Cornier et al. 2004(Cornier et al. , 2006(Cornier et al. , 2007Adochio et al. 2009;Tregellas et al. 2011). The run-in diet had a macronutrient composition of 40% protein, 40% fat, and 20% carbohydrate in order to mimic post-RYGB nutritional recommendations. ...
Bariatric surgery is associated with significant and sustained weight loss and improved metabolic outcomes. It is unclear if weight loss alone is the main mechanism of improved metabolic health. The purpose of this trial was to compare indices of appetite regulation, insulin sensitivity and energy intake (EI) between participants achieving 10 kg of weight loss via Roux‐en‐Y Gastric Bypass (RYGB) or dietary restriction (DIET); intake of a very low calorie liquid diet (800 kcal/d; 40% protein, 40% fat, 20% carbohydrate that matched the post‐RYGB dietary protocol). Adults qualifying for bariatric surgery were studied before and after 10 kg of weight loss (RYGB [n = 6]) or DIET [n = 17]). Appetite (hunger, satiety, and prospective food consumption [PFC]), appetite–related hormones, and metabolites (ghrelin, PYY, GLP‐1, insulin, glucose, free fatty acids [FFA], and triglycerides [TG]) were measured in the fasting state and every 30 min for 180 min following breakfast. Participants were provided lunch to evaluate acute ad libitum EI, which was similarly reduced in both groups from pre to post weight loss. Fasting ghrelin was reduced to a greater extent following RYGB compared to DIET (P = 0.04). Area under the curve (AUC) for ghrelin (P = 0.01), hunger (P < 0.01) and PFC (P < 0.01) increased after DIET compared to RYGB, following 10 kg weight loss. Satiety AUC increased after RYGB and decreased after DIET (P < 0.01). Glucose and insulin (fasting and AUC) decreased in both groups. FFA increased in both groups, with a greater increase in AUC seen after RYGB versus DIET (P = 0.02). In summary, appetite–related indices were altered in a manner that, if maintained, may promote a sustained reduction in energy intake with RYGB compared to DIET. Future work with a larger sample size and longer follow‐up will be important to confirm and extend these findings.
... However, the mechanism(s) that regulate and initiate the inflammatory response in obesity are not clearly understood. High-fat diet (HFD)-induced glucose intoler-ance and insulin resistance have been observed in both lean rodents (21,22,24,43) and humans (6) in as little as three days of high-fat feeding. Interestingly, Lee and colleagues demonstrated in mice that inflammation is not necessary for the 3-day HFD-induced glucose intolerance and insulin resistance (24), despite a marked increase in proinflammatory gene expression in white adipose tissue (WAT). ...
Systemic insulin resistance and glucose intolerance occur with as little as 3 days of a high-fat diet (HFD) in mice and humans; the mechanisms that initiate acute insulin resistance are unknown. Most laboratories house mice at 22{degree sign}C, which is below their thermoneutral temperature (~30{degree sign}C). Cold stress has been shown to increase white adipose tissue (WAT) browning, alter lipid trafficking and impair immune function, while energy intake and expenditure decrease with increasing ambient temperature; importantly, dysregulation of these parameters have been strongly linked to obesity-induced insulin resistance. Therefore, we compared acute changes in glucose metabolism and the metabolic phenotype in lean mice in response to a control (CON) diet or HFD housed at standard vivarium (22{degree sign}C) and thermoneutral (30{degree sign}C) temperatures. Glucose intolerance occurred following 1 or 5 days of HFD, and was independent of housing temperature or adiposity; however, the reduction in tissue-specific glucose clearance with HFD diverged by temperature with reduced brown adipose tissue (BAT) glucose uptake at 22{degree sign}C but reduced soleus glucose uptake at 30{degree sign}C. Fasting glucose, food intake and energy expenditure were significantly lower at 30{degree sign}C, independent of diet. Additionally, markers of browning in both BAT and inguinal subcutaneous WAT (scWAT), but not perigonadal epididymal WAT (eWAT), decreased at 30{degree sign}C. Together, we find housing temperature has a significant impact on the cellular pathways that results in glucose tolerance in response to acute HFD exposure. Thus, even short-term changes in housing temperature should be highly considered in interpretation of metabolic studies in mice.
... Numerous studies have investigated the impact of positive energy balance induced through overfeeding of varied duration and composition on metabolic outcomes. Excessive energy intake impairs insulin sensitivity [12][13][14] and alters adipose gene expression [15][16][17]. Many metabolic diseases such as type 2 diabetes, obesity and the metabolic syndrome result from a chronic state of energy imbalance created by low physical activity and/or an excessive energy intake. ...
Background:
Short-term overfeeding combined with reduced physical activity impairs metabolic function and alters the expression of key genes within adipose tissue. We have shown that daily vigorous-intensity running can prevent these changes independent of any net effect on energy imbalance. However, which type, intensity and/or duration of exercise best achieves these benefits remains to be ascertained.
Methods/design:
Forty-eight healthy young men will be recruited and randomly allocated to one of four experimental conditions for 1 week: (1) to ingest 50% more energy than normal by over-consuming their habitual diet whilst simultaneously restricting their physical activity below 4000 steps day-1(i.e. energy surplus; SUR group); (2) the same regimen but with a daily 45-min bout of vigorous-intensity arm crank ergometry at 70% of maximum oxygen uptake (SUR + ARM group); (3) the same regimen but with a daily 45-min bout of moderate-intensity treadmill walking at 50% of maximum oxygen uptake (SUR + MOD group); (4) the same regimen but with the addition of intermittent short bouts of walking during waking hours (SUR + BREAKS group). Critically, all exercise groups will receive additional dietary energy intake to account for the energy expended by exercise, thus maintaining a matched energy surplus. At baseline and follow-up, fasted blood samples, abdominal subcutaneous adipose tissue and skeletal muscle biopsies will be obtained and oral glucose tolerance tests conducted.
Discussion:
This study will establish the impact of different forms of daily exercise on metabolic function at the whole-body level as well as within adipose tissue and skeletal muscle in the context of a standardised energy surplus.
Trial registration:
ISRCTN, ISRCTN18311163 . Registered on 24 June 2015.
... This has revealed that defects in liver glucose metabolism are an early feature of deteriorating metabolic health 2 . Indeed, studies in humans [3][4][5] , dogs [6][7][8][9] , and rodents [10][11][12][13][14][15] have shown that a deterioration in hepatic insulin and/or glucose action (i.e. glucose effectiveness) occurs rapidly in response to nutrient oversupply, and thus represents a primary pathogenic manifestation. ...
In humans, low-energy diets rapidly reduce hepatic fat and improve/normalise glycemic control. Due to difficulties in obtaining human liver, little is known about changes to the lipid species and pathway fluxes that occur under these conditions. Using a combination of stable isotope, and targeted metabolomic approaches we investigated the acute (7–9 days) hepatic effects of switching high-fat high-sucrose diet (HFD) fed obese mice back to a chow diet. Upon the switch, energy intake was reduced, resulting in reductions of fat mass and hepatic triacyl-and diacylglycerol. However, these parameters were still elevated compared to chow fed mice, thus representing an intermediate phenotype. Nonetheless, glucose intolerance and hyperinsulinemia were completely normalized. The diet reversal resulted in marked reductions in hepatic de novo lipogenesis when compared to the chow and HFD groups. Compared with HFD, glycerolipid synthesis was reduced in the reversal animals, however it remained elevated above that of chow controls, indicating that despite experiencing a net loss in lipid stores, the liver was still actively esterifying available fatty acids at rates higher than that in chow control mice. This effect likely promotes the re-esterification of excess free fatty acids released from the breakdown of adipose depots during the weight loss period.
... Overfeeding is a risk factor for type 2 diabetes and may cause insulin resistance even before weight gain develops [1,2]. Studies have consistently shown that individuals who had a low birthweight (LBW) due to a suboptimal fetal environment have higher risk of developing metabolic diseases including type 2 diabetes [3,4]. ...
Aims/hypothesis:
Individuals who had a low birthweight (LBW) are at an increased risk of insulin resistance and type 2 diabetes when exposed to high-fat overfeeding (HFO). We studied genome-wide mRNA expression and DNA methylation in subcutaneous adipose tissue (SAT) after 5 days of HFO and after a control diet in 40 young men, of whom 16 had LBW.
Methods:
mRNA expression was analysed using Affymetrix Human Gene 1.0 ST arrays and DNA methylation using Illumina 450K BeadChip arrays.
Results:
We found differential DNA methylation at 53 sites in SAT from LBW vs normal birthweight (NBW) men (false discovery rate <5%), including sites in the FADS2 and CPLX1 genes previously associated with type 2 diabetes. When we used reference-free cell mixture adjustments to potentially adjust for cell composition, 4,323 sites had differential methylation in LBW vs NBW men. However, no differences in SAT gene expression levels were identified between LBW and NBW men. In the combined group of all 40 participants, 3,276 genes (16.5%) were differentially expressed in SAT after HFO (false discovery rate <5%) and there was no difference between LBW men and controls. The most strongly upregulated genes were ELOVL6, FADS2 and NNAT; in contrast, INSR, IRS2 and the SLC27A2 fatty acid transporter showed decreased expression after HFO. Interestingly, SLC27A2 expression correlated negatively with diabetes- and obesity-related traits in a replication cohort of 142 individuals. DNA methylation at 652 CpG sites (including in CDK5, IGFBP5 and SLC2A4) was altered in SAT after overfeeding in this and in another cohort.
Conclusions/interpretation:
Young men who had a LBW exhibit epigenetic alterations in their adipose tissue that potentially influence insulin resistance and risk of type 2 diabetes. Short-term overfeeding influences gene transcription and, to some extent, DNA methylation in adipose tissue; there was no major difference in this response between LBW and control participants.
... The estimates were confirmed using resting metabolic rate as assessed by indirect calorimetry and multiplied by an activity factor of 1.3. This method has been used successfully by our group in a number of prior studies (Cornier et al., 2004Cornier et al., , 2006Cornier et al., , 2007Cornier et al., , 2009 Adochio et al., 2009; Wang et al., 2012). All food was prepared and provided by the Clinical Translational Research Center metabolic kitchen. ...
The mechanisms responsible for the propensity to gain weight or remain normal weight are poorly understood. The objective of this study was to study the neuronal response to visual food cues during short-term energy imbalance in healthy adults recruited as obesity-resistant (OR) or obesity-prone (OP) based on self-identification, body mass index, and personal/family weight history. Twenty-five OR and 28 OP subjects were studied in underfed (UF) and overfed (OF) as compared to eucaloric (EU) conditions in a randomized crossover design. Each study phase included a 3-day run-in diet, 1 day of controlled feeding (basal energy needs for EU, 40% above/below basal energy needs for OF/UF), and a test day. On the test day, fMRI was performed in the acute fed stated (30 min after a test meal) while subjects viewed images of foods of high hedonic value and neutral non-food objects. Measures of appetite and hormones were also performed before and every 30 min after the test meal. UF was associated with significantly increased activation of insula, somatosensory cortex, inferior and medial prefrontal cortex (PFC), parahippocampus, precuneus, cingulate, and visual cortex in OR. However, UF had no impact in OP. As a result, UF was associated with significantly greater activation, specifically in the insula, inferior PFC, and somatosensory cortex in OR as compared to OP. While OF was overall associated with reduced activation of inferior visual cortex, no group interaction was observed with OF. In summary, these findings suggest that individuals resistant to weight gain and obesity are more sensitive to short-term energy imbalance, particularly with UF, than those prone to weight gain. The inability to sense or adapt to changes in energy balance may represent an important mechanism contributing to excess energy intake and risk for obesity.
... A major risk factor for the development of type 2 diabetes is the presence of hepatic insulin resistance [2]. Defects in hepatic insulin action develop rapidly in response to nutrient excess in both animals and humans and occur prior to the development of peripheral insulin resistance [3][4][5][6][7][8][9], indicating that defects in hepatic glucose metabolism are a primary event in the development of impaired glucose handling. There is evidence demonstrating an association between abnormalities in hepatic lipid metabolism and the development of insulin resistance and glucose intolerance [9][10][11][12][13]. ...
... The estimates were confirmed using RMR as assessed by indirect calorimetry, multiplied by an activity factor of 1.3. This method has been used successfully by our group in a number of prior studies [9,10,[24][25][26][27]. All the food was prepared and provided by the Clinical Translational Research Center (CTRC) metabolic kitchen. ...
We have previously shown that propensity for weight gain, energy balance state and sex are important determinants of the neuronal response to visual food cues. It is not clear, though, whether these factors also impact the neuronal response to taste. The objective of this study was to examine the neuronal response to sweet taste during energy imbalance in men and women recruited to be obesity-prone (OP) or obesity-resistant (OR). OP (13 men and 12 women) and OR (12 men and 12 women) subjects were studied after 1 day of eucaloric, overfed and underfed conditions in a randomized crossover design. On each test day, fMRI was performed in the respective acute fed state while subjects received in random order 60 trials each of 1 M sucrose solution (SU), or artificial saliva (AS) following a visual cue predicting the taste. The neuronal response to SU versus AS expectation was significantly greater in the amygdala, orbitofrontal cortex, putamen and insula in OR versus OP; SU receipt was not different between groups. There were also sex-based differences with men having greater neuronal response to SU versus AS receipt in the caudate than women. The results, however, were not impacted by the state of energy balance. In summary, response to expectation but not receipt of basic sweet taste was different in OR compared to OP, highlighting the importance of learning and conditioning in the propensity to gain weight. Response to sucrose taste receipt was stronger in men than women, raising questions about the effect of sex hormones on brain response to food.
... The findings of diet-induced insulin resistance originating in the liver and not muscle have also been reported in rats (48,93,105,157,177) and dogs (44,101). Importantly, it has been shown that short-term overfeeding studies in humans also cause a rapid deterioration in whole body insulin sensitivity that appears to be due to defects in the control of hepatic glucose metabolism rather than effects on muscle insulin action (26,43,47). Furthermore, the normalization of glycemic control in T2D individuals after short-term calorie restriction was associated with an improvement in hepatic glucose metabolism, whereas muscle remained insulin resistant (111). ...
The incidence of insulin resistance and type 2 diabetes (T2D) is increasing at alarming rates. In the quest to understand the underlying causes of and to identify novel therapeutic targets to treat T2D, scientists have become increasingly reliant on the use of rodent models. Here we provide a discussion on the regulation of rodent glucose metabolism, highlighting key differences and similarities that exist between rodents and humans. In addition, some of the issues and considerations associated with assessing glucose homeostasis and insulin action are outlined. We also discuss the role of the liver versus skeletal muscle in regulating whole-body glucose metabolism in rodents, emphasizing the importance of defective hepatic glucose metabolism in the development of impaired glucose tolerance, insulin resistance and T2D.
... As discussed earlier, PI3K is a critical mediator in the insulin signaling pathway and excessive binding of regulatory subunit monomers to P13K can impair normal insulin action 102, 103 ( Fig. 1.2). Increased levels of skeletal muscle p85/55/50 are detected in insulin resistant subjects, as well as in healthy subjects only after 3 days of overfeeding 73,104 . Conversely, long-term caloric restriction in rodent decreased skeletal muscle p55/50 protein expression in parallel with improvement in insulin resistance 96 . ...
... In accordance with previous studies using high-caloric diets (9,12), there were decreased baseline FFA plasma levels in both groups after intervention. Since baseline insulin plasma levels only increased significantly in the IHCD group, and since there was no change in FFA AUC 60 -180min during the OGTT in either group (indicating normal insulin sensitivity of the adipose tissue) the decreased baseline levels of FFA are most likely not due to an insulin-mediated suppression of lipolysis per se, but we speculate may reflect an increased triglyceride synthesis within the adipose tissue, e.g., through effect of the hormone acylation-stimulating protein (ASP) (20,49). ...
A high-caloric intake combined with a sedentary lifestyle is an important player in the development of type 2 diabetes mellitus (T2DM). The present study was undertaken to examine if the level of physical activity has impact on the metabolic effects of a high-caloric (+2,000 kcal/day) intake. Therefore, healthy individuals on a high caloric intake were randomized to either 10,000 or 1,500 steps per day for 14 days. Step-number, total energy expenditure, dietary records, neuropsychological tests, maximal oxygen uptake (VO2max), whole body dual-energy X-ray absorptiometry (DXA)- and abdominal magnetic resonance imaging (MRI)- scans, continuous glucose monitoring (CGM), and oral glucose tolerance tests (OGTT) with stable isotopes were performed before and after the intervention. Both study groups gained the same amount of body weight. However, the inactive group accumulated significantly more visceral fat compared to the active group. Following the two-week period, the inactive group also experienced a poorer glycaemic control, increased endogenous glucose production, decreased hepatic insulin extraction, increased baseline plasma levels of total cholesterol and LDL, and a decreased cognitive function with regard to capacity of attention. In conclusion, we find evidence to support that habitual physical activity may prevent pathophysiological symptoms associated with diet-induced obesity.
... Supra-physiological elevations of circulating nonesterified fatty acids (NEFA) by infusion of lipid emulsion induce insulin resistance in humans (5). However, short-term overfeeding (3-9 days) reduces fasting NEFA (6)(7)(8)(9), despite reducing insulin sensitivity (3,9). Increases in circulating triacylglycerol, diacylglycerol (10) and ceramide species (11) are observed in obese compared with lean individuals and may contribute to insulin resistance. ...
Objectives:
While chronic obesity is associated with alterations in circulating glycerolipids, sphingolipids and plasmalogens, the effects of short-term overfeeding in humans are unclear.
Design and methods:
Healthy individuals (n = 40) were overfed by 1,250 kcal day(-1) for 28 days. Insulin sensitivity (hyperinsulinemic-euglycemic clamp), abdominal fat distribution and serum lipidomics (mass spectrometry) were assessed.
Results:
Overfeeding increased liver fat, insulin resistance, serum C-reactive protein and urinary F2-isoprostanes. HDL increased (11% ± 2%, P < 0.001) while LDL, triglycerides and nonesterified fatty acids were unchanged. Three hundred and thirty three serum lipids were detected, of which 13% increased and 20% decreased with overfeeding. Total diacylglycerol and lysoalkylphosphatidylcholine (LPC(O)) concentrations decreased (P < 0.01), while total ceramide, Cer22:0 and Cer24:0 increased (P ≤ 0.01). The most notable increases were observed in the HDL-associated phosphatidylethanolamine-based plasmalogens and their precursors alkylhosphatidylethanolamine (18 ± 5% and 38 ± 8% respectively, P ≤ 0.01).
Conclusions:
Overfeeding led to weight gain and changes in the serum lipid profile. Increases in ceramides were noted, which left unchecked may promote systemic insulin resistance. Uniform increases were observed in plasmalogens and their precursors. Because plasmalogens are powerful antioxidants, this may be an appropriate response against increased oxidative stress generated by over-nutrition. The metabolic consequences of changes in concentrations of many circulating lipid species with overfeeding require further study. Copyright © 2013 The Obesity Society.
... In support of findings in animals [7,19,21,23,24] and humans [25,30,31], our data show that an HFD rapidly impairs the ability of insulin to suppress hepatic glucose output, with peripheral insulin resistance developing subsequently. Furthermore, our data suggest that the liver quantitatively has the most significant impact on postprandial glycaemia, as both peak glucose intolerance and hepatic insulin resistance occurred within 3-7 days of HFD, despite the absence of muscle insulin resistance at this time. ...
Aims/hypothesis:
While it is well known that diet-induced obesity causes insulin resistance, the precise mechanisms underpinning the initiation of insulin resistance are unclear. To determine factors that may cause insulin resistance, we have performed a detailed time-course study in mice fed a high-fat diet (HFD).
Methods:
C57Bl/6 mice were fed chow or an HFD from 3 days to 16 weeks and glucose tolerance and tissue-specific insulin action were determined. Tissue lipid profiles were analysed by mass spectrometry and inflammatory markers were measured in adipose tissue, liver and skeletal muscle.
Results:
Glucose intolerance developed within 3 days of the HFD and did not deteriorate further in the period to 12 weeks. Whole-body insulin resistance, measured by hyperinsulinaemic-euglycaemic clamp, was detected after 1 week of HFD and was due to hepatic insulin resistance. Adipose tissue was insulin resistant after 1 week, while skeletal muscle displayed insulin resistance at 3 weeks, coinciding with a defect in glucose disposal. Interestingly, no further deterioration in insulin sensitivity was observed in any tissue after this initial defect. Diacylglycerol content was increased in liver and muscle when insulin resistance first developed, while the onset of insulin resistance in adipose tissue was associated with increases in ceramide and sphingomyelin. Adipose tissue inflammation was only detected at 16 weeks of HFD and did not correlate with the induction of insulin resistance.
Conclusions/interpretation:
HFD-induced whole-body insulin resistance is initiated by impaired hepatic insulin action and exacerbated by skeletal muscle insulin resistance and is associated with the accumulation of specific bioactive lipid species.
... The estimates were confirmed using RMR as assessed by indirect calorimetry, multiplied by an activity factor of 1.3. This method has been used successfully by our group in a number of prior studies (Adochio, Leitner, Gray, Draznin, & Cornier, 2009;Cornier, Bergman, & Bessesen, 2006;Cornier, et al., 2004;Cornier, Von Kaenel, Bessesen, & Tregellas, 2007; All food was prepared and provided by the Clinical Translational Research Center (CTRC) metabolic kitchen. Subjects presented to the CTRC every morning, ate breakfast, and picked up the remainder of their daily meals which were packed in coolers. ...
While the majority of Americans are now overweight, some individuals maintain their weight with minimal effort. This study investigated behavioral differences between 58 individuals recruited as either obese-resistant (OR) or obese-prone (OP) based on self-identification, BMI, and personal/family weight history. Subjects were studied during Eucaloric (EU), Overfed (OF), and Underfed (UF) phases which included a run-in diet, 1day intervention diet, and a study day. At baseline, subjects completed the Three Factor Eating Questionnaire (TFEQ) and Power of Food Scale (PFS). On the study day, ratings of appetite, food appeal and desire, and food cravings were performed in response to a breakfast shake. OF resulted in reduced hunger and food desire while UF resulted in increased hunger and food appeal and desire. While hunger did not differ between groups, OP had higher scores for TFEQ measures (hunger, restraint and disinhibition), higher "hedonic hunger" as measured by the PFS, and greater food cravings and ratings of food appeal and desire. These results suggest that subjective hunger and desire for food change significantly after only one day of over- or underfeeding. Additionally, we found several behavioral differences between groups that are likely to promote weight gain over time in the OP.
... Because lipolytic flux from WAT drives hepatic gluconeogenesis and therefore hepatic GP, one implication of our findings is that the lack of antilipolytic effects of brain insulin after overfeeding contributes to hepatic insulin resistance (18,19). Thus, our studies suggest that one of the mechanism through which the brain controls hepatic GP is regulation of WAT lipol-ysis, which highlights the potential importance of organ crosstalk in the central regulation of nutrient partitioning. ...
Insulin controls fatty acid (FA) release from white adipose tissue (WAT) through direct effects on adipocytes and indirectly through hypothalamic signaling by reducing sympathetic nervous system outflow to WAT. Uncontrolled FA release from WAT promotes lipotoxicity, which is characterized by inflammation and insulin resistance that leads to and worsens type 2 diabetes. Here we tested whether early diet-induced insulin resistance impairs the ability of hypothalamic insulin to regulate WAT lipolysis and thus contributes to adipose tissue dysfunction. To this end we fed male Sprague-Dawley rats a 10% lard diet (high fat diet (HFD)) for 3 consecutive days, which is known to induce systemic insulin resistance. Rats were studied by euglycemic pancreatic clamps and concomitant infusion of either insulin or vehicle into the mediobasal hypothalamus. Short term HFD feeding led to a 37% increase in caloric intake and elevated base-line free FAs and insulin levels compared with rats fed regular chow. Overfeeding did not impair insulin signaling in WAT, but it abolished the ability of mediobasal hypothalamus insulin to suppress WAT lipolysis and hepatic glucose production as assessed by glycerol and glucose flux. HFD feeding also increased hypothalamic levels of the endocannabinoid 2-arachidonoylglycerol after only 3 days. In summary, overfeeding impairs hypothalamic insulin action, which may contribute to unrestrained lipolysis seen in human obesity and type 2 diabetes.
... The previously observed decrease in fasting triglyceride (TG) and FFA levels after the short-term HF overfeeding diet in this study cohort (26) has also been reported in other short-term overfeeding studies (31,32). Although slightly increased fasting plasma insulin levels in the NBW subjects may contribute to suppress lipolysis, fasting insulin levels did not increase in the LBW subjects, and increased insulin secretion is thus unlikely to be the full explanation for the marked reduction of fasting plasma FFA levels during HF overfeeding (27). ...
Fibroblast growth factor 21 (FGF21) is a metabolic factor involved in glucose and lipid metabolism. However, little is known about the physiological role of FGF21 during a dietary challenge in humans.
Twenty healthy low birth weight (LBW) with known risk of type 2 diabetes and 26 control (normal birth weight (NBW)) young men were subjected to 5 days of high-fat (HF) overfeeding (+50%). Basal and clamp insulin-stimulated serum FGF21 levels were examined before and after the diet, and FGF21 mRNA expression was measured in muscle and fat biopsies respectively.
Five days of HF overfeeding diet significantly (P<0.001) increased fasting serum FGF21 levels in both the groups (P<0.001). Furthermore, insulin infusion additionally increased serum FGF21 levels to a similar extent in both the groups. Basal mRNA expression of FGF21 in muscle was near the detection limit and not present in fat in both the groups before and after the dietary challenge. However, insulin significantly (P<0.001) increased FGF21 mRNA in both muscle and fat in both the groups during both diets.
Short-term HF overfeeding markedly increased serum FGF21 levels in healthy young men with and without LBW but failed to increase muscle or fat FGF21 mRNA levels. This suggests that the liver may be responsible for the rise of serum FGF21 levels during overfeeding. In contrast, the increase in serum FGF21 levels during insulin infusion may arise from increased transcription in muscle and fat. We speculate that increased serum FGF21 levels during HF overfeeding may be a compensatory response to increase fatty acid oxidation and energy expenditure.
... Consistent with these observations, experimental studies on the effects of HFHC meals in animals and human subjects have shown that such meals are associated with insulin resistance (5 -8) . For instance, acute bouts of HFHC meals over a period of 5 d are associated with the development of significant insulin resistance in healthy lean individuals (9,10) . The mechanisms underlying the induction of insulin resistance are not understood. ...
It has been reported that high-fat, high-carbohydrate (HFHC) meals increase oxidative stress and inflammation. We examined whether repeated intake of excess energy in the form of HFHC meals alters reactive oxygen species (ROS) generation and the expression levels of antioxidant enzymes and mitochondrial proteins in mononuclear cells, and to determine whether this is associated with insulin resistance. We recruited healthy lean individuals (n 10). The individuals were divided into two groups: one group (n 5) ingested 10878·4 kJ/d (2600 kcal/d; 55-70 % carbohydrate, 9·5-16 % fat, 7-20 % protein) recommended by the Dietary Reference Intake for Koreans for 4 d and the other group (n 5) ingested a HFHC meal containing 14 644 kJ/d (3500 kcal/d). Then, measurements of blood insulin and glucose levels, together with suppressor of cytokine signalling-3 (SOCS-3) expression levels, were performed in both groups. Also, cellular and mitochondrial ROS levels as well as malondialdehyde (MDA) levels were measured. Expression levels of cytosolic and mitochondrial antioxidant enzymes, and mitochondrial complex proteins were analysed. Repeated intake of HFHC meals induced an increase in homeostasis model of assessment-insulin resistance (HOMA-IR), together with an increase in SOCS-3 expression levels. While a single intake of the HFHC meal increased cytosolic and mitochondrial ROS, repeated intake of HFHC meals reduced them and increased the levels of MDA, cytosolic and mitochondrial antioxidant enzymes, and several mitochondrial complex proteins. Repeated intake of HFHC meals induced cellular antioxidant mechanisms, which in turn increased lipid peroxidation (MDA) and SOCS-3 expression levels, induced hyperinsulinaemia and increased HOMA-IR, an index of insulin resistance. In conclusion, excess energy added to a diet can generate detrimental effects in a short period.
... Human studies have shown that varying amounts and duration of overfeeding can lead to elevations in fasting insulin levels in the setting of normoglycemia [8-14]. Our group has previously found that 3 days of overfeeding (50% caloric excess) in lean healthy individuals led to a significant decrease in whole-body insulin sensitivity [15,16]. Most recently, Brøns, et al. found that 5 days of high-fat overfeeding (50% caloric excess) in lean individuals resulted in no change in whole-body insulin sensitivity as measured by M-value and Glucose Disposal Rate (GDR) [17]. ...
Early molecular changes of nutritionally-induced insulin resistance are still enigmatic. It is also unclear if acute overnutrition alone can alter insulin signaling in humans or if the macronutrient composition of the diet can modulate such effects.
To investigate the molecular correlates of metabolic adaptation to either high-carbohydrate (HC) or high-fat (HF) overfeeding, we conducted overfeeding studies in 21 healthy lean (BMI < 25) individuals (10 women, 11 men), age 20-45, with normal glucose metabolism and no family history of diabetes. Subjects were studied first following a 5-day eucaloric (EC) diet (30% fat, 50% CHO, 20% protein) and then in a counter balanced manner after 5 days of 40% overfeeding of both a HC (20% fat, 60% CHO) diet and a HF (50% fat, 30% CHO) diet. At the end of each diet phase, in vivo insulin sensitivity was assessed using the hyperinsulinemic-euglycemic clamp technique. Ex vivo insulin action was measured from skeletal muscle tissue samples obtained 15 minutes after insulin infusion was initiated.
Overall there was no change in whole-body insulin sensitivity as measured by glucose disposal rate (GDR, EC: 12.1 ± 4.7; HC: 10.9 ± 2.7; HF: 10.8 ± 3.4). Assessment of skeletal muscle insulin signaling demonstrated increased tyrosine phosphorylation of IRS-1 (p < 0.001) and increased IRS-1-associated phosphatidylinositol 3 (PI 3)-kinase activity (p < 0.001) following HC overfeeding. In contrast, HF overfeeding increased skeletal muscle serine phosophorylation of IRS-1 (p < 0.001) and increased total expression of p85α (P < 0.001).
We conclude that acute bouts of overnutrition lead to changes at the cellular level before whole-body insulin sensitivity is altered. On a signaling level, HC overfeeding resulted in changes compatible with increased insulin sensitivity. In contrast, molecular changes in HF overfeeding were compatible with a reduced insulin sensitivity.
... Obese individuals who have recently lost substantial amounts of weight became insulinresistant when put on a short-term hypercaloric diet, while lean individuals remained sensitive to insulin under identical circumstances. 50 This phenomenon is explained, at least to some extent, by the ability of nutrient excess to block the activation of IRS/ PI 3kinase signal transduction. 51 Indeed, blunting of signal transduction by macronutrients has been observed in peripheral tissues as well as in brain tissue. ...
Eating behavior is determined by a balance of memories in terms of reward and punishment to satisfy the urge to consume food. Refilling empty energy stores and hedonistic motivation are rewarding aspects of eating. Overfeeding, associated adverse GI effects, and obesity implicate punishment. In the current review, evidence is given for the hypothesis that bariatric surgery affects control over eating behavior. Moreover, any caloric overload will reduce the feeling of satiety. Durable weight loss after bariatric surgery is probably the result of a new equilibrium between reward and punishment, together with a better signaling of satiation due to beneficial metabolic changes. We propose to introduce three main treatment goals for bariatric surgery: 1) acceptable weight loss, 2) improvement of eating control, and 3) metabolic benefit. To achieve this goal, loss of 50% to 70% of excess weight will be appropriate (i.e. 30% to 40% loss of initial weight), depending on the degree of obesity prior to operation.
Skeletal muscle microvascular blood flow (MBF) plays an important role in glucose disposal in muscle. Impairments in muscle MBF contribute to insulin resistance and pre-diabetes. Animal studies show that short-term (3 day) high-fat feeding blunts skeletal muscle MBF prior to impairing insulin-stimulated glucose disposal. It is not known if this occurs in humans. We investigated the temporal impact of a 7-day high-calorie high-fat (HCHF) diet intervention (+52% kJ; 41% fat) on fasting and postprandial cardiometabolic outcomes in 14 healthy adults (18-37 years). Metabolic health and vascular responses to a mixed meal challenge (MMC) were measured at pre- (day 0), mid- (day 4) and post-intervention (day 8). There were no significant differences in body weight, body fat %, fasting blood glucose, and fasting plasma insulin concentrations at pre-, mid- and post-intervention. Compared to pre-intervention there was a significant increase in insulin (but not glucose) total area under the curve, in response to the MMC at mid-intervention (p=0.041) and at post-intervention (p=0.028). Unlike at pre- and mid-intervention, at post-intervention muscle MBF decreased at 60 min (p=0.024) and 120 min (p=0.023) following the MMC. However, macrovascular blood flow was significantly increased from 0 to 60 mins (p<0.001) and 120 mins (p<0.001) following the MMC at pre-, mid- and post-intervention. Therefore, short-term HCHF feeding in healthy individuals leads to elevated postprandial insulin but not glucose levels and a blunting of meal-induced skeletal muscle MBF responses but not macrovascular blood flow responses.
Insulin signalling in the central nervous system regulates energy homeostasis by controlling metabolism in several organs and by coordinating organ crosstalk. Studies performed in rodents, non-human primates and humans over more than five decades using intracerebroventricular, direct hypothalamic or intranasal application of insulin provide evidence that brain insulin action might reduce food intake and, more importantly, regulates energy homeostasis by orchestrating nutrient partitioning. This Review discusses the metabolic pathways that are under the control of brain insulin action and explains how brain insulin resistance contributes to metabolic disease in obesity, the metabolic syndrome and type 2 diabetes mellitus.
Hypothalamic regulation of lipid and glucose homeostasis is emerging, but whether the dorsal vagal complex (DVC) senses nutrients and regulates hepatic nutrient metabolism remain unclear. Here, we found in rats DVC oleic acid infusion suppressed hepatic secretion of VLDL-TG, which was disrupted by inhibiting DVC long-chain fatty acyl-CoA synthetase that in parallel disturbed lipid homeostasis during intravenous lipid infusion. DVC glucose infusion elevated local glucose levels similarly as intravenous glucose infusion and suppressed hepatic glucose production. This was independent of lactate metabolism as inhibiting lactate-dehydrogenase failed to disrupt glucose sensing and neither could DVC lactate infusion recapitulated glucose effect. DVC oleic acid and glucose infusion failed to lower VLDL-TG secretion and glucose production in high-fat fed rats, while inhibiting DVC farnesoid X receptor enhanced oleic acid but not glucose sensing. Thus, an impairment of DVC nutrient sensing may lead to the disruption of lipid and glucose homeostasis in metabolic syndrome.
This systematic review has examined more than 300 original papers dealing with the biology of overfeeding. Studies have varied from 1 day to 6 months. Overfeeding produced weight gain in adolescents, adult men and women and in older men. In longer term studies, there was a clear and highly significant relationship between energy ingested and weight gain and fat storage with limited individual differences. There is some evidence for a contribution of a genetic component to this response variability. The response to overfeeding was affected by the baseline state of the groups being compared: those with insulin resistance versus insulin sensitivity; those prone to obesity versus those resistant to obesity; and those with metabolically abnormal obesity versus those with metabolically normal obesity. Dietary components, such as total fat, polyunsaturated fat and carbohydrate influenced the patterns of adipose tissue distribution as did the history of low or normal birth weight. Overfeeding affected the endocrine system with increased circulating concentrations of insulin and triiodothyronine frequently present. Growth hormone, in contrast, was rapidly suppressed. Changes in plasma lipids were influenced by diet, exercise and the magnitude of weight gain. Adipose tissue and skeletal muscle morphology and metabolism are substantially altered by chronic overfeeding.
Currently, it is unclear whether short-term overfeeding in healthy people significantly affects postprandial glucose regulation, as most human overfeeding studies have utilized induced experimental conditions such as the euglycemic-hyperinsulinemic clamp technique to assess glucoregulation. The aim of this study was to quantify glucose fluxes [rates of meal glucose appearance (Ra), disposal (Rd), and endogenous glucose production (EGP)] in response to 5 and 28 days of overfeeding (+45% energy) while maintaining habitual macronutrient composition (31.0 ± 1.9% fat, 48.6 ± 2.2% carbohydrate, 16.7 ± 1.4% protein) in healthy, lean young men. Meal tolerance testing was combined with the triple-stable isotope glucose tracer approach. Visceral adipose volume increased by ~15% with 5 days of overfeeding, while there was no further change at 28 days. In contrast, body mass (+1.6 kg) and fat mass (+1.3 kg) were significantly increased only after 28 days of overfeeding. Fasting EGP, Rd, and insulin were increased at 5 but unchanged after 28 days. Postprandial glucose and insulin responses were unaltered by 5 days of overfeeding but were modestly increased after 28 days (P < 0.05). However, meal Ra and glucose Rd were significantly increased after both 5 and 28 days of overfeeding (P < 0.05). Despite this, overfeeding did not lead to alterations to postprandial EGP suppression. Thus, in contrast to findings from euglycemic-hyperinsulinemic clamp studies, chronic overfeeding did not affect the ability to suppress EGP or stimulate Rd under postprandial conditions. Rather, glucose flux was appropriately maintained following 28 days of overfeeding through modest increases in postprandial glycemia and insulinemia.
Background:
Increased consumption of high-fat diets is associated with the development of insulin resistance and type 2 diabetes. Current models to study the mechanisms of high-fat diet-induced IR in humans are limited by their long duration or low efficacy. In the present study we developed and characterized an acute dietary model of saturated fatty acid-enriched diet induced insulin resistance.
Methods:
High caloric diets enriched with saturated fatty acids (SFA) or carbohydrates (CARB) were evaluated in subjects with normal and impaired glucose tolerance (NGT or IGT). Both diets were compared to a standard eucaloric American Heart Association (AHA) control diet in a series of crossover studies. Whole body insulin resistance was estimated as steady state plasma glucose (SSPG) concentrations during the last 30min of a 3-h insulin suppression test.
Results:
SSPG was increased after a 24-h SFA diet (by 83±74% vs. control, n=38) in the entire cohort, which was comprised of participants with NGT (92±82%, n=22) or IGT (65±55%, n=16) (all p<0.001). SSPG was also increased after a single SFA breakfast (55±32%, p=0.008, n=7). The increase in SSPG was less pronounced after an overnight fast following a daylong SFA diet (24±31%, p=0.04, n=10), and further attenuated 24h after returning to the control diet (19±35%, p=0.09, n=11). SSPG was not increased after a 24-h CARB diet (26±50%, p=0.11, n=12).
Conclusions:
A short-term SFA-enriched diet induced whole body insulin resistance in both NGT and IGT subjects. Insulin resistance persisted overnight after the last SFA meal and was attenuated by one day of a healthy diet. This model offers opportunities for identifying early mechanisms and potential treatments of dietary saturated fat induced insulin resistance.
De novo lipogenesis (DNL), the synthesis of saturated and monounsaturated fatty acids from acetyl-CoA, occurs in most, if not all mammalian cell types. The liver and the adipose tissue are the major sites of DNL where excess nutrients are converted into DNL-derived fatty acids that then become the energy supply of other organs or are stored as triglycerides. DNL in the adipose tissue has been studied to a lesser extent than hepatic DNL. Similar to hepatic DNL, it appears that insulin and a systemic surplus of monosaccharides are powerful stimulants of DNL in white and brown adipose tissue. Although DNL in the liver and adipose tissues share regulatory mechanisms, adipose tissue DNL appears to be a marker of metabolic health whereas hepatic DNL often is increased in unfavorable metabolic states. Here we will discuss mechanisms orchestrating DNL in WAT and BAT and in the liver in physiology and the dysregulation of DNL in obesity and related disorders. We will also review several bioactive lipids that are products of adipose tissue DNL and their role in metabolic health.
Although metabolic abnormalities common in obesity are well-defined, the metabolic and endocrine responses that occur in the early stages of weight gain are not. The overall objective of my dissertation was to characterize the metabolic and endocrine responses during 2 weeks of overeating. We conducted a battery of metabolic tests in a total of 23 healthy non-obese volunteers before, during, and after a 2-week overeating intervention. Subjects remained in the hospital for the entire 2-week overeating period to ensure strict control over their diet (i.e., they consumed 70kcals/kg FFM/day [~4000kcals/day]) and their physical activity (i.e., they were limited to 1500 steps per day). STUDY 1 of my dissertation examined some important metabolic adaptations to overeating, and we found that 2-weeks of overeating increased whole-body insulin resistance. However, the impaired systemic insulin sensitivity was not accompanied by changes in markers of impaired insulin action within skeletal muscle. Interestingly, muscle lipid accumulation did not increase despite consuming about twice the normal amount of dietary fat (~150 grams/day). STUDY 2 of my dissertation focused on the endocrine responses to overeating, and as anticipated we found that the large and frequent meals provided during the overeating period resulted in a chronic elevation in plasma insulin concentration (p
Besides the well-characterized effects of brain insulin and leptin in regulating food intake, insulin and leptin signaling to the central nervous system modulates a variety of metabolic processes, such as glucose and lipid homeostasis, as well as energy expenditure. This review summarizes the current literature on the contribution of central nervous insulin and leptin action to metabolic control in animals and humans. Potential therapeutic options based on the direct delivery of these peptides to the brain by, for example, intranasal administration, are discussed.
Background
Obesity and the metabolic syndrome are dramatically increasing problems. Red blood cell distribution width (RDW), the variability in size of circulating red blood cells, has been demonstrated to be altered in different clinical settings. This analysis aimed to investigate the relationship between RDW and obesity in adolescents and in an animal model of diet-induced obesity (DIO). Methods
Seventy-nine male adolescents (aged 13-17 years) were studied. Thirty-seven of them were overweight (body mass index90th percentile). RDW, markers of inflammation and stem cell factor (SCF) were determined. In an animal study, mice were fed with different diets for 15 weeks. RDW was determined using an animal blood count machine. ResultsRDW differed significantly between normal-weight adolescents (13.070.09) and overweight adolescents (13.39 +/- 0.10, P=0.015), whereas erythrocyte counts and haematocrit did not differ. RDW correlated to markers of inflammation and inversely to SCF. In the mice animal model, nutritional changes increased RDW, whereas overweight per se did not change RDW. ConclusionsRDW is elevated in overweight and reflects the inflammatory state. RDW potentially represents an additional and cost-effective tool to indicate inflammation. Future studies are needed to understand the differential influences of nutrition and overweight on RDW.
A lifestyle characterized by inactivity and a high-calorie diet is a known risk factor for impaired insulin sensitivity and development of Type 2 diabetes mellitus. To investigate possible links, nine young healthy men (24 ± 3 yr; body mass index of 21.6 ± 2.5 kg/m(2)) completed 14 days of step reduction (10,000 to 1,500 steps/day) and overfeeding (+50% kcal). Body composition (dual X-ray absorptiometry, MRI), aerobic fitness (maximal O(2) consumption), systemic inflammation and insulin sensitivity [oral glucose tolerance test (OGTT), hyperinsulinemic euglycemic clamp] were assessed before (day 0), during (days 3 and 7), and immediately after the intervention (day 14), with follow-up tests (day 30). Body weight had increased at days 7 and 14 (P < 0.05). The amount of visceral fat had increased at day 14 compared with day 0 (P < 0.05). The insulin response to the OGTT had increased at days 7 and 14 (P < 0.05). Insulin sensitivity, estimated using the Matsuda index, had decreased at days 3 and 7 (P < 0.01). At day 14, glucose infusion rates had decreased by ∼44% during the euglycemic clamps (P < 0.05). Also, plasma levels of leptin and adiponectin had increased (P < 0.05), whereas no changes were seen in inflammatory markers. At day 30, body weight and whole body adiposity were still elevated compared with day 0 (P < 0.05), whereas the insulin sensitivity as well as the insulin response to the OGTT did not differ from baseline. The glucose response to the OGTT was only affected at day 30, with a decrease compared with day 0. Our data show that insulin sensitivity was impaired after 3 days of inactivity and overfeeding. Impairments in insulin sensitivity occurred before changes in body composition, supporting the notion that the initial steps in impairment of insulin sensitivity may be linked directly to the effects of inactivity and a high calorie intake.
The very low GH concentration in obesity is commonly attributed to high body fat mass; however, the influence of overeating on GH secretion is not clear.
The aim of the study was to examine the effects of 2 wk of overeating on changes in GH secretion.
Subjects were admitted to the hospital and stayed within the Michigan Clinical Research Unit throughout the entire 2-wk overeating period.
We studied seven healthy, nonobese men (body mass index, 24 ± 1 kg/m(2); age, 25 ± 1 yr).
Subjects ate standardized meals containing 70 kcal/kg fat free mass/d (∼4000 kcal/d) for 2 wk.
Twenty-four-hour plasma concentrations of GH (every 20 min) and insulin (every 2 h) were measured before overeating (baseline), on d 3, and after 2 wk of overeating.
Compared with baseline, average 24-h plasma GH concentration declined nearly 80% by d 3 of overeating (1.30 ± 0.18 vs. 0.36 ± 0.09 ng/ml; P = 0.01). This marked suppression of GH secretion occurred in the absence of an increase in body weight (77.0 ± 2.2 vs. 76.4 ± 2.4 kg). At the same time, average 24-h insulin concentration doubled (16.6 ± 2.1 vs. 31.7 ± 5.8 μU/ml; P = 0.009). After 2 wk, body weight significantly increased (79.0 ± 2.1 kg; P < 0.001), and body fat increased by more than 10% (P = 0.002). However, this did not induce a further suppression in plasma GH concentration (0.33 ± 0.08 ng/ml).
Only a few days of overeating markedly suppressed GH secretion before any measurable weight gain and was accompanied by chronic hyperinsulinemia. Increased body weight and body fat by 2 wk of overeating did not further suppress GH secretion.
Several lines of evidence suggest that ovarian hormones influence glucose homeostasis, although their exact role in humans has not been clearly defined. In the present study, we sought to test the hypothesis that ovarian hormones regulate glucose homeostasis by examining the effect of pharmacologically induced ovarian hormone deficiency on glucose disposal and insulin secretion. Young, healthy women with regular menstrual patterns were studied during the follicular and luteal phases of their cycle at baseline and after 2 mo of treatment with gonadotropin-releasing hormone agonist (GnRHa; n = 7) or placebo (n = 6). Using hyperglycemic clamps, in combination with stable isotope-labeled (i.e., (13)C and (2)H) glucose tracers, we measured glucose disposal and insulin secretion. Additionally, we assessed body composition and regional fat distribution using radiologic imaging techniques as well as glucoregulatory hormones. Ovarian hormone suppression with GnRHa did not alter body composition, abdominal fat distribution, or thigh tissue composition. There was no effect of ovarian suppression on total, oxidative, or nonoxidative glucose disposal expressed relative to plasma insulin level. Similarly, no effect of ovarian hormone deficiency was observed on first- or second-phase insulin secretion or insulin clearance. Finally, ovarian hormone deficiency was associated with an increase in circulating adiponectin levels but no change in leptin concentration. Our findings suggest that a brief period of ovarian hormone deficiency in young, healthy, eugonadal women does not alter glucose disposal index or insulin secretion, supporting the conclusion that ovarian hormones play a minimal role in regulating glucose homeostasis. Our data do, however, support a role for ovarian hormones in the regulation of plasma adiponectin levels.
The task of maintaining energy balance involves not only making sure that the number of calories ingested equals the number of calories burned but also involves ensuring nutrient balance. This means that over time, the quantity of carbohydrate, fat and protein consumed equals the amount of each oxidized. While the body has the ability to convert protein to carbohydrate and carbohydrate to fat, over long periods of time the body establishes nutrient balance with a high degree of accuracy storing excess nutrients as fat. To make decisions about food intake, the brain must assimilate information about the quantity of nutrients ingested and their disposition through the body over time. This is a very complex time ordered process as different tissues may be in different states of energy balance at different intervals following food ingestion. The fundamental task for the brain is to assess the influx of nutrients relative to stored pools of those nutrients and the rate at which they are being oxidized. It has been suggested that this task is particularly difficult for dietary fat because the stored pool of lipid is quite large compared to either the stored pools of carbohydrate and protein or the quantity of fat ingested per day. It is clear that some organisms resist weight gain even in the face of highly palatable diets. In fact most individuals eat less on any given day than they could given their maximal capacity for consumption. A central question then is: what restrains food intake in the setting of widely available highly palatable food? In this paper we will discuss the evidence that the movement of dietary fat between tissues may play an important role in the fidelity of nutrient sensing and as a result, resistance or susceptibility to obesity. In particular, the relative metabolism of dietary fat favoring oxidation over storage may be associated with more robust signaling of positive energy balance and resistance to dietary induced obesity in both humans and rats.
This report deals with the association between the constituents of lean body mass (LBM) and resting metabolic rate (RMR) before and after a 100-d overfeeding period. Computed-tomography (CT) scan of 22 young adult males at nine different body levels were used to estimate adipose tissue mass (ATMCT), LBMCT, skeletal-muscle mass (SMMCT), and non-muscular LBMCT (NM-LBMCT). Before overfeeding, all body constituents, except ATMCT, were significantly correlated with RMR. Only body mass changes were significantly correlated with RMR changes. Comparison of these results with those of several studies in the literature reveals that the relationship between RMR and fat-free mass is highly influenced by the size of the SD for the latter variable. In stepwise-multiple-regression analysis, only SMMCT could be used to predict RMR. It was concluded that SMMCT and ATMCT, but not NM-LBMCT, increased during overfeeding and that the best correlates of RMR remain LBMCT, SMMCT, and body massType: JOURNAL ARTICLELanguage: Eng
Possible adaptive mechanisms that may defend against weight gain during periods of excessive energy intake were investigated by overfeeding six lean and three overweight young men by 50% above baseline requirements with a mixed diet for 42 d [6.2 +/- 1.9 MJ/d (mean +/- SD), or a total of 265 +/- 45 MJ]. Mean weight gain was 7.6 +/- 1.6 kg (58 +/- 18% fat). The energy cost of tissue deposition (28.7 +/- 4.4 MJ/kg) matched the theoretical cost (26.0 MJ/kg). Basal metabolic rate (BMR) increased by 0.9 +/- 0.4 MJ/d and daily energy expenditure assessed by whole-body calorimetry (CAL EE) increased by 1.8 +/- 0.5 MJ/d. Total free-living energy expenditure (TEE) measured by doubly labeled water increased by 1.4 +/- 2.0 MJ/d. Activity and thermogenesis (computed as CAL EE--BMR and TEE--BMR) increased by only 0.9 +/- 0.4 and 0.9 +/- 2.1 MJ/d, respectively. All outcomes were consistent with theoretical changes due to the increased fat-free mass, body weight, and energy intake. There was no evidence of any active energy-dissipating mechanisms.
The body mass of adoptees was compared with the body mass of both biologic and adoptive parents using data from the Danish Adoption Register. Chi-square analyses revealed that biologic heritability is small and is confined to thin, not obese body mass. It is probable that the inheritance of thin body mass constitutes a mild protective factor that mitigates against development of obesity caused by environmental factors.
Both the amount and composition of food eaten influence body-weight regulation. The purpose of this study was to determine whether and by what mechanism excess dietary fat leads to greater fat accumulation than does excess dietary carbohydrate. We overfed isoenergetic amounts (50% above energy requirements) of fat and carbohydrate (for 14 d each) to nine lean and seven obese men. A whole-room calorimeter was used to measure energy expenditure and nutrient oxidation on days 0, 1, 7, and 14 of each overfeeding period. From energy and nutrient balances (intake-expenditure) we estimated the amount and composition of energy stored. Carbohydrate overfeeding produced progressive increases in carbohydrate oxidation and total energy expenditure resulting in 75-85% of excess energy being stored. Alternatively, fat overfeeding had minimal effects on fat oxidation and total energy expenditure, leading to storage of 90-95% of excess energy. Excess dietary fat leads to greater fat accumulation than does excess dietary carbohydrate, and the difference was greatest early in the overfeeding period.
No current treatment for obesity reliably sustains weight loss, perhaps because compensatory metabolic processes resist the maintenance of the altered body weight. We examined the effects of experimental perturbations of body weight on energy expenditure to determine whether they lead to metabolic changes and whether obese subjects and those who have never been obese respond similarly.
We repeatedly measured 24-hour total energy expenditure, resting and nonresting energy expenditure, and the thermic effect of feeding in 18 obese subjects and 23 subjects who had never been obese. The subjects were studied at their usual body weight and after losing 10 to 20 percent of their body weight by underfeeding or gaining 10 percent by overfeeding.
Maintenance of a body weight at a level 10 percent or more below the initial weight was associated with a mean (+/- SD) reduction in total energy expenditure of 6 +/- 3 kcal per kilogram of fat-free mass per day in the subjects who had never been obese (P < 0.001) and 8 +/- 5 kcal per kilogram per day in the obese subjects (P < 0.001). Resting energy expenditure and nonresting energy expenditure each decreased 3 to 4 kcal per kilogram of fat-free mass per day in both groups of subjects. Maintenance of body weight at a level 10 percent above the usual weight was associated with an increase in total energy expenditure of 9 +/- 7 kcal per kilogram of fat-free mass per day in the subjects who had never been obese (P < 0.001) and 8 +/- 4 kcal per kilogram per day in the obese subjects (P < 0.001). The thermic effect of feeding and nonresting energy expenditure increased by approximately 1 to 2 and 8 to 9 kcal per kilogram of fat-free mass per day, respectively, after weight gain. These changes in energy expenditure were not related to the degree of adiposity or the sex of the subjects.
Maintenance of a reduced or elevated body weight is associated with compensatory changes in energy expenditure, which oppose the maintenance of a body weight that is different from the usual weight. These compensatory changes may account for the poor long-term efficacy of treatments for obesity.
Women (n 160) aged 50 to 65 years were asked to weigh their food for 4 d on four occasions over the period of 1 year, using the PETRA (Portable Electronic Tape Recorded Automatic) scales. Throughout the year, they were asked to complete seven other dietary assessment methods: a simple 24 h recall, a structured 24 h recall with portion size assessments using photographs, two food-frequency questionnaires, a 7 d estimated record or open-ended food diary, a structured food-frequency (menu) record, and a structured food-frequency (menu) record with portion sizes assessed using photographs. Comparisons between the average of the 16 d weighed records and the first presentation of each method indicated that food-frequency questionnaires were not appreciably better at placing individuals in the distribution of habitual diet than 24 h recalls, due partly to inaccuracies in the estimation of frequency of food consumption. With a 7 d estimated record or open-ended food diary, however, individual values of nutrients were most closely associated with those obtained from 16 d weighed records, and there were no significant differences in average food or nutrient intakes.
In 10 moderately obese women, 24-h energy expenditure (24EE) was measured in a respiration chamber under four conditions: 1) before weight loss (body weight = 77.9 kg), 2) during weight loss (63.9 kg), 3) after realimentation (62.5 kg), and 4) 6-15 mo after the study diet with ad libitum diet (67.7 kg). The 14 +/- 8 kg (mean +/- SD) weight loss produced a decrease in 24EE of 1498 +/- 1138 kJ/d (P < 0.001), ie, a decrease of weight of 107 kJ.kg body wt-1.d-1. The subsequent 24EE (conditions 3 and 4) remained lower than the value before weight loss. A significant correlation was found between changes before and after weight regain in basal respiratory quotient (RQ) and the spontaneous rate of body-weight gain after cessation of the period of low energy intake (r = 0.89, P < 0.01); this suggests that the value of the postabsorptive RQ may be a predictor of relapse of weight gain. After discontinuation of the low energy diet, an elevated postabsorptive RQ shows that the endogenous lipid oxidation is low, a condition favoring weight gain.
Alterations in energy balance must be accommodated by adjustments in the net storage of the major energy-yielding macronutrients: carbohydrate, protein, and fat. This study used continuous whole-body calorimetry to measure changes in energy expenditure and substrate oxidation during a 12-d imposed energy imbalance in six lean men on mixed diets (overfeeding: 16.5 MJ/d, +33%, n = 3; underfeeding: 3.5 MJ/d, -67%, n = 3). Changes in total energy expenditure (TEE) and its components were modest; TEE changed by +6.2% (overfeeding) and -10.5% (underfeeding). In consequence, body weight changed by +2.90 and -3.18 kg. Marked changes in metabolic fuel selection occurred over the course of the study. Carbohydrate intake (540 and 83 g/d for overfeeding and underfeeding, respectively) exerted direct autoregulatory feedback on carbohydrate oxidation (551 and 106 g/d at day 12 for overfeeding and underfeeding, respectively). Subjects were close to balance by day 5. Changes in protein oxidation were small and not sufficient to prevent the oxidation of body protein mass, or its accretion, in response to energy deficit or surplus. Fat oxidation (59 and 177 g/d for overfeeding and underfeeding, respectively) was not sensitive to dietary fat intake (150 and 20 g/d, for overfeeding and underfeeding, respectively), rather, its oxidation was inversely related to the oxidation of other substrates. Changes in fat balance accounted for 74.1% and 84.0% of the energy imbalance during overfeeding and underfeeding, respectively. This study shows a clear oxidative hierarchy for the macronutrients. Metabolic fuel selection is dominated by the need to maintain carbohydrate balance. This induces inappropriate counterregulatory alterations in fat oxidation during energy surplus.
Humans show considerable interindividual variation in susceptibility to weight gain in response to overeating. The physiological
basis of this variation was investigated by measuring changes in energy storage and expenditure in 16 nonobese volunteers
who were fed 1000 kilocalories per day in excess of weight-maintenance requirements for 8 weeks. Two-thirds of the increases
in total daily energy expenditure was due to increased nonexercise activity thermogenesis (NEAT), which is associated with
fidgeting, maintenance of posture, and other physical activities of daily life. Changes in NEAT accounted for the 10-fold
differences in fat storage that occurred and directly predicted resistance to fat gain with overfeeding (correlation coefficient
= 0.77, probability < 0.001). These results suggest that as humans overeat, activation of NEAT dissipates excess energy to
preserve leanness and that failure to activate NEAT may result in ready fat gain.
It is commonly asserted that the average American gains 5 lb (2.3 kg) or more over the holiday period between Thanksgiving and New Year's Day, yet few data support this statement.
To estimate actual holiday-related weight variation, we measured body weight in a convenience sample of 195 adults. The subjects were weighed four times at intervals of six to eight weeks, so that weight change was determined for three periods: preholiday (from late September or early October to mid-November), holiday (from mid-November to early or mid-January), and postholiday (from early or mid-January to late February or early March). A final measurement of body weight was obtained in 165 subjects the following September or October. Data on other vital signs and self-reported health measures were obtained from the patients in order to mask the main outcome of interest.
The mean (+/-SD) weight increased significantly during the holiday period (gain, 0.37+/-1.52 kg; P<0.001), but not during the preholiday period (gain, 0.18+/-1.49 kg; P=0.09) or the postholiday period (loss, 0.07+/-1.14 kg; P=0.36). As compared with their weight in late September or early October, the study subjects had an average net weight gain of 0.48+/-2.22 kg in late February or March (P=0.003). Between February or March and the next September or early October, there was no significant additional change in weight (gain, 0.21 kg+/-2.3 kg; P=0.13) for the 165 participants who returned for follow-up.
The average holiday weight gain is less than commonly asserted. Since this gain is not reversed during the spring or summer months, the net 0.48-kg weight gain in the fall and winter probably contributes to the increase in body weight that frequently occurs during adulthood.
In the current obesity epidemic, the ability to remain lean is beginning to be uncommon. Therefore, it was considered of interest to characterize such subjects.
From a population of premenopausal women (n = 270), all 40 years of age, those with a similar body mass index (BMI) as women at the age of 21 years, born the same year (BMI = 21.1 kg/m(2)) were selected among nonsmokers and compared with the remaining nonsmoking women.
Lean women showed, as expected, low waist-to-hip circumference ratio and abdominal sagittal diameter as well as absence of other disease risk factors. Compared with the remaining women, 17 beta-estradiol was high and androgens were low, whereas insulin-like growth factor I and thyroid hormones showed no differences. Dihydroepiandrosterone sulfate was lower, whereas cortisol, measured in saliva repeatedly over a day, and adrenocorticotropin hormone were not different. Results from questionnaires indicated higher education and socioeconomic status, frequent sports activities, and better psychosocial adaptation and psychological health. A tetranucleotide repeat polymorphism in the fourth [corrected] intron of the aromatase P450 gene was longer among the lean (187 base pairs) than the rest of the women. Women with opposite phylogenetic characteristic have a short microsatellite (168 base pairs) in this gene locus.
Lean, nonsmoking women enjoy an excellent health in not only anthropometric and metabolic factors, but also in neuroendocrine, endocrine, and psychological variables. The endocrine measurements suggest a well-functioning aromatase, which in turn might have a genetic background, contributing to health. The aromatase gene might be important for regulation of body fat mass.
Obesity has reached epidemic proportions in the United States and other developed nations. In the United States, 27% of adults are obese and an additional 34% are overweight. Research in the past decade has shown that genetic influences clearly predispose some individuals to obesity. The marked increase in prevalence, however, appears to be attributable to a toxic environment that implicitly discourages physical activity while explicitly encouraging the consumption of supersized portions of high-fat, high-sugar foods. Management of the obesity epidemic will require a two-pronged approach. First, better treatments, including behavioral, pharmacologic, and surgical interventions, are needed for individuals who are already obese. The second and potentially more promising approach is to prevent the development of obesity by tackling the toxic environment. This will require bold public policy initiatives such as regulating food advertising directed at children. The authors call not for the adoption of a specific policy initiative, but instead propose that policy research, based on viewing obesity as a public health problem, become a central focus of research.
After 13 days of weight maintenance diet (13,720 ± 620 kJ/day, 40% fat, 15% protein, and 45% carbohydrate), five young men (71.3 ± 7.1 kg, 181 ± 8 cm; means ± SD) were overfed for 9 days at 1.6 times their maintenance requirements (i.e., +8,010 kJ/day). Twenty-four-hour energy expenditure (24-h EE) and basal metabolic rate (BMR) were measured on three occasions, once after 10 days on the weight-maintenance diet and after 2 and 9 days of overfeeding. Physical activity was monitored throughout the study, body composition was measured by underwater weighing, and nitrogen balance was assessed for 3 days during the two experimental periods. Overfeeding caused an increase in body weight averaging 3.2 kg of which 56% was fat as measured by underwater weighing. After 9 days of overfeeding, BMR increased by 622 kJ/day, which could explain one-third of the increase in 24-h EE (2,038 kJ/day); the remainder was due to the thermic effect of food (which increased in proportion with excess energy intake) and the increased cost of physical activity, related to body weight gain. This study shows that approximately one-quarter of the excess energy intake was dissipated through an increase in EE, with 75% being stored in the body. Under our experimental conditions of mixed overfeeding in which body composition measurements were combined with those of energy balance, it was possible to account for all of the energy ingested in excess of maintenance requirements.
Insulin and leptin are hypothesized to be 'adiposity signals' for the long-term regulation of body weight by the brain. Accordingly, a change in the plasma levels of leptin or insulin indicates a state of altered energy homeostasis and adiposity, and the brain responds by adjusting food intake to restore adipose tissue mass to a regulated level. The candidate site for the brain's detection of leptin adiposity signaling is the hypothalamic arcuate nucleus, where leptin inhibits expression neuropeptide Y and increases expression of the pro-opiomelanocortin (POMC) precursor of alphaMSH. Insulin also inhibits arcuate nucleus expression of neuropeptide Y but its effects on other hypothalamic signaling systems are not known. Leptin-responsive neurons in the arcuate nucleus are hypothesized to project to the paraventricular nucleus and lateral hypothalamic area where they are proposed to influence the expression of peptides that regulate food intake. Future development of this model will incorporate brain pathways for integration of leptin and insulin adiposity signaling to the hypothalamus with meal-related signals that act in the caudal brainstem. Recent research showing that leptin and insulin enhance the satiety action of peripheral CCK, thereby causing meals to be terminated earlier and reducing cumulative food intake, suggests that hypothalamic pathways that are sensitive to leptin and insulin adiposity signals have anatomical connections with caudal brainstem neurons that respond to meal-related signals and regulate meal size. The recent findings that insulin alters the expression and function of neural transporters for dopamine and norepinephrine indicate that adiposity signals may influence food intake by acting on non-peptide neurotransmitter systems.
Blood glucose, plasma concentrations of insulin, free fatty acids (FFA) and glycerol were measured in 11 healthy lean young adults, in response to a standard high carbohydrate meal, before and during overfeeding with a high carbohydrate or a high fat diet. The plasma insulin was unaffected by overfeeding, whilst the hypercaloric high carbohydrate diet enhanced carbohydrate tolerance and the hypercaloric high fat diet had the reverse effect. Both types of overfeeding depressed the postabsorptive and absorptive concentrations of plasma FFA. Overfeeding with the high carbohydrate diet had no effect on the plasma glycerol concentrations recorded before and after ingestion of the standard breakfast. Overfeeding with high fat diet also failed to alter the postabsorptive concentration of plasma glycerol but the plasma glycerol levels rose following the standard high carbohydrate meal. These findings indicate that: a) overfeeding with a high carbohydrate diet enhances the utilization of glucose by increasing sensitivity to insulin, whilst overfeeding with a high fat diet has the opposite effect; b) esterification of FFA in adipose tissue is stimulated by overfeeding independently of the composition of the diet; c) basal lipolysis in adipose tissue as judged by the postabsorptive plasma glycerol concentration is unaffected by overfeeding but the antilipolytic effects of insulin on adipose tissue appear to be impaired following the standard meal, when subjects are overfed with a high fat diet.
The effects of a hypercaloric high carbohydrate diet on lipolysis and esterification were studied in biopsy samples of adipose tissue obtained from 5 healthy subjects. Overfeeding with carbohydrate enhanced the rate of esterification of free fatty acids (FFA) without any alteration in the rate of lipolysis. The release of FFA from adipose tissue was inhibited. These observations indicate that the utilization of glucose and FFA by adipose tissue for the synthesis of triglycerides was facilitated during weight gain on a high carbohydrate diet.
Quantitatively accurate measurements of plasma free fatty acid (FFA) turnover can be made if the FFA tracer is infused intravenously and arterial blood is sampled. To be certain that arterialized-venous blood provides comparable information, plasma FFA concentration and specific activity were measured in both arterial and arterialized-venous blood in 19 volunteers undergoing infusion of [1-14C]palmitate infusion before and during a euglycemic, hyperinsulinemic clamp. Heated hand vein blood was obtained using either the heated box (n = 9 subjects) or heating pad (n = 10 subjects) technique. The heated box arterialized-venous blood had palmitate concentration and specific activity equal to arterial blood. The use of the heating pad resulted in small (3%), but statistically significant (P less than .05), underestimates of palmitate specific activity. In addition, plasma lactate concentrations were significantly higher in heated hand vein blood than arterial blood. In summary, heated hand vein blood is a satisfactory alternative to arterial blood for tracer studies of FFA metabolism.
We undertook this study to determine whether there are differences in the responses of different persons to long-term overfeeding and to assess the possibility that genotypes are involved in such differences. After a two-week base-line period, 12 pairs of young adult male monozygotic twins were overfed by 4.2 MJ (1000 kcal) per day, 6 days a week, for a total of 84 days during a 100-day period. The total excess amount each man consumed was 353 MJ (84,000 kcal). During overfeeding, individual changes in body composition and topography of fat deposition varied considerably. The mean weight gain was 8.1 kg, but the range was 4.3 to 13.3 kg. The similarity within each pair in the response to overfeeding was significant (P less than 0.05) with respect to body weight, percentage of fat, fat mass, and estimated subcutaneous fat, with about three times more variance among pairs than within pairs (r approximately 0.5). After adjustment for the gains in fat mass, the within-pair similarity was particularly evident with respect to the changes in regional fat distribution and amount of abdominal visceral fat (P less than 0.01), with about six times as much variance among pairs as within pairs (r approximately 0.7). We conclude that the most likely explanation for the intrapair similarity in the adaptation to long-term overfeeding and for the variations in weight gain and fat distribution among the pairs of twins is that genetic factors are involved. These may govern the tendency to store energy as either fat or lean tissue and the various determinants of the resting expenditure of energy.
Basal metabolic rate (BMR), thermic effect of food (TEF), and total daily energy expenditure (TDEE) were measured in six nonobese and seven obese adolescents during periods of weight maintenance and 2 wk of carbohydrate overfeeding. BMR and TEF were measured by indirect calorimetry and TDEE by the doubly labeled water method. Fasting blood levels of insulin, thyroid, and norepinephrine (NE) and urinary excretion of NE and 4-hydroxy-3-methoxymandelic acid (VMA) were measured before and after overfeeding. Energy intake was 1.61 X BMR during maintenance and 2.45 X BMR during overfeeding. BMR increased comparably in both groups during overfeeding (obese, 7.9 +/- 1.2%, nonobese, 8.6 +/- 1.9%). TEF was similar and did not change significantly during overfeeding (maintenance: obese, 9.4 +/- 0.6%; nonobese, 9.8 +/- 0.4% vs. overfeeding: obese, 8.6 +/- 0.3%; nonobese, 9.2 +/- 0.7%). TDEE did not differ significantly between obese and nonobese. Increases in insulin and 3,5,3'-triiodothyronine levels were significant but did not differ between the two groups. Plasma NE and urinary excretion of VMA and NE did not increase during overfeeding. The thermogenic response to food or to overfeeding does not appear reduced in obese adolescents, nor does facultative thermogenesis appear to be a significant factor in weight maintenance in adolescents.
Short-term mixed calorie overfeeding increases basal energy expenditure in man but its effects on the thermic effect of a meal (TEM) are unclear. The thermogenic and hormonal responses to an 800-kcal liquid mixed meal were measured in six lean and six obese subjects during weight maintenance, during 18 d of overfeeding 1000 kcal/d, and during 18 d of a 589 kcal/d diet (obese subjects only). There was no change in the TEM in lean subjects between weight maintenance and overfeeding. In the obese group the TEM was lower during both overfeeding (p less than 0.05) and underfeeding (p less than 0.05) compared with weight maintenance. Overfeeding increased rates of net postprandial glucose oxidation and decreased lipid oxidation in the lean subjects only. Alterations in glucose oxidation rates and the insulin response to meals may contribute to an impaired TEM in human obesity during overnutrition.
Tracer methodology has been applied extensively to the estimation of endogenous glucose production (Ra) during euglycemic glucose clamps. The accuracy of this approach has been questioned due to the observation of significantly negative estimates for Ra when insulin levels are high. We performed hyperinsulinemic (300 μU/ml)-euglycemic glucose clamps for 180 min in normal dogs and compared the standard approach, an unlabeled exogenous glucose infusate (cold GINF protocol, n = 12), to a new approach in which a tracer (D-[3-3H]glucose) was added to the exogenous glucose used for clamping (hot GINF protocol, n = 10). Plasma glucose, insulin and glucagon concentrations, and glucose infusion rates were similar for the two protocols. Plasma glucose specific activity was 20 ± 1% of basal (at 120–180 min) in the cold GINF studies, and 44 ± 3 to 187 ± 5% of basal in the hot GINF studies. With the one-compartment, fixed pool volume model of Steele, Ra, for the cold GINF studies was –2.4 ± 0.7 mg · min−1 · kg−1 at 25 min and remained significantly negative until 110 min (P < .05). For the hot GINF studies, Ra was never significantly less than zero (P > .05) and was greater than in the cold GINF studies at 20–90 min (P < .05). There was substantially less between-(78%) and within- (40%) experiment variation for the hot GINF studies compared with the cold GINF studies. An alternate approach (regression method) to the application of the one-compartment model, which allows for a variable and estimable effective distribution volume, yielded Ra estimates that were suppressed 60–100% from basal.
In conclusion, the one-compartment, fixed pool volume model of glucose kinetics is inadequate for the estimation of Ra during euglycemic glucose clamps. Two new strategies for estimating Ra from the one-compartment model, the hot GINF protocol and the regression method calculation, yielded more accurate and physiologically plausible estimates of Ra than currently used methodology.
The contribution of reduced energy expenditure to the development of obesity has been a point of controversy. We measured 24-hour energy expenditure (adjusted for body composition, age, and sex), in a respiratory chamber, in 95 southwestern American Indians. Energy expenditure correlated with the rate of change in body weight over a two-year follow-up period (r = -0.39, P less than 0.001). The estimated risk of gaining more than 7.5 kg in body weight was increased fourfold in persons with a low adjusted 24-hour energy expenditure (200 kcal per day below predicted values) as compared with persons with a high 24-hour energy expenditure (200 kcal per day above predicted values; P less than 0.01). In another 126 subjects, the adjusted metabolic rate at rest at the initial visit was also found to predict the gain in body weight over a four-year follow-up period. When the 15 subjects who gained more than 10 kg were compared with the remaining 111 subjects, the initial mean (+/- SD) adjusted metabolic rate at rest was lower in those who gained weight (1694 +/- 103 vs. 1764 +/- 109 kcal per day; P less than 0.02) and increased to 1813 +/- 134 kcal per day (P less than 0.01) after a mean weight gain of 15.7 +/- 5.7 kg. In a group of 94 siblings from 36 families, values for adjusted 24-hour energy expenditure aggregated in families (intraclass correlation = 0.48). We conclude that a low rate of energy expenditure may contribute to the aggregation of obesity in families.
The effects on adipocyte metabolism of increasing daily caloric intake by approximately 60% for 14 days was studied in seven nondiabetic moderately obese southwestern Native American Indians. Mean body weight increased by 3.0 +/- 0.3 kg, without any change in average size of isolated abdominal adipocytes. Overfeeding resulted in a 58% increase (P less than 0.01) in mean fasting plasma insulin concentration, whereas fasting plasma glucose concentration remained constant. Basal and maximum (8 nmol/L) insulin-stimulated glucose transport rates by isolated adipocytes increased by 83% (P less than 0.02) and 110% (P less than 0.01), respectively, after overfeeding, associated with an increase of 118% (P less than 0.01) in the incremental response to maximal insulin stimulation. However, no differences in either the sensitivity (ED50 of insulin for the stimulation of glucose transport) or the responsiveness (percent stimulation by insulin) of glucose transport were seen in isolated adipocytes as a result of overfeeding. Maximum insulin-stimulated total glucose utilization rates by isolated adipocytes incubated at 5.5 mmol/L glucose were 63% greater after overfeeding, due to increases in lactate formation, triglyceride synthesis, and CO2 production. Mono125I-(Tyr A14)-insulin binding per cell and per cell surface area was similar before and after overfeeding. The lipolytic rate of isolated adipocytes, in the absence and presence of 25 nmol/L and 2 mumol/L isoproterenol, was decreased by 75% (P less than 0.02), 45% (P less than 0.05), and 27% (P less than 0.05), respectively, after overfeeding. However, overfeeding did not result in a significant difference in the sensitivity of antilipolysis to insulin.(ABSTRACT TRUNCATED AT 250 WORDS)
Glucose concentration may be determined enzymatically by a glucose-oxidaseproce- dure in which the amount of oxygendepletion from a solution saturated with oxygen is observed. The difference between the initial and final oxygenlevelsas detected by a polarographicoxygen analyzer is a measure of glucose concentration. Blood is sampledcontinuouslyby meansof a double-lumen catheter inserted into an arm vein and connected to the flow system. A peristaltic proportioning pump then propels glucose-oxidasereagent and the blood-heparin mixture through a dialyzer. The re- agent-dialysate mixture passes through a 1-mm. delay coil before passing to the polarographicoxygen sensor. Glucose concentration is proportional to the oxygen depletion in the mixture flowing past the sensor. The studies outlined in this paper describe work directed towards the development of a miniature system intended for continuousmonitoring and control of blood-glucoselevel. CONSTANT hthNITORING of blood glucose is now a practical procedure. Automatic control of blood sugar is based upon continuous monitoring (1-3). Tn previous studies, blood was sampled contimmuously by means of a double-lumen catlmeter inserted into an arm veimmammdconnected to instrumemmts for automated chemical analysis.t Studies based oim this procedure, utilizing small amounts of blood (0.1 ml./min.), have beemi reported (4). However, a more conmpact instrument was believed to be necessary. Accordingly, we have beemm interested in developing a minia- turized system desigimed specifically for physiologic monitorimig and control of blood sugar. Glucose concentration flay be determined enzymatically by a glucose- oxidase procedure imiwhich the amoumit of oxygeim depletion from a solu-
The carbohydrate intake of seven healthy men was increased from 220-265 g/d to 620-770 g/d for 17 days, while protein and fat intake remained constant. Carbohydrate loading did not affect the preprandial plasma glucose levels after an overnight fast, but reduced the postprandial increment in plasma glucose levels after 5, 11, and 17 days of overfeeding. Preprandial plasma insulin levels were slightly increased during carbohydrate overfeeding, but no increase in the postprandial rise in insulin levels was found until 11 days after the start of carbohydrate loading. Whole-body rates of carbohydrate oxidation and of glucose conversion to fat were estimated by indirect calorimetry. Basal carbohydrate oxidation rate was increased by 95% at the end of 17 days of overfeeding, but there was no potentiation in the stimulation of the carbohydrate oxidation rate induced by a meal. There was no net fat synthesis from glucose before carbohydrate loading; carbohydrate overfeeding produced nonprotein respiratory exchange ratios greater than 1.00, suggesting net fat synthesis from glucose. Meals did not stimulate net lipogenesis from glucose, either before or after overfeeding. These results indicate that the improvement in carbohydrate tolerance associated with short-term carbohydrate loading does not appear to depend on elevated insulin levels. Increased carbohydrate oxidation and lipogenesis elevated carbohydrate disposal is more than necessary to account for the improvement in carbohydrate tolerance.
The effect of overfeeding on the body weight, body fat, water content, energy expenditure, and digestibility of energy and nitrogen was investigated over 42 days in six young men. The metabolic rates in standard situations of work and rest were determined. Energy intakes were apparently increased by 6.2 MJ/day and energy expenditure fell slightly by 0.3 MG/day during overfeeding. Fecal and urinary losses of energy were a similar proportion of the gross energy intake in control and overfeeding periods (8%). Metabolizable energy intakes calculated from food tables agreed well with values derived from digestibility measurements in the control period (mean difference = +2%) but not in the overfeeding period (+8%). The implications of this are discussed. Mean body weight gain was 6.0 kg, 10% of initial weight; mean fat gain was 3.7 kg and water gain 1.8 liter. There were considerable interindividual differences in the weight and fat gain for a given excess energy intake. Metabolic rates in standard tasks were 10% higher at the end of overfeeding but expressed as kilojoules per kilogram per minute were similar to control values. Mean energy gain (144 MJ = fat gain X 39 kJ/g) was less than excess energy intake even allowing for overestimation of intakes using food tables and increases in metabolic rate. Such a discrepancy is unlikely to be due to unmeasured increases in metabolic rate but could have arisen from errors in the calculation of the variables involved. In this study where moderate weight gains were achieved by overfeeding mainly fat, increases in metabolic rate appear to be associated with increased body size and tissue gain rather than a luxuskonsumption mechanism.
To determine the effect of increased glycogen stores on hepatic carbohydrate metabolism, 15 nondiabetic volunteers were studied before and after 4 d of progressive overfeeding. Glucose production and gluconeogenesis were assessed with [2-3H] glucose and [6-14C] glucose (Study I, n = 6) or [3-3H] glucose and [U-14C]-alanine (Study II, n = 9) and substrate oxidation was determined by indirect calorimetry. Overfeeding was associated with significant (P < 0.01) increases in plasma glucose (4.97 +/- 0.10 to 5.09 +/- 0.11 mmol/liter), insulin (18.8 +/- 1.5 to 46.6 +/- 10.0 pmol/liter) and carbohydrate oxidation (4.7 +/- 1.4 to 18.0 +/- 1.5 mumol.kg-1.min-1) and a decrease in lipid oxidation (1.2 +/- 0.2 to 0.3 +/- 0.1 mumol.kg-1.min-1). Hepatic glucose output (HGO) increased in Study I (10.2 +/- 0.5 to 13.1 +/- 0.9 mumol.kg-1.min-1, P < 0.01) and Study II (11.17 +/- 0.67 to 13.33 +/- 0.83 mumol.kg-1.min-1, P < 0.01), and gluconeogenesis decreased (57.6 +/- 6.4 to 33.4 +/- 4.9 mumol/min, P < 0.01), indicating an increase in glycogenolysis. The increase in glycogenolysis was only partly compensated by an increase in glucose cycle activity (2.2 +/- 0.2 to 3.4 +/- 0.4 mumol.kg-1.min-1, P < 0.01) and the fall in gluconeogenesis, thus resulting in increased HGO. The suppression of gluconeogenesis despite increased lactate and alanine (glycerol was decreased) was associated with decreased free fatty acid (FFA) oxidation and negligible FFA enhanced gluconeogenesis. These studies suggest that increased liver glycogen stores alone can overwhelm normal intrahepatic mechanisms regulating carbohydrate metabolism resulting in increased HGO in nondiabetic man.
Plasma glucose, insulin, and glucagon levels were measured before and after long-term overfeeding (4.2 MJ/d during a 100-day period) in 24 lean adults (12 pairs of monozygotic twins). Fasting plasma glucose, insulin, and glucagon were significantly increased by overfeeding. During a 75-g oral glucose tolerance test (OGTT), no major alteration in glucose tolerance was observed and insulin area under the curve was increased. During a meal test, insulin and glucagon areas under the curve were increased. The pre-overfeeding values for glucose, insulin, and glucagon (fasting and areas) were not correlated with the gains in body weight and in fat mass. However, fasting glucagon before overfeeding was positively correlated with the gains in abdominal visceral fat and in femoral fat. The changes with overfeeding in insulin area during the OGTT were positively correlated with the changes in total subcutaneous fat, even after adjustment for total body fat gain. Significant twin intrapair similarity was observed for fasting plasma glucagon before overfeeding and for the changes in fasting insulin and glucagon with overfeeding. These results indicate that (1) in response to long-term overfeeding, both fasting insulin and glucagon are increased; (2) initial levels of glucose, insulin, and glucagon do not predict the gains in body weight and total body fat during overfeeding, but are related to changes in indicators of fat topography; (3) the changes in total subcutaneous fat represent an important correlate of insulin changes with overfeeding; and (4) the genotype could be an important determinant of insulin and glucagon responses to a prolonged positive-energy-balance period.
The effect of an increase in dietary fat content on fat and carbohydrate balances and energy expenditure (EE) was studied in nine formerly obese women with genetic predisposition to obesity (postobese) and a closely matched control group. Isocaloric low- (20% fat energy) and high-fat diets (50%) were consumed for 3 days preceding and during a 24-h respiratory chamber stay, whereas a medium-fat diet (30%) was consumed only on the day of measurement. After adjustment for 24-h energy intake to equal 24-h EE, 24-h fat balance was increased when the dietary fat content increased (P < 0.0002). No differences in macronutrient balances were found on the low-fat and medium-fat diets, but on the high-fat diet the postobese women failed to increase ratio of fat to carbohydrate oxidation appropriately (0.59 g/g, 95% confidence interval 0.47-0.67 vs. controls 1.02 g/g, 0.88-1.12; P = 0.002). This caused a positive adjusted fat balance (+11.0 g/day, 2.3-19.6 vs. controls -8.9 g/day, -17.5 to -0.2; P < 0.001) and a negative carbohydrate balance (-41.8 g/day, -69.5 to -14.0 vs. controls +23.2 g/day, -4.6 to +50.9; P < 0.001). Decreasing the dietary fat content increased 24-h EE in the postobese women (P = 0.02), whereas it was unaffected in the control group. Independent of energy balance, an increase in dietary fat content to 50% fat energy results in preferential fat storage, impaired suppression of carbohydrate oxidation, and reduction of 24-h EE in postobese women.
As one of the postulated roles of the ob gene product, leptin, is regulation of energy balance and preservation of normal body composition, we investigated the effect of acute and chronic calorie excess (weight gain) on serum leptin in humans. Two protocols were employed: 1) acute (12-h) massive (120 Cal/kg) voluntary overfeeding of eight healthy individuals; and 2) chronic overfeeding to attain 10% weight gain, with its subsequent maintenance for additional 2 weeks, involving six normal males. In the acute experiments (protocol 1), circulating leptin rose by 40% over baseline (P < 0.01) during the final hours of overfeeding; this increase persisted until the next morning. At the point of achievement and the 2-week maintenance of 10% weight gain (protocol 2), a more than 3-fold rise in the basal leptin concentration was observed (P < 0.01). A direct linear relationship was found between the magnitude of the leptin response to weight gain and the percent gain of body fat (r = 0.88; P < 0.01). In summary, 1) in contrast to normal food intake (8), short term massive overfeeding is associated with a moderate elevation of circulating leptin levels that persists until next feeding cycle is initiated; and 2) a 10% weight gain causes different changes in the body composition, and the resulting rise in circulating leptin parallels the increase in the percentage of body fat. In conclusion, these studies document acute elevation of leptin in response to positive energy balance and suggest that developing resistance to leptin is associated with bigger fat deposition during weight gain in humans.
An impaired fat oxidation has been implicated to play a role in the etiology of obesity, but it is unclear to what extent impaired fat mobilization from adipose tissue or oxidation of fat is responsible. The present study aimed to examine fat mobilization from adipose tissue and whole body fat oxidation stimulated by exercise in seven formerly obese women (FO) and eight matched controls (C). Lipolysis in the periumbilical subcutaneous adipose tissue, whole body energy expenditure (EE), and substrate oxidation rates were measured before, during, and after a 60-min bicycle exercise bout of moderate intensity. Lipolysis was assessed by glycerol release using microdialysis and blood flow measurement by 133Xe clearance technique. The FO women had lower resting EE than C (3.77 +/- 1.01 vs. 4.88 +/- 0.74 kJ/min, P < 0.05) but responded similarly to exercise. Adipose tissue glycerol release was twice as high in FO than in C at rest (0.455 +/- 0.299 vs. 0.206 +/- 0.102 mumol.100 g-1.min-1, P < 0.05) but increased similarly in FO and C in response to exercise. Despite higher plasma nonesterified fatty acids (NEFA) in FO (P < 0.001), fat oxidation rates during rest and recovery were lower in FO than in C (1.32 +/- 0.84 vs. 3.70 +/- 0.57 kJ/min, P < 0.02) and fat oxidation for a given plasma NEFA concentration was lower at rest (P < 0.001) and during exercise (P = 0.01) in the formerly obese group. In conclusion, fat mobilization both at rest and during exercise is intact in FO, whereas fat oxidation is subnormal despite higher circulation NEFA levels. The lower resting EE and the failure to use fat as fuel contribute to a positive fat balance and weight gain in FO subjects.
A low resting metabolic rate (RMR) for a given body size and composition is partly genetically determined and has been suggested to be a risk factor for weight gain. Moreover, a low relative RMR has been reported in some, but not all, studies of formerly obese persons. The inconsistent reports may be due to a lack of statistical power to detect small differences in RMR and improper adjustment for body size and composition.
We conducted a meta-analysis based on published studies of RMR in formerly obese persons [body mass index (in kg/m2) < or = 27] and matched control subjects who had never been obese.
We performed both an individual subject data meta-analysis and a traditional meta-analysis.
The individual subject data meta-analysis included 124 formerly obese and 121 control subjects. RMR adjusted for differences in fat-free mass and fat mass was 2.9% lower in formerly obese subjects than in control subjects (P = 0.09). A low relative RMR (> 1 SD below the mean of the control group) was found in 3.3% of the control subjects and in 15.3% of the formerly obese subjects [difference: 12% (95% CI: 4.7%, 19.3%); P < 0.003]. The traditional meta-analysis was based on 12 studies (including 94 formerly obese and 99 control subjects) and included 3 studies not represented in the individual subject data analysis. In this analysis, relative RMR was lower in the formerly obese group than in the control group by 5.1% (95% CI: 1.7%, 8.6%).
Formerly obese subjects had a 3-5% lower mean relative RMR than control subjects; the difference could be explained by a low RMR being more frequent among the formerly obese subjects than among the control subjects. Whether the cause of the low RMR is genetic or acquired, the existence of a low RMR is likely to contribute to the high rate of weight regain in formerly obese persons.
The rapid increase in obesity over the past 2 decades serves as a serious threat to health and quality of life. Data from familial, twin, and adoption studies strongly suggest that genetics contributes to a substantial portion of the variation in body weight and body fatness within a population. Because it is likely substantial changes have occurred in the gene pool over this period, it must be that changes in the environment have increased the susceptibility of obesity in many genetic phenotypes. This article discusses how changes in various environmental factors are contributing toward constant positive energy balance, leading to body weight dysregulation. Efforts aimed at managing obesity should be directed toward modification of the environment.
The global obesity epidemic is being driven in large part by a mismatch between our environment and our metabolism. Human physiology developed to function within an environment where high levels of physical activity were needed in daily life and food was inconsistently available. For most of mankind's history, physical activity has 'pulled' appetite so that the primary challenge to the physiological system for body weight control was to obtain sufficient energy intake to prevent negative energy balance and body energy loss. The current environment is characterized by a situation whereby minimal physical activity is required for daily life and food is abundant, inexpensive, high in energy density and widely available. Within this environment, food intake 'pushes' the system, and the challenge to the control system becomes to increase physical activity sufficiently to prevent positive energy balance. There does not appear to be a strong drive to increase physical activity in response to excess energy intake and there appears to be only a weak adaptive increase in resting energy expenditure in response to excess energy intake. In the modern world, the prevailing environment constitutes a constant background pressure that promotes weight gain. We propose that the modern environment has taken body weight control from an instinctual (unconscious) process to one that requires substantial cognitive effort. In the current environment, people who are not devoting substantial conscious effort to managing body weight are probably gaining weight. It is unlikely that we would be able to build the political will to undo our modern lifestyle, to change the environment back to one in which body weight control again becomes instinctual. In order to combat the growing epidemic we should focus our efforts on providing the knowledge, cognitive skills and incentives for controlling body weight and at the same time begin creating a supportive environment to allow better management of body weight.
Most genetic research in the area of human obesity asks the question 'Why are certain people obese?' Considerably less attention has been paid to the question of why certain people are not obese, particularly given the obesogenic environment that permeates the western culture. We present data from human and animal studies and evolutionary arguments supporting the notion that genetic studies of thinness or obesity resistance may yield important and complementary findings to genetic studies of obesity. We offer strategies for further refining the definition of thinness, weigh the advantages and disadvantages of potential sampling strategies and suggest candidate genes for thinness or obesity resistance.
Acute increases in plasma levels of long-chain fatty acids raise plasma insulin levels by stimulating insulin secretion or by decreasing insulin clearance. In normal subjects, long-term elevations of fatty acids also stimulate insulin secretion. In fact, they increase insulin precisely to the degree needed to compensate for the fatty acid-induced insulin resistance. In contrast, in individuals who are genetically predisposed to develop type 2 diabetes (prediabetic subjects), the free fatty acid (FFA) stimulation of insulin secretion is not sufficient to fully compensate for the FFA-induced insulin resistance. Therefore, obesity, if associated with elevated fatty acid levels, may lead to hyperglycemia in prediabetic but not in normal individuals.
SAS system for mixed modes. Cary (NC)7 SAS Institute Inc
- Rc Littell
Littell RC. SAS system for mixed modes. Cary (NC)7 SAS Institute Inc; 1996. p. 87 -134.
Short-term, mixed-diet overfeeding in man: no evidence for bluxuskonsumptionQ
- Ravussin E Y Schutz
- Acheson
- Kj
Ravussin E, Schutz Y, Acheson KJ, et al. Short-term, mixed-diet overfeeding in man: no evidence for bluxuskonsumptionQ. Am J Physiol 1998;249:E470 -77.
From instinct to intellect: the challenge of maintaining healthy weight in the modern world
- Peters
Obesity: responding to the global epidemic
- Wadden
Influences of glucose loading and of injected insulin on hepatic glucose output
- Steele