Roger H Unger

University of Texas Southwestern Medical Center | UT Southwestern · Division of General Internal Medicine

Significance Both type 1 and type 2 diabetes are associated with reduced β-cell mass or function, resulting from decreased proliferation and increased apoptosis. Understanding the signals governing β-cell survival and regeneration is critical for developing strategies to maintain healthy populations of these cells in individuals. Both forms of diab...

Hyperglucagonemia is a hallmark in obesity and type 2 diabetes (T2DM). Suppression of glucagon signaling improves glycemic control in T2DM. We evaluated glucagon homeostasis in lean and obese mice and people. Discordant with the canonical rise in glucagon with fasting, our studies show that fasting (4, 8, 16 and 24 h) caused a progressive decrease...

The antidiabetic potential of glucagon receptor antagonism presents an opportunity for use in an insulin-centric clinical environment. To investigate the metabolic effects of glucagon receptor antagonism in type 2 diabetes, we treated Leprdb/dband Lepob/obmice with REMD 2.59, a human monoclonal antibody and competitive antagonist of the glucagon re...

Significance Sodium-glucose cotransporter 2 (SGLT2) inhibitors lower blood glucose in humans with diabetes. These drugs inhibit the reabsorption of glucose in the kidney, resulting in its urine excretion. It was reported that SGLT2 inhibitors increase the secretion of glucagon and increase endogenous glucose production by the liver. These effects w...

Glucagon supports glucose homeostasis by stimulating hepatic gluconeogenesis, in part by promoting the uptake and conversion of amino acids into gluconeogenic precursors. Genetic disruption or pharmacologic inhibition of glucagon signaling results in elevated plasma amino acids and compensatory glucagon hypersecretion involving expansion of pancrea...

Glucagon receptor (GcgR) blockade has been proposed as an alternative to insulin monotherapy for treating Type 1 diabetes mellitus since deletion or inhibition of GcgRs corrects hyperglycemia in diabetic models. The factors regulating glycemia in a setting devoid of insulin and glucagon function remain unclear, but may include the hormone ghrelin....

In August 2016, several leaders in glucagon biology gathered for the European Association for the Study of Diabetes Hagedorn Workshop in Oxford, England. A key point of discussion focused around the need for basal insulin to allow for the therapeutic benefit of glucagon blockade in the treatment of diabetes. Among the most enlightening experimental...

Since the discovery of glucagon’s opposing actions to insulin, drugs targeting the inhibition of glucagon action have been pondered. In recent years, several attempts to generate small molecules or antibodies that impair glucagon action have been pursued as potential therapeutics for type 2 diabetes. In the current issue of Diabetes Care , Kazda et...

Mitochondrial metabolism plays an integral role in glucose-stimulated insulin secretion (GSIS) in β-cells. In addition, the diabetogenic role of glucagon released from α-cells plays a major role in the etiology for both type 1 and type 2 diabetes, since un-opposed hyperglucagonemia is a pertinent contributor to diabetic hyperglycaemia. Titrating ex...

Although insulin monotherapy prevents death from ketoacidosis, it does not prevent either the hyperglycemic surges or the hypoglycemic plunges of glucose levels that plague the majority of patients with type 1 diabetes. However significant improvements have occurred with the combination of continuous insulin delivery matched by continuous glucose m...

Glucose homeostasis is primarily controlled by two opposing hormones, insulin and glucagon, and diabetes results when insulin fails to inhibit glucagon action. Recent efforts to control glucagon in diabetes have focused on antagonizing the glucagon receptor, which is effective in lowering blood glucose levels but leads to hyperglucogonemia in roden...

Significance Subcutaneous injections of insulin sustain life in mammals unable to produce insulin (type 1 diabetes) but do not prevent hyperglycemic and hypoglycemic swings or decrease hemoglobin A1c levels to normal amounts. In mice treated with insulin alone, repeated episodes of transient elevated blood glucose cause long-term damage. We show th...

A variety of leptin actions require a re-examination of classic concepts of metabolic diseases. Here we present evidence for two physiologic pathways: a pathway that protects nonadipose tissues from overaccumulation of potentially toxic lipids and unrecognized paracrine interactions between α and β cells revealed by leptin's ability to suppress dia...

AimObese diabetic (ZDF fa/fa) rats with genetic leptin resistance suffer chronic lipotoxicity associated with age-related lung restriction and abnormal alveolar ultrastructure. We hypothesized that these abnormalities impair adaptation to ambient hypoxia.Methods Male fa/fa and lean (+/+) ZDF rats (4-months old) were exposed to 21% or 13% O2 for 3 w...

Significance Diet-induced type 2 diabetes (T2D) is becoming a worldwide epidemic. Patients with T2D fail to respond to insulin normally and have elevated blood glucose and insulin. In autoimmune diabetes, blood glucose is elevated due to uncontrolled glucagon, a hormone normally suppressed and opposed by insulin. To study the role of glucagon in T2...

Recruitment of alveolar microvascular reserves, assessed from the relationship between pulmonary diffusing capacity (DLCO) and perfusion (Q˙c), is critical to maintenance of arterial blood oxygenation. Leptin-resistant ZDF fatty diabetic (fa/fa) rats exhibit restricted cardiopulmonary physiology under anesthesia. To assess alveolar microvascular fu...

Science is marked by the death of dogmas; the discovery that adipocytes are more than just lipid-storing cells but rather produce potent hormones is one such example that caught physiologists by surprise and reshaped our views of metabolism. While we once considered the adipocyte as a passive storage organ for efficient storage of long-term energy...

A new report in this issue of Diabetes provides evidence that at least some metabolic actions of glucagon may be mediated by fibroblast growth factor 21 (FGF21). Habegger et al. (1) report that native glucagon raises plasma FGF21 levels in human subjects, confirming the report by Arafat et al. (2). They also find that a synthetic glucagon receptor...

The biguanides, first discovered as glucose-lowering agents isolated from French lilac (Galega officinalis) plants, are one of the most effective first-line drugs to treat type 2 diabetes. Despite the wide use of the biguanides metformin and phenformin, their mechanism of action has been unclear. In a recent study, Miller et al.(1) describe a new m...

Aims: Insulin is lipogenic and may invoke inflammation. We wished to determine if well controlled human and mice with type 1 diabetes had iatrogenic hyperinsulinemia as an explanation for the increased rate of coronary artery disease (CAD) in type 1 diabetes. Methods: Type 1 diabetic subjects with HbA1C less than 7.0% had plasma insulin measured...

OBJECTIVE To evaluate racial/ethnic differences in pancreatic triglyceride (TG) levels and their relationship to β-cell dysfunction in humans. RESEARCH DESIGN AND METHODS We studied black, Hispanic, and white adults who completed three research visits: screening and an oral glucose tolerance test; frequently sampled intravenous glucose tolerance t...

To determine unambiguously if suppression of glucagon action will eliminate manifestations of diabetes, we expressed glucagon receptors in livers of glucagon receptor-null (GcgR(-/-)) mice before and after β-cell destruction by high-dose streptozotocin. Wild type (WT) mice developed fatal diabetic ketoacidosis after streptozotocin, whereas GcgR(-/-...

The hormone glucagon has long been dismissed as a minor contributor to metabolic disease. Here we propose that glucagon excess, rather than insulin deficiency, is the sine qua non of diabetes. We base this on the following evidence: (a) glucagon increases hepatic glucose and ketone production, catabolic features present in insulin deficiency; (b) h...

To determine whether glucagon suppression by leptin represents a direct effect on α cells rather than an indirect effect mediated via the hypothalamus. We devised an in vitro α-cell suppression assay in cultured hamster InR1G9 cells. InR1G9 hamster cells were infected with adenovirus containing mouse leptin receptors, and they were then incubated w...

The adipokine, leptin, regulates blood glucose and the insulin secretory function of beta cells, while also modulating immune cell function. We hypothesized that the dual effects of leptin may prevent or suppress the autoreactive destruction of beta cells in a virally induced rodent model of type 1 diabetes. Nearly 100% of weanling BBDR rats treate...

To determine the role of glucagon action in the metabolic phenotype of untreated insulin deficiency. We compared pertinent clinical and metabolic parameters in glucagon receptor-null (Gcgr(-/-)) mice and wild-type (Gcgr(+/+)) controls after equivalent destruction of β-cells. We used a double dose of streptozotocin to maximize β-cell destruction. Gc...

The Zucker diabetic fatty (ZDF fa/fa) rat with genetic leptin insensitivity develops obesity and Type 2 diabetes mellitus (T2DM) with age accompanied by hyperplastic changes in the distal lung (Am J Physiol Lung Cell Mol Physiol 298: L392-L403, 2010). To determine the functional consequences of structural changes, we developed a rebreathing (RB) te...

New results have brought to light the importance of the regulation of glucagon by β-cells in the development of diabetes. In this perspective, we examine the normal paracrinology of α- and β-cells in nondiabetic pancreatic islets. We propose a Sherringtonian model of coordinated reciprocal secretory responses of these juxtaposed cells that secrete...

Pulmonary dysfunction develops in type 2 diabetes mellitus (T2DM) in direct correlation with glycemia and is exacerbated by obesity; however, the associated structural derangement has not been quantified. We studied lungs from obese diabetic (fa/fa) male Zucker diabetic fatty (ZDF) rats at 4, 12, and 36 wk of age, before and after onset of T2DM, co...

In nonobese diabetic mice with uncontrolled type 1 diabetes, leptin therapy alone or combined with low-dose insulin reverses the catabolic state through suppression of hyperglucagonemia. Additionally, it mimics the anabolic actions of insulin monotherapy and normalizes hemoglobin A1c with far less glucose variability. We show that leptin therapy, l...

Once considered divine retribution for sins, comorbidities of obesity (metabolic syndrome) are today attributed to obesity-induced metabolic defects. Here, we propose that obesity and hyperleptinemia protect lipid-intolerant nonadipose organs against lipotoxic lipid spillover during sustained caloric surplus. Metabolic syndrome is ascribed to lipot...

The aim of this study was to determine if the fat accumulation in the exocrine pancreas fat of obese Zucker diabetic fatty (ZDF) rodents, like that in their endocrine pancreas, precedes the onset of type 2 diabetes mellitus (T2DM). As the fat content of whole pancreas, but not islets, can now be measured in humans by magnetic resonance spectroscopy...

In the 20th century industrialized nations have become afflicted with an unprecedented pandemic of increased adiposity. In the United States, the epicenter of the epidemic, over 2/3 of the population, is overweight and 1 of every 6 Americans carries the diagnosis of metabolic syndrome. Although genes determine susceptibility to environmental factor...

To validate magnetic resonance spectroscopy (MRS) as a tool for non-invasive quantification of pancreatic triglyceride (TG) content and to measure the pancreatic TG content in a diverse human population with a wide range of body mass index (BMI) and glucose control. To validate the MRS method, we measured TG content in the pancreatic tissue of 12 l...

Obesity is an established risk factor in the pathogenesis of insulin resistance, type 2 diabetes mellitus and cardiovascular disease; all components that are part of the metabolic syndrome. Traditionally, insulin resistance has been defined in a glucocentric perspective. However, elevated systemic levels of fatty acids are now considered significan...

In this issue of PNAS, the laboratory that discovered leptin (1) reports the development of a novel in vivo imaging strategy that permits noninvasive estimation of leptin expression (2). They have engineered a BAC transgenic mouse strain expressing a luciferase reporter gene under the control of adipocyte-specific leptin regulatory sequences. Becau...

Terminally ill insulin-deficient rodents with uncontrolled diabetes due to autoimmune or chemical destruction of β-cells were made hyperleptinemic by adenoviral transfer of the leptin gene. Within ≈10 days their severe hyperglycemia and ketosis were corrected. Despite the lack of insulin, moribund animals resumed linear growth and appeared normal....

Some 50 million Americans carry a diagnosis of metabolic syndrome, a combination of life-shortening disorders including type 2 diabetes (T2D). In both humans and rodents, lipids accumulate in those organs that are most affected in the metabolic syndrome. Ectopic lipid overload may, through the process of lipoapoptosis, disable or destroy normal car...

Glucagon AntibodiesImmunoassay for GlucagonPhysiological Studies in DogsDiscussionSummaryReferencesDiscussion on Glucagon

To determine whether adipocyte storage capacity influences the onset and severity of type 2 diabetes and other components of the metabolic syndrome, we made normal and db/db mice resistant to obesity by overexpressing leptin receptor-b on the aP2-Lepr-b promoter. On a 4% diet, these mice have no phenotype, but on a 60% fat diet, they resist diet-in...

The conventional glucocentric perspective of type 2 diabetes views hyperglycemia as a primary disease caused by an etiologically uncertain combination of obesity-associated insulin resistance and beta cell loss (a disease of glucose metabolism to be treated with antihyperglycemic agents, including high-dose insulin, if necessary). By contrast, the...

Until 60 years ago, fatty heart was an accepted clinical entity. Since then, its very existence has been questioned, despite the fact that 2 of 3 Americans are now obese or overweight and obesity has been shown to be correlated with cardiac functional abnormalities. In 2000, a syndrome of "lipotoxic cardiomyopathy" resembling earlier pathologic des...

The objective of this study was to determine whether the late failure of beta-cells in islets transplanted via the portal vein is caused by excess insulin-stimulated lipogenesis and lipotoxicity and, if so, whether the damage can be prevented by reducing lipogenesis surrounding the islets. Based on the premise that high portal vein levels of nutrie...

The risk of heart failure in type 2 diabetes mellitus is greater than can be accounted for by hypertension and coronary artery disease. Rodent studies indicate that in obesity and type 2 diabetes mellitus, lipid overstorage in cardiac myocytes produces lipotoxic intermediates that cause apoptosis, which leads to heart failure. In humans with diabet...

Intense hyperleptinemia completely depletes adipocyte fat of normal rats within 14 days. To determine the mechanism, epididymal fat pads from normal wild-type (+/+) and obese (fa/fa) Zucker Diabetic Fatty (ZDF) donor rats were transplanted into normal +/+ and fa/fa ZDF recipients. Hyperleptinemia induced by adenovirus-leptin administration depleted...

Alpha-lipoic acid (alpha-LA) mimics the hypothalamic actions of leptin on food intake, energy expenditure, and activation of AMP-activated protein kinase (AMPK). To determine if, like leptin, alpha-LA protects against cardiac lipotoxicity, alpha-LA was fed to transgenic mice with cardiomyocyte-specific overexpression of the acyl CoA synthase (ACS)...

Obesity is a major risk factor for heart disease. In the face of obesity's growing prevalence, it is important for physicians to be aware of emerging research of novel mechanisms through which adiposity adversely affects the heart. Conventional wisdom suggests that either hemodynamic (that is, increased cardiac output and hypertension) or metabolic...

By locally infecting epididymal adipocytes of obese diabetic mice with the uncoupling protein-1 transgene, Yamada et al. (2006[this issue of Cell Metabolism]) unexpectedly induce leptin sensitivity with hypophagia and improvement in abnormal glucose and lipid abnormalities.

Hyperleptinemia rapidly depletes adipocyte fat in lean rats, whereas comparable hyperleptinemia produced by adipocytes in diet-induced obesity does not, implying a leptinergic blockade in adipocytes during overnutrition. Indeed, activated STAT-3 in white adipose tissue (WAT) of normal rats was less on a 60% high fat diet (HFD) than on 4% fat, despi...

In this review, we attempt to deduce teleologically the physiological mission of leptin. Because overnutrition and diet-induced obesity are the only known causes of hyperleptinemia, we contrast the differences in overnutrition in normally leptinized rodents, in which the added lipids are confined to adipocytes, with those of unleptinized rodents, i...

In this review, we propose that actions of the lipid-lowering, apoptosis-inhibiting effects of certain "longevity genes" oppose the life-shortening consequences of lipotoxicity and lipoapoptosis. We note that lipotoxicity occurs whenever leptin action is deficient, or whenever satiety is overridden, as in forced or voluntary overfeeding ("supersizi...

In obese rodents, excess myocardial lipid accumulation (lipotoxicity) of myocardium may cause cardiomyopathy that in the obese Zucker diabetic fatty (ZDF) fa/fa rat can be prevented by treatment with troglitazone (TGZ). To determine the underlying mechanisms, we measured total 5'-AMP-activated kinase (AMPK) protein and its activated, phosphorylated...

Leptin has been shown to activate AMP-activated protein kinase (AMPK), an enzyme that regulates the activities of key enzymes of lipid synthesis and metabolism. We assess here (i) whether AMPK activity is diminished in rodents deficient in leptin or the leptin receptor, and (ii) the effects of treating the diabetes-prone, leptin-receptor-deficient...

Fatty acids flow from adipocytes to nonadipose tissues during fasting and exercise and normally are fully oxidized. To determine if nonadipose tissues can export unoxidized FA when FA influx exceeds oxidation, neonatal cardiomyocytes were cultured in 1 μCi ¹⁴C-palmitate in the presence of etomoxir to block oxidation. The cells took up and stored 25...

Sustained hyperleptinemia induced in normal rats causes the rapid disappearance of body fat. This is attributed to a marked increase in uncoupled fatty acid oxidation in the white adipocytes, which also occurs in hyperthyroidism. Because hyperleptinemic rats have normal plasma T3 or T4 levels, we tested the possibility of "localized hyperthyroidism...

The physiologic function of the progressive hyperleptinemia of diet-induced obesity is unknown. However, that lipotoxicity in nonadipose tissues of congenitally unleptinized obese rodents is far greater than in hyperleptinemic diet-induced obesity rodents has suggested an antilipotoxic role. To test this hypothesis, mice with severe lipotoxic cardi...

Hyperlipidemia appears to play an integral role in loss of glucose-stimulated insulin secretion (GSIS) in type 2 diabetes. This impairment can be simulated in vitro by chronic culture of 832/13 insulinoma cells with high concentrations of free fatty acids, or by study of lipid-laden islets from Zucker diabetic fatty rats. Here we show that impaired...

To determine whether the antilipogenic actions of insulin-induced gene 1 (insig-1) demonstrated in cultured preadipocytes also occur in vivo, we infected Zucker diabetic fatty (ZDF) (fa/fa) rats, with recombinant adenovirus containing insig-1 or -2 cDNA. An increase of both proteins appeared in their livers. In control ZDF (fa/fa) rats infected wit...

New evidence suggests that leptin and other anorexigenic agents reduce appetite by inactivating hypothalamic AMP-activated protein kinase (AMPK), thereby increasing malonyl CoA levels. This preview examines AMP biology and its role in malonyl-CoA generation and attempts to integrate its central actions with its peripheral antilipotoxic actions with...

Adenovirus-induced hyperleptinemia rapidly depletes body fat in normal rats without increasing free fatty acids and ketogenesis, implying that fat-storing adipocytes are oxidizing the fat. To analyze the ultrastructural changes of adipocytes accompanying this functional transformation, we examined the fat tissue by electron microscopy. After 14 day...

To determine if increased local production of glucocorticoids by the pancreatic islets might play a role in the spontaneous noninsulin-dependent diabetes mellitus of obesity, we compared islet 11beta-HSD-1 mRNA and activity in islets of obese prediabetic and diabetic Zucker Diabetic Fatty (ZDF) (fa/fa) rats and lean wild-type (+/+) controls. In dia...

The obesity crisis in the United States has been associated with an alarming increase in the prevalence of the metabolic syndrome (MSX) disease cluster. Here we review evidence that the MSX reflects a failure of a system of intracellular lipid homeostasis that prevents lipotoxicity in the organs of overnourished individuals by confining the lipid o...

Approximately two-thirds of the US population are overweight, which means that insulin resistance is probably the most common metabolic abnormality in the USA. I propose three novel concepts concerning the causes and consequences of insulin resistance that challenge current thinking. First, there is the evidence that resistance to insulin-stimulate...

The metabolic syndrome in association with obesity is a major clinical problem inducing hypertension, diabetes mellitus, and atherosclerosis. Leptin induces angiogenesis by its proliferative effects on endothelial cells (ECs) via OB receptor (OB-Rb) gene. We evaluated the growth of ECs and intracellular signalings in response to leptin in vitro and...

We have examined gene expression in the fat tissue of normal mice at the onset of diet-induced obesity. Insulin-induced gene 1 (insig-1) mRNA rose progressively with a high-fat diet and declined on a restricted diet. Because insig-1 binds sterol regulatory element-binding protein cleavage-activating protein in the endoplasmic reticulum, thereby blo...

Recent experimental data suggest that adiposity directly damages the heart by promoting ectopic deposition of triglyceride, a process known as myocardial steatosis. The goal of this study was to develop and validate proton magnetic resonance spectroscopy ((1)H MRS) as an in vivo tool to measure myocardial lipid content. Complementary studies in rat...

Here we explore the physiologic role of leptin as a liporegulatory hormone responsible for maintaining intracellular homeostasis in the face of wide variations in caloric intake. Normally, rats can tolerate a 60% fat diet because 96% of the surplus fat is deposited in adipocytes. In contrast, when leptin is congenitally absent or inactive, even on...

The balance between cell division and cell death determines the cell population of an organ. When cell death exceeds cell replacement in an organ, a functional deficit is created. A metabolic cause of programmed cell death, lipoapoptosis, has recently been identified to occur in obesity and aging. If nonadipose tissues are exposed to an excess of l...

Leptin, troglitazone, and high fat feeding profoundly influence the lipid content of various tissues. To determine if they affect the expression of stearoyl CoA desaturase (SCD)-1 and -2, their mRNA was measured in livers of normal, hyperleptinemic, troglitazone-treated, and fat-fed rats. Hyperleptinemia, which reduces tissue TG by downregulating l...

Adenovirus-induced hyperleptinemia causes rapid disappearance of body fat in normal rats, presumably by up-regulating fatty acid oxidation within white adipocytes. To determine the role of peroxisomal proliferation-activated receptor (PPAR)alpha expression, which was increased during the rapid loss of fat, we infused adenovirus-leptin into PPAR alp...

Morbid obesity is the result of massive expansion of white adipose tissue (WAT) and requires recruitment of adipocyte precursor cells and their supporting infrastructure. To characterize the change in the expression profile of the preexisting WAT at the start of obesity, when adipocyte hypertrophy is present but hyperplasia is still minimal, we emp...

Indirect evidence implicates leptin resistance in the pathogenesis of the lipotoxicity that complicates obesity and results in the metabolic syndrome. In this issue of Developmental Cell, two groups identify protein tyrosine phosphatase 1B (PTP1B) as a cause of leptin resistance through dephosphorylation of Jak2.

Am J Hypertens (2002) 15, 190A–190A; doi:10.1016/S0895-7061(02)02787-5 P-436: Fatty heart disease - myocardial steatosis in humans Lidia S. Szczepaniak1, Robert L. Dobbins1, Gregory J. Metzker1, Greta S. D'Ambrosia1, Debbie Arbique1, Wanpen Vongpatanasin1, Roger Unger1, Ronald G. Victor1 and Donald W. Reynolds11Cardiovascular Clinical Research Cen...

Dietary human obesity indirectly contributes to heart disease by increasing plasma lipids and predisposing to diabetes and hypertension. Recent work in a rodent model of genetic obesity has advanced the novel hypothesis that, in addition to this conventional thinking, obesity per se also constitutes a direct cause of left ventricular dysfunction by...

I review evidence that leptin is a liporegulatory hormone that controls lipid homeostasis in nonadipose tissues during periods of overnutrition. When adipocytes store excess calories as triacylglycerol (TG), leptin secretion rises so as to prevent accumulation of lipids in nonadipose tissues, which are not adapted for TG storage. Whenever leptin ac...

A recently identified function of leptin is to protect nonadipose tissues from the nonoxidative metabolic products of long-chain fatty acids (FAs) during periods of overnutrition by increasing the beta-oxidative metabolism of surplus FAs and reducing lipogenesis. When this protective system fails, harmful products of nonoxidative metabolism such as...

Obesity-related diseases now threaten to reach epidemic proportions in the United States. Here we review in a rodent model of genetic obesity, the fa/fa Zucker diabetic fatty (ZDF) rat, the mechanisms involved in the most common complications of diet-induced human obesity, i.e., noninsulin-dependent diabetes mellitus, and myocardial dysfunction. In...

To test the hypothesis that the physiologic liporegulatory role of hyperleptinemia is to prevent steatosis during caloric excess, we induced obesity by feeding normal Harlan Sprague-Dawley rats a 60% fat diet. Hyperleptinemia began within 24 h and increased progressively to 26 ng/ml after 10 weeks, correlating with an approximately 150-fold increas...

To test the hypothesis that the physiologic liporegulatory role of hyperleptinemia is to prevent steatosis during caloric excess, we induced obesity by feeding normal Harlan Sprague-Dawley rats a 60% fat diet. Hyperleptinemia began within 24 h and increased progressively to 26 ng/ml after 10 weeks, correlating with an ∼150-fold increase in body fat...

Leptin resistance has been implicated in the pathogenesis of obesity-related complications involving abnormalities of lipid metabolism that resemble those of old age. To determine whether development of leptin resistance in advancing age might account for such abnormalities, we compared the effects of hyperleptinemia (>40 ng/ml) induced in 2-month-...

In normal rats, adenovirus-induced hyperleptinemia causes disappearance of visible body fat, downregulation of lipogenic enzymes, and upregulation of oxidative enzymes and thermogenic proteins. In addition, preadipocyte markers replace mature adipocyte markers, suggesting dedifferentiation. In weight loss induced by caloric restriction, by contrast...

It is proposed that an important function of leptin is to confine the storage of triglycerides (TG) to the adipocytes, while limiting TG storage in nonadipocytes. Excess TG deposition in nonadipocytes leads to impairment of functions, increased ceramide formation, which triggers nitric oxide-mediated lipotoxicity and lipoapoptosis. The fact that TG...

Peroxisome proliferator-activated receptor-gamma coactivator-1 (PGC-1), a cold-induced protein expressed in brown adipose tissue (BAT), plays a role in adaptive thermogenesis by up-regulating uncoupling proteins (UCP). Here, we explore its relationship to the thermogenic actions of leptin, which also up-regulates UCPs. We find that PGC-1 messenger...

Liver-derived hyperleptinemia induced in normal rats by adenovirus-induced gene transfer causes rapid disappearance of body fat, whereas the endogenous adipocyte-derived hyperleptinemia of obesity does not. Here we induce liver-derived hyperleptinemia in rats with adipocyte-derived hyperleptinemia of acquired obesity caused by ventromedial hypothal...

It is widely believed that the primary physiologic role of leptin is to prevent obesity by regulating food intake and thermogenesis through actions on hypothalamic centers. Here we sugest that the first premise, the anti-obesity role, is untenable, and present evidence for an alternative physiologic role, namely antisteatotic activity in which fatt...