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Relationship between WAT lipolysis and de novo lipogenesis. (A) Up-regulation of glucose transporter 4 and de novo lipogenesis-related pathways. Induction of gene expression (red boxes) in hMADS adipocytes with HSL gene silencing were determined by DNA microarray analysis and validated by reverse transcription-quantitative PCR (indicated by *). (B) Up-regulation of glucose transporter 4 and de novo lipogenesis-related pathway gene expression in hMADS adipocytes. mRNA levels were determined by reverse transcription-quantitative PCR (n = 9–12). ** p<0.01 versus siGFP. (C) Correlations between glucose transporter 4, carbohydrate responsive element-binding protein, and fatty acid synthase mRNA levels and, lipolysis in human WAT (n = 45). (D) Up-regulation of glucose transporter 4 and de novo lipogenesis-related pathway gene expression in adipocytes from obese individuals treated with placebo or nicotinic acid (n = 12 per group). * p<0.05, ** p<0.01 versus before treatment. ACC, acetylCoA carboxylase; ACL, ATP citrate lyase; ACS, acetyl-CoA synthase; ChREBP, carbohydrate responsive element-binding protein; DCT, dicarboxylate transporter; FAE, fatty acid elongase; FAS, fatty acid synthase; GPDH, glycerol-3-phosphate dehydrogenase; GLUT4, glucose transporter 4; G6PDH, glucose-6-phosphate dehydrogenase; LDH, lactate dehydrogenase; MDH, malate dehydrogenase; ME, malic enzyme; PC, pyruvate carboxylase; PDH, pyruvate dehydrogenase; PK, pyruvate kinase; SCD, stearoylCoA desaturase.
Source publication
When energy is needed, white adipose tissue (WAT) provides fatty acids (FAs) for use in peripheral tissues via stimulation of fat cell lipolysis. FAs have been postulated to play a critical role in the development of obesity-induced insulin resistance, a major risk factor for diabetes and cardiovascular disease. However, whether and how chronic inh...
Citations
... Insulin inhibits glucagon secretion and suppresses endogenous glucose production. Additionally, insulin influences adipose tissue metabolism by suppressing lipolysis and promoting glucose uptake [12][13][14]. Insulin also contributes to maintaining skeletal muscle mass by suppressing intramuscular protein breakdown rates. It stimulates vasodilation in arterial smooth muscle, enhancing blood flow, and the delivery of insulin and glucose to muscle cells [15][16][17]. ...
Diabetes, particularly type 2 diabetes (T2D), is the main component of metabolic syndrome. It is highly prevalent and has drastically increased with sedentary lifestyles, notably behaviors linked to ease of access and minimal physical activity. Central to this condition is insulin, which plays a pivotal role in regulating glucose levels in the body by aiding glucose uptake and storage in cells, and what happens to diabetes? In diabetes, there is a disruption and malfunction in insulin regulation. Despite numerous efforts, effectively addressing diabetes remains a challenge. This article explores the potential of photoactivatable drugs in diabetes treatment, with a focus on light-activated insulin. We discuss its advantages and significant implications. This article is expected to enrich the existing literature substantially, offering a comprehensive analysis of potential strategies for improving diabetes management. With its minimal physical intrusion, light-activated insulin promises to improve patient comfort and treatment adherence. It offers precise regulation and localized impact, potentially mitigating the risks associated with conventional diabetes treatments. Additionally, light-activated insulin is capable of explicitly targeting RNA and epigenetic factors. This innovative approach may pave the way for more personalized and effective diabetes treatments, addressing not only the symptoms but also the underlying biological causes of the disease. The advancement of light-activated insulin could revolutionize diabetes management. This study represents a pioneering introduction to this novel modality for diabetes management.
... Dysfunctional white adipocyte lipolysis links to insulin resistance, obesity, and related disorders such as type 2 diabetes (T2D), dyslipidemia, and metabolic dysfunction-associated steatotic liver disease (MASLD, formerly NAFLD) (2)(3)(4). Elevated unstimulated lipolysis during obesity leads to increased FFA levels (2,3), peripheral insulin resistance, lipotoxicity, and ectopic fat accumulation, particularly in the liver (5)(6)(7). Therefore, identifying drug targets to improve adipocyte metabolic function is crucial for preventing obesity-related metabolic disorders. ...
Excessive lipolysis in white adipose tissues (WAT) leads to insulin resistance (IR) and ectopic fat accumulation in insulin-sensitive tissues. However, the impact of Gi-coupled receptors in restraining adipocyte lipolysis through inhibition of cAMP production remained poorly elucidated. Given that the Gi-coupled P2Y13 receptor (P2Y13-R) is a purinergic receptor expressed in WAT, we investigated its role in adipocyte lipolysis and its effect on IR and metabolic dysfunction-associated steatotic liver disease (MASLD). In human, mRNA expression of P2Y13-R in WAT was negatively correlated to adipocytes lipolysis. In mice, adipocytes lacking P2Y13-R displayed higher intracellular cAMP levels, indicating impaired Gi signaling. Consistently, the absence of P2Y13-R was linked to increased lipolysis in adipocytes and WAT explants via hormone-sensitive lipase activation. Metabolic studies indicate that mice lacking P2Y13-R show a greater susceptibility to diet-induced IR, systemic inflammation, and MASLD compared to their wild-type counterparts. Assays conducted on precision-cut liver slices exposed to WAT conditioned medium and on liver-specific P2Y13-R knockdown mice suggested that P2Y13-R activity in WAT protects from hepatic steatosis, independently of liver P2Y13-R expression. In conclusion, our findings support the idea that targeting adipose P2Y13-R activity may represent a pharmacological strategy to prevent obesity-associated disorders, including type 2 diabetes and MASLD.
... As a decrease in lipolysis is associated with enhanced insulin sensitivity (25), the lactate-induced reduction in lipolysis could theoretically improve insulin sensitivity. We used [3-3 H] glucose and a hyperinsulinemic-euglycemic clamp to investigate insulin sensitivity and glucose metabolism. ...
Background: Lactate may inhibit lipolysis and thus enhance insulin sensitivity, but there is a lack of metabolic human studies. This study aimed to determine how hyperlactatemia affects lipolysis, glucose- and protein metabolism, and insulin sensitivity in healthy men. Methods: In a single-blind, randomized, cross-over design, eight healthy men were studied after an overnight fast on two occasions: 1) during a sodium-lactate infusion (LAC) and 2) during a sodium-matched NaCl infusion (CTR). Both days consisted of a 3-hour postabsorptive period followed by a 3-hour hyperinsulinemic-euglycemic clamp (HEC). Lipolysis rate, endogenous glucose production (EGP), and delta glucose rate of disappearance (ΔRd glu ) were evaluated using [9,10- ³ H]palmitate and [3- ³ H]glucose tracers. In addition, whole-body- and forearm protein metabolism was assessed using [ ¹⁵ N]phenylalanine, [ ² H 4 ]tyrosine, [ ¹⁵ N]tyrosine, and [ ¹³ C]urea tracers. Results: In the postabsorptive period, plasma lactate increased to 2.7±0.5 mmol/L during LAC vs. 0.6±0.3 mmol/L during CTR (p<0.001). In the postabsorptive period, palmitate flux was 30% lower during LAC compared to CTR (84±32 mmol/min vs. 120±35 mmol/min, p=0.003). During the HEC, palmitate flux was suppressed similarly during both interventions (p=0.7). EGP, ΔRd glu , and M-value were similar during LAC and CTR. During HEC, LAC increased whole-body phenylalanine flux (p=0.02) and protein synthesis (p=0.03) compared with CTR; LAC did not affect forearm protein metabolism compared to CTR. Conclusion: Lactate infusion inhibited lipolysis by 30% under postabsorptive conditions but did not affect glucose metabolism or improve insulin sensitivity. In addition, whole-body phenylalanine flux was increased. Clinical trial registrations: NCT04710875
... Besides resilience to diet-induced obesity, HFD-exposed HSL−/− mice were partially protected to HFD-induced impairments in glucose tolerance. However, we did not observe the improvement in glucose tolerance that has previously been reported for haplo-insufficient HSL mice (Girousse et al., 2013). Again, differences in age, extent of back crossing, as well as diets (different fat content) and extent of fasting before experiments could explain this discrepancy. ...
Hormone‐sensitive lipase (HSL) is active throughout the brain and its genetic ablation impacts brain function. Its activity in the brain was proposed to regulate bioactive lipid availability, namely eicosanoids that are inflammatory mediators and regulate cerebral blood flow (CBF). We aimed at testing whether HSL deletion increases susceptibility to neuroinflammation and impaired brain perfusion upon diet‐induced obesity. HSL−/−, HSL+/−, and HSL+/+ mice of either sex were fed high‐fat diet (HFD) or control diet for 8 weeks, and then assessed in behavior tests (object recognition, open field, and elevated plus maze), metabolic tests (insulin and glucose tolerance tests and indirect calorimetry in metabolic cages), and CBF determination by arterial spin labeling (ASL) magnetic resonance imaging (MRI). Immunofluorescence microscopy was used to determine coverage of blood vessels, and morphology of astrocytes and microglia in brain slices. HSL deletion reduced CBF, most prominently in cortex and hippocampus, while HFD feeding only lowered CBF in the hippocampus of wild‐type mice. CBF was positively correlated with lectin‐stained vessel density. HSL deletion did not exacerbate HFD‐induced microgliosis in the hippocampus and hypothalamus. HSL−/− mice showed preserved memory performance when compared to wild‐type mice, and HSL deletion did not significantly aggravate HFD‐induced memory impairment in object recognition tests. In contrast, HSL deletion conferred protection against HFD‐induced obesity, glucose intolerance, and insulin resistance. Altogether, this study points to distinct roles of HSL in periphery and brain during diet‐induced obesity. While HSL−/− mice were protected against metabolic syndrome development, HSL deletion reduced brain perfusion without leading to aggravated HFD‐induced neuroinflammation and memory dysfunction. image
... This is likely, at least in part, to explain the observed reduction in FFA after metformin treatment. Noteworthily, a partial inhibition of lipolysis in adipocytes may improve insulin sensitivity (56). The improvement of insulin sensitivity is considered a consequence of the changes induced by metformin in lipid metabolism (19). ...
Background
Metformin is a drug with a long history of providing benefits in diabetes management and beyond. The mechanisms of action of metformin are complex, and continue to be actively debated and investigated. The aim of this study is to identify metabolic signatures associated with metformin treatment, which may explain the pleiotropic mechanisms by which metformin works, and could lead to an improved treatment and expanded use.
Methods
This is a cross-sectional study, in which clinical and metabolomic data for 146 patients with type 2 diabetes were retrieved from Qatar Biobank. Patients were categorized into: Metformin-treated, treatment naïve, and non-metformin treated. Orthogonal partial least square discriminate analysis and linear models were used to analyze differences in the level of metabolites between the metformin treated group with each of the other two groups.
Results
Patients on metformin therapy showed, among other metabolites, a significant increase in 3-hydroxyoctanoate and 3-hydroxydecanoate, which may have substantial effects on metabolism.
Conclusions
This is the first study to report an association between 3-hydroxy medium chain fatty acids with metformin therapy in patients with type 2 diabetes. This opens up new directions towards repurposing metformin by comprehensively understanding the role of these metabolites.
... Age-related increases in disease incidence and metabolic decline are linked to insulin resistance (IR), a core mechanism of metabolic syndrome contributing to cardiovascular events [28,29]. IR was a significant risk factor for CVDs, linking obesity with type 2 diabetes and CVDs [30]. IR is a significant contributor to the development of diabetes, promoting pathological changes like accelerated atherosclerosis, which is essential in CVD development [31,32]. ...
Background
The triglyceride-glucose (TyG) index is regarded as a sophisticated surrogate biomarker for insulin resistance, offering a refined means for evaluating cardiovascular diseases (CVDs). However, prospective cohort studies have not simultaneously conducted baseline and multi-timepoint trajectory assessments of the TyG index in relation to CVDs and their subtypes in elderly participants.
Methods
After excluding data deficiencies and conditions that could influence the research outcomes, this study ultimately incorporated a cohort of 20,185 participants, with data chronicles extending from 2016 to 2022. The TyG index was calculated as Ln [fasting triglyceride (mg/dL) × fasting glucose (mg/dL)/2]. Latent Class Trajectory Model (LCTM) was used to assess the change trends of the TyG index over multiple time points. Utilizing the Cox proportional-hazards models, we assessed the relationship between the baseline quartiles of the TyG index and various trajectories with CVDs and subtypes.
Results
During the mean follow-up time of 4.25 years, 11,099 patients experienced new CVDs in the elderly population. After stratifying by baseline TyG quartiles, the higher TyG level was associated with an increased risk of CVDs; the aHR and 95% CI for the highest quartile group were 1.28 (1.19–1.39). Five trajectory patterns were identified by the LCTM model. The low gradual increase group as the reference, the medium stable group, and the high gradual increase group exhibited an elevated risk of CVDs onset, aHR and 95%CIs were 1.17 (1.10–1.25) and 1.25 (1.15–1.35). Similar results were observed between the trajectories of the TyG index with subtypes of CVDs.
Conclusion
Participants with high levels of baseline TyG index and medium stable or high gradual increase trajectories were associated with an elevated risk of developing CVDs in elderly populations.
... Антиліполітичний ефект ацетату може бути спричинений зниженням фосфорилювання гормончутливої ліпази [1,26]. Отримано комбіновані дані (від гризунів і людей), які свідчать, що часткове пригнічення внутрішньоклітинного ліполізу позитивно впливає на чутливість до інсуліну без впливу на масу жирової тканини в довгостроковій перспективі [21]. Наприклад, ректальне введення сумішей КЛЖК із високим вмістом ацетату знижує концентрацію циркулюючого гліцерину [5]. ...
The article highlights the research data on the role of saccharolytic and proteolytic fermentation products in the pathogenetic mechanisms of the development of metabolically associated diseases. A brief description of the composition, number and function of the normal intestinal microbiome is given. Data on the peculiarities of saccharolytic and proteolytic fermentation in the intestines are given. The role of the gut microbiota in the formation of such metabolically associated diseases as obesity, type 2 diabetes mellitus and non‑alcoholic fatty liver disease has also been described. The influence of short‑chain fatty acids, namely propionate, succinate and butyrate, in regulating the metabolism and secretion of insulin, leptin, as well as satiety hormones, namely glucagon‑like peptide 1 and peptide YY, is given in detail. The effects of proteolytic fermentation products on the metabolism and functioning of the intestine‑liver axis, as well as on the processes of carbohydrate metabolism, are carefully described. Descriptions of the effects of protein fermentation products of intestinal microbiota on intestinal pro‑inflammatory reactions and the progression of non‑alcoholic fatty liver disease are provided. The combined data, obtained from rodent and human investigations, regarding effects of short‑chain fatty acids on adipose tissue metabolism. In particular, the ability of acetate to inhibit intracellular lipolysis in adipocytes has been proven. The effects of essential short‑chain fatty acids on intestinal permeability are also described. The most important role of short‑chain fatty acids in the development of inflammatory processes, in particular low‑grade inflammation characteristic of metabolically associated diseases, is emphasized. The data have been presented from investigations of the role of acetate, butyrate and propionate in non‑alcoholic fatty liver disease and type 2 diabetes mellitus.
... This is supported by experimental data showing an acute infusion of exogenous NEFA into circulation causes transient insulin resistance in humans [45]. The relationship between obesity associated increases in plasma NEFA and insulin resistance is further supported by human longitudinal studies [46]. In human obesity, there is a significant correlation between increased adipocyte lipolysis and reduced insulin sensitivity. ...
... Further, in morbidly obese patients undergoing bariatric surgery the change in adipose explant lipolysis pre-vs. post-surgery directly correlated with insulin sensitivity such that patients with the greatest reduction in explant lipolysis showed the strongest improvements in insulin sensitivity [46]. These data support the hypothesis that disruption of Activin E signaling by genetic ablation of Inhbe increases adipose lipolysis, leading to an increase in circulating NEFA, which contributes directly to insulin resistance in these mice. ...
Objective
The liver is a central regulator of energy metabolism exerting its influence both through intrinsic processing of substrates such as glucose and fatty acid as well as by secreting endocrine factors, known as hepatokines, which influence metabolism in peripheral tissues. Human genome wide association studies indicate that a predicted loss-of-function variant in the Inhibin βE gene (INHBE), encoding the putative hepatokine Activin E, is associated with reduced abdominal fat mass and cardiometabolic disease risk. However, the regulation of hepatic Activin E and the influence of Activin E on adiposity and metabolic disease are not well understood. Here, we examine the relationship between hepatic Activin E and adipose metabolism, testing the hypothesis that Activin E functions as part of a liver-adipose, inter-organ feedback loop to suppress adipose tissue lipolysis in response to elevated serum fatty acids and hepatic fatty acid exposure.
Methods
The relationship between hepatic Activin E and non-esterified fatty acids (NEFA) released from adipose lipolysis was assessed in vivo using fasted CL 316,243 treated mice and in vitro using Huh7 hepatocytes treated with fatty acids. The influence of Activin E on adipose lipolysis was examined using a combination of Inhbe knockout mice, a mouse model of hepatocyte-specific overexpression of Activin E, and mouse brown adipocytes treated with Activin E enriched media.
Results
Increasing hepatocyte NEFA exposure in vivo by inducing adipose lipolysis through fasting or CL 316,243 treatment increased hepatic Inhbe expression. Similarly, incubation of Huh7 human hepatocytes with fatty acids increased expression of INHBE. Genetic ablation of Inhbe in mice increased fasting circulating NEFA and hepatic triglyceride accumulation. Treatment of mouse brown adipocytes with Activin E conditioned media and overexpression of Activin E in mice suppressed adipose lipolysis and reduced serum FFA levels, respectively. The suppressive effects of Activin E on lipolysis were lost in CRISPR-mediated ALK7 deficient cells and ALK7 kinase deficient mice. Disruption of the Activin E-ALK7 signaling axis in Inhbe KO mice reduced adiposity upon HFD feeding, but caused hepatic steatosis and insulin resistance.
Conclusions
Taken together, our data suggest that Activin E functions as part of a liver-adipose feedback loop, such that in response to increased serum free fatty acids and elevated hepatic triglyceride, Activin E is released from hepatocytes and signals in adipose through ALK7 to suppress lipolysis, thereby reducing free fatty acid efflux to the liver and preventing excessive hepatic lipid accumulation. We find that disrupting this Activin E-ALK7 inter-organ communication network by ablation of Inhbe in mice increases lipolysis and reduces adiposity, but results in elevated hepatic triglyceride and impaired insulin sensitivity. These results highlight the liver-adipose, Activin E-ALK7 signaling axis as a critical regulator of metabolic homeostasis.
... Under normal circumstances, skeletal muscle accounts for approximately 80% of insulin-stimulated systemic glucose uptake and disposal. Insulin resistance (IR) in skeletal muscle, which manifests as abnormal glucose metabolism and metabolic syndrome, is the primary pathology of T2D (Girousse et al., 2013;Petersen et al., 2007). Therefore, improving IR is critical for combating systemic insulin resistance and T2D (Lorenzo et al., 2008). ...
... As an extract of DA, previous studies have shown that AVI not only has bone-strengthening effects but also has the potential to improve skeletal muscle function. Moreover, recent scientific experiments have demonstrated that AVI can reduce steatosis and fat accumulation in the liver (Gong et al., 2018), suggesting that AVI may improve insulin resistance in skeletal muscle by regulating glucose and lipid metabolism. ...
Ethnopharmacological relevance:
Dipsacus asper Wall. Ex C.B. Clarke (DA), a perennial herb, is one of the most commonly used herbs in Traditional Chinese Medicine for strengthening muscles and bones and regulating blood vessels. Akebia saponin D (ASD/AVI) is a triterpenoid saponin extracted from the root of DA, which has favorable pharmacological properties such as anti-osteoporosis, anti-apoptosis, liver protection and hypolipidemic.
Aim of the study:
To explore the underlying mechanisms and regulatory role of Akebia saponin D (ASD/AVI) on high-fat diet-induced insulin resistance in skeletal muscle.
Materials and methods:
C2C12 cells were used to explore the best concentration in the skeletal muscle insulin resistance model in an in vitro experiment. The protective effect of AVI on insulin resistance and the corresponding signaling pathway were detected by glucose content measurement, quantitative PCR, and Western blot. A high-fat diet STZ-induced insulin resistance mice model was used to evaluate the protective function of AVI in vivo. After four weeks of treatment, ITT, OGTT, and treadmill tests were applied to examine insulin sensitivity and their serum and skeletal muscle tissues were collected for further analysis.
Results:
AVI effectively reduced body weight, blood glucose levels and calorie intake in insulin-resistant mice, and reduced lipid accumulation and in their muscle tissue. AVI also improved glucose uptake and insulin sensitivity in both in vivo and in vitro experiments. Following AVI administration, there was an increase in the expression of the AMPK signaling pathway. Our experiments further confirmed that AVI specifically targets the IGF1R, thereby more effectively regulating the insulin signaling pathway.
Conclusion:
AVI improves type 2 diabetes-induced insulin resistance in skeletal muscle by activating the IGF1R-AMPK signaling pathway, promoting glucose uptake and energy metabolism in IR.
... On the other hand, PPARγ binds to peroxisome proliferator response element (PPRE) in the promoter regions of the target genes involved in glucose and lipid metabolism, and activates their expression [23]. In this way, the activation of PPARγ can regulate lipid metabolism-related genes, including HSL and ATGL, which can affect lipid breakdown and adipocyte differentiation [24]. Similarly, the binding of PPARγ to insulin receptor substrate 1 (IRS1) [25] and glucose transporters (GLUT) 1 and 4 may repress the activity of IRS1 [25] and GLUTs 1 and 4 [26], thereby causing an imbalance in glucose homeostasis by increasing the uptake of glucose. ...
Obesity is known as a transgenerational vicious cycle and has become a global burden due to its unavoidable complications. Modern approaches to obesity management often involve the use of pharmaceutical drugs and surgeries that have been associated with negative side effects. In contrast, natural antioxidants, such as flavonoids, have emerged as a promising alternative due to their potential health benefits and minimal side effects. Thus, this narrative review explores the potential protective role of flavonoids as a natural antioxidant in managing obesity. To identify recent in vivo studies on the efficiency of flavonoids in managing obesity, a comprehensive search was conducted on Wiley Online Library, Scopus, Nature, and ScienceDirect. The search was limited to the past 10 years; from the search, we identified 31 articles to be further reviewed. Based on the reviewed articles, we concluded that flavonoids offer novel therapeutic strategies for preventing obesity and its associated co-morbidities. This is because the appropriate dosage of flavonoid compounds is able to reduce adipose tissue mass, the formation of intracellular free radicals, enhance endogenous antioxidant defences, modulate the redox balance, and reduce inflammatory signalling pathways. Thus, this review provides an insight into the domain of a natural product therapeutic approach for managing obesity and recapitulates the transgenerational inheritance of obesity, the current available treatments to manage obesity and its side effects, flavonoids and their sources, the molecular mechanism involved, the modulation of gut microbiota in obesity, redox balance, and the bioavailability of flavonoids. In toto, although flavonoids show promising positive outcome in managing obesity, a more comprehensive understanding of the molecular mechanisms responsible for the advantageous impacts of flavonoids—achieved through translation to clinical trials—would provide a novel approach to inculcating flavonoids in managing obesity in the future as this review is limited to animal studies.
