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Exendin-4 enhances lipolytic and oxidative pathways with SIRT1 activation in vitro. Differentiated 3T3-L1 adipocytes were exposed to exendin-4 (1 nmol/l, 20 nmol/l and 100 nmol/l) for 24 h. (a) Immunoblotting analysis of SIRT1 and signalling proteins involved in lipid metabolism. (b) The expression, relative to β-tubulin, of SIRT1 and ATGL, p-AMPK to AMPK, and p-ACC to ACC. (c) Immunoblotting analysis of oxidative signals and (d) the expression of PPARα, PGC-1α and UCP-1 relative to β-tubulin. (e) Intracellular NAD⁺ level and (f) NAD⁺/NADH ratio. Values are mean ± SEM. *p < 0.05 and **p < 0.01 compared with the controls; ††p < 0.01 compared with mice receiving exendin-4, 1 nmol/l. Ctrl, control; Exe-4, exendin-4; NC, normal control
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Aims/hypothesis:
Accumulating evidence has revealed the significant role of glucagon-like peptide-1 (GLP-1) in weight loss. Sirtuin 1 (SIRT1) plays a vital role in the regulation of lipid metabolism. Here, we investigated the contribution of lipolytic and oxidative changes in white adipose tissue (WAT) to the weight-lowering effect induced by the...
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Obesity has been recognized as a low-grade, chronic inflammatory disease that leads to an increase in obesity-associated disorders, including type 2 diabetes (T2D), fatty liver diseases and cancer. Glucagon-like peptide-1 (GLP-1) is an effective drug for T2D, and it not only has glucose-regulating effects but also has anti-inflammatory effects in o...
The hormonal factors implicated as transmitters of signals from the gut to pancreatic β-cells are referred to as incretins. Gastric inhibitory polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) are incretins. In addition to the insulinotropic effects, we have shown, using the GIP receptor and GLP-1 receptor-deficient mice, that GIP and GLP-1 hav...
Glucagon-like peptide-1 (GLP-1) receptor plays an essential role in regulating glucose metabolism. GLP-1 receptor agonists have been widely used for treating diabetes and other insulin resistance-related diseases. However, mechanisms underlying the anti-diabetic effects of GLP-1 receptor agonists remain largely unknown. In this study, we investigat...
Citations
... Although findings regarding the impact of weight loss on adipose triglyceride lipase and lipid droplet protein expression were mixed [16,17,41], they indicate a complex interaction between obesity duration and its "severity." Our study indirectly suggests that a critical threshold for the "severity" of obesity might be a BMI [42]. GLP-1 was also reported to reduce lipogenic effect [43], increase lipolysis [43,44], and reduce adiposity in human adipocytes [44]. ...
Introduction
This study aimed to evaluate the impact of achieving < 37.7% excess body-weight loss (EBWL) within 3 months of postlaparoscopic sleeve gastrectomy (LSG) on clinical outcomes and its correlation with adipocyte function.
Methods
Patients (n = 176) who underwent LSG between January 2019 and January 2023 were included. Weight loss and status of health markers were monitored postoperatively. The cohort was stratified based on EBWL < 37.7% at 3 months or not. Variables including neutrophil-to-lymphocyte ratio (NLR), insulin resistance, and comorbidities were analyzed. Omental visceral and subcutaneous adipose tissue samples were used to analyze the differences in adipocyte function by western blot.
Results
Patients with EBWL < 37.7% at 3 months post-LSG (suboptimal group) comprised less likelihood of achieving ≥ 50% EBWL than those who achieved ≥ 37.7% EBWL (optimal group) at 6 months (42.55% vs. 95.52% in optimal group, p < 0.001), 12 months (85.11% vs. 99.25% in optimal group, p < 0.001) and 24 months (77.14% vs. 94.74% in optimal group, p = 0.009) post-LSG. High BMI (OR = 1.222, 95% CI 1.138–1.312, p < 0.001), NLR ≥ 2.36 (OR = 2.915, 95% CI 1.257–6.670, p = 0.013), and female sex (OR = 3.243, 95% CI 1.306–8.051, p = 0.011) significantly predicted EBWL < 37.7% at 3 months post-LSG. Patients with NLR ≥ 2.36 had significantly lower adipose triglyceride lipase in omental fat (p = 0.025).
Conclusion
EBWL < 37.7% at 3 months post-LSG is a strong predictor of subsequent suboptimal weight loss. High BMI, NLR ≥ 2.36, and female sex are risk factors in predicting EBWL < 37.7% at 3 months post-LSG. These findings may offer a reference to apply adjuvant weight loss medications to patients who are predisposed to suboptimal outcomes.
Graphical Abstract
... expenditure. Moreover, GLP-1RA negatively influences the expression of peroxisome proliferator-activated receptors (PPARs), leading to a downregulation of proteins associated with lipid metabolism (37,41,42). ...
Obesity, a chronic global health problem, is associated with an increase in various comorbidities, such as cardiovascular disease, type 2 diabetes mellitus, hypertension, and certain types of cancer. The increasing global prevalence of obesity requires research into new therapeutic strategies. Glucagon-like peptide-1 receptor agonists, specifically semaglutide and liraglutide, designed for type 2 diabetes mellitus treatment, have been explored as drugs for the treatment of obesity. This minireview describes the molecular mechanisms of semaglutide and liraglutide in different metabolic pathways, and its mechanism of action in processes such as appetite regulation, insulin secretion, glucose homeostasis, energy expenditure, and lipid metabolism. Finally, several clinical trial outcomes are described to show the safety and efficacy of these drugs in obesity management.
... Brown remodeling of WAT endows it with BAT-like characteristics and transforms it into an energy-disposal site, instead of simply being a place to store energy [31]. A growing number of studies have demonstrated the capacity of WAT to burn off excessive energy [32,33]. The energy-dispensing function of the WAT is mainly mediated by UCP1 activation, which separates oxidative phosphorylation from ATP production and consequently causes thermogenic activity in the WAT [34]. ...
Objective
Obesity is characterized by excessive accumulation of white adipose tissue (WAT). Conversely, brown adipose tissue is protective against obesity. We recently reported liraglutide, a glucagon-like peptide-1 receptor agonist (GLP-1RA), could inhibit high-fat-diet-induced obesity by browning of WAT. However, the molecular mechanism involved is not well defined. Hence, we aimed to explore whether GLP-1RA could promote brown remodeling in WAT by regulating miRNAs.
Methods
After the obesity model was successfully constructed, C57BL/6J mice were treated with liraglutide (200 μg/kg/d) or equivoluminal saline subcutaneously for 12 weeks. Then, the deposition of abdominal fat was measured by CT scanning. At the end of the treatments, glucose and insulin tolerance in mice were assessed. Serum lipid levels were monitored and epididymal WAT (eWAT) were collected for analysis. Quantitative real-time PCR and western blot analyses were conducted to evaluate the expression of genes and miRNAs associated with white fat browning.
Results
Liraglutide significantly reduced body weight and visceral fat mass. Levels of lipid profile were also improved. Liraglutide upregulated the expression of browning-related genes in eWAT. Meanwhile, the expression level of miRNAs (miR-196a and miR-378a) positively associated with the browning of WAT were increased, while the expression of miR-155, miR-199a, and miR-382 negatively related with browning of WAT were decreased.
Conclusion
Our findings suggest that liraglutide could promote brown remodeling of visceral WAT by bi-regulating miRNAs; this might be one of the mechanisms underlying its effect on weight loss.
... Alterations have also been noted regarding waist measurements. 17,18 Despite some 20 Our understanding suggests that drawing comparisons between different trials hints at a shared method of action. Yet, significant disparities concerning pharmacokinetic attributes exist (for instance, one daily lixisenatide injection does not extend throughout an entire 24-h cycle). ...
Glucagon-like peptide 1 receptor agonists (GLP-1RAs) have emerged as promising therapeutic agents with potent anti-inflammatory properties and diverse clinical implications. This in-depth review article explores the mechanisms behind the anti-inflammatory actions of GLP-1RAs and assesses their prospective applicability in a wide range of disease scenarios. The current review establishes the significance of comprehending the anti-inflammatory role of GLP-1RAs and identifies pertinent research gaps. A concise overview of inflammation and its clinical consequences underscores the critical need for effective anti-inflammatory interventions. Subsequently, the article elucidates the intricate mechanisms through which GLP-1RAs modulate immune cell signaling and regulate the nuclear factor-kappa B (NF-κB) pathway. Detailed discussions encompass their impact on inflammatory responses, cytokine production, and attenuation of oxidative stress. The exposition is substantiated by a collection of pertinent examples and an extensive array of references from both preclinical and clinical investigations. The historical trajectory of GLP-1RA drugs, including exenatide, lixisenatide, liraglutide, and semaglutide, is traced to delineate their development as therapeutic agents. Moreover, the review emphasizes the therapeutic potential of GLP-1RAs in specific disease contexts like type 2 diabetes, a neurodegenerative disorder, and inflammatory bowel disease (IBD), shedding light on their anti-inflammatory effects through rigorous examination of preclinical and clinical studies. The article also provides an outlook on future perspectives for GLP-1RAs, encompassing the domains of diabetes, neurodegenerative diseases, and IBD. In conclusion, GLP-1RAs exhibit substantial anti-inflammatory effects, rendering them promising therapeutic agents with broad clinical implications. They are very useful in a wide variety of diseases because they regulate immunological responses, block NF-κB activation, and decrease production of pro-inflammatory cytokines. Ongoing research endeavors aim to optimize their therapeutic use, delineate patient-specific treatment paradigms, and explore novel therapeutic applications. GLP-1RAs represent a significant breakthrough in anti-inflammatory therapy, offering novel treatment options, and improved patient outcomes.
... GLP-1 inhibits glucose uptake and promotes β-oxidation in cultured astrocytes [53]. GLP-1RAs treatment reduces adiposity by promoting lipolysis, fatty acid oxidation and mitochondrial biogenesis in the WAT, liver, muscle and BAT of obese mice and in 3T3-L1 adipocytes and shows amelioration of liver steatosis by promoting mitochondrial fatty acid β-oxidation and inhibiting lipogenesis [54,55]. Moreover, exposure to GLP-1 increases energy expenditure in muscle at least in part through the upregulation of fat oxidation [56]. ...
Hyperglycemia strongly affects endothelial function and activation, which in turn increases the risk of atherosclerotic cardiovascular disease. Among pharmacotherapies aimed at lowering blood glucose levels, glucagon-like peptide 1 receptor agonists (GLP-1RA) represent a class of drugs involved in the improvement of the endothelium damage and the progression of cardiovascular diseases. They show antihypertensive and antiatherosclerotic actions due at least in part to direct favorable actions on the coronary vascular endothelium, such as oxidative stress reduction and nitric oxide increase. However, cumulative peripheral indirect actions could also contribute to the antiatherosclerotic functions of GLP-1/GLP-1R agonists, including metabolism and gut microbiome regulation. Therefore, further research is necessary to clarify the specific role of this drug class in the management of cardiovascular disease and to identify specific cellular targets involved in the protective signal transduction. In the present review, we provide an overview of the effects of GLP-1RAs treatment on cardiovascular disease with particular attention on potential molecular mechanisms involving endothelium function on formation and progression of atherosclerotic plaque.
... Incretin-based therapies may also be able to induce lipolysis [134]. In this regard, Xu and colleagues showed that exendin-4 promoted lipolysis in adipocytes through an antioxidant action and the activation of phosphorylated hormone-sensitive lipase (HSL), which is directly involved in lipolysis [135]. Thus, the modulation of lipogenic and lipolytic processes by incretin-based drugs may reduce adiposity and body fat mass, potentially positively preventing dyslipidemia-induced complications. ...
Atherosclerosis is the leading cause of death worldwide, especially in patients with type 2 diabetes mellitus (T2D). GLP-1 receptor agonists and DPP-4 inhibitors were demonstrated to play a markedly protective role for the cardiovascular system beyond their glycemic control. Several cardiovascular outcome trials (CVOT) reported the association between using these agents and a significant reduction in cardiovascular events in patients with T2D and a high cardiovascular risk profile. Moreover, recent evidence highlights a favorable benefit/risk profile in myocardial infarction and percutaneous coronary revascularization settings. These clinical effects result from their actions on multiple molecular mechanisms involving the immune system, platelets, and endothelial and vascular smooth muscle cells. This comprehensive review specifically concentrates on these cellular and molecular processes mediating the cardiovascular effects of incretins-like molecules, aiming to improve clinicians' knowledge and stimulate a more extensive use of these drugs in clinical practice as helpful cardiovascular preventive strategies.
... The molecular machinery mediating the browning effects of GLP-1RA is complex and appears to include not only effectors of the AMPK pathway, but also protein signalling typically involved in cell growth control, such as the phosphoinositide 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway, whose activation by liraglutide was found to promote the accumulation of multilocular lipid droplets and mitochondrial biogenesis in brown adipocytes in vitro ( Fig. 1) [143]. Similar results have also been reported for exendin-4, which increased the expression of PGC1α and UCP1 via activation of SIRT1 when added to 3T3-L1 adipocytes cultures [144]. These results highlight that SIRT1 is a key bioenergetic regulator shared by both β3-AR-and GLP-1R-mediated thermogenic signalling pathways. ...
Background:
Adaptive thermogenesis represents the main mechanism through which the body generates heat in response to external stimuli, a phenomenon that includes shivering and non-shivering thermogenesis. The non-shivering thermogenesis is mainly exploited by adipose tissue characterized by a brown aspect, which specializes in energy dissipation. A decreased amount of brown adipose tissue has been observed in ageing and chronic illnesses such as obesity, a worldwide health problem characterized by dysfunctional adipose tissue expansion and associated cardiometabolic complications. In the last decades, the discovery of a trans-differentiation mechanism ("browning") within white adipose tissue depots, leading to the generation of brown-like cells, allowed to explore new natural and synthetic compounds able to favour this process and thus enhance thermogenesis with the aim of counteracting obesity. Based on recent findings, brown adipose tissue-activating agents could represent another option in addition to appetite inhibitors and inhibitors of nutrient absorption for obesity treatment.
Purpose:
This review investigates the main molecules involved in the physiological (e.g. incretin hormones) and pharmacological (e.g. β3-adrenergic receptors agonists, thyroid receptor agonists, farnesoid X receptor agonists, glucagon-like peptide-1, and glucagon receptor agonists) modulation of adaptive thermogenesis and the signalling mechanisms involved.
... Exenatide is an FDA-approved drug in the incretin mimetic class and is indicated for treatment of type 2 diabetes mellitus and obesity when used in combination with diet and exercise (9). Furthermore, clinical trials have demonstrated that such GLP-1 analogues have the ability to induce weight loss (10,11) and prevent development of hepatic steatosis (12). However, little is known about the effect of exenatide treatment on mitochondrial respiration. ...
Objective
To compare administration of the glucagon-like peptide-1 (GLP-1) analogue, exenatide, versus dietary supplementation with the omega-3 fatty acid-rich Calanus oil on obesity-induced alterations in mitochondrial respiration.
Methods
Six-week-old female C57BL/6JOlaHSD mice were given high fat diet (HFD, 45% energy from fat) for 12 weeks to induce obesity. Thereafter, they were divided in three groups where one received exenatide (10 μg/kg/day) via subcutaneously implanted mini-osmotic pumps, a second group received 2% Calanus oil as dietary supplement, while the third group received HFD without any treatment. Animals were sacrificed after 8 weeks of treatment and tissues (skeletal muscle, liver, and white adipose tissue) were collected for measurement of mitochondrial respiratory activity by high-resolution respirometry, using an Oroboros Oxygraph-2k (Oroboros instruments, Innsbruck, Austria).
Results
It was found that high-fat feeding led to a marked reduction of mitochondrial respiration in adipose tissue during all three states investigated – LEAK, OXPHOS and ETS. This response was to some extent attenuated by exenatide treatment, but not with Calanus oil treatment. High-fat feeding had no major effect on hepatic mitochondrial respiration, but exenatide treatment resulted in a significant increase in the various respiratory states in liver. Mitochondrial respiration in skeletal muscle was not significantly influenced by high-fat diet or any of the treatments. The precise evaluation of mitochondrial respiration considering absolute oxygen flux and ratios to assess flux control efficiency avoided misinterpretation of the results.
Conclusions
Exenatide increased hepatic mitochondrial respiration in high-fat fed mice, but no clear beneficial effect was observed in skeletal muscle or fat tissue. Calanus oil did not negatively affect respiratory activity in these tissues, which maintains its potential as a dietary supplement, due to its previously reported benefits on cardiac function
... Second, although the changes of adipose tissue respond to GLP-1 analogues treatment has been studied from the gene expression, lipidomic perspectives (29,32),comprehensive protein level profiling is rare. Gene expression and protein expression diverge (33). ...
... Interestingly, protein O35659 was not identified by TMT LC-MS in our study, which was consistent with another study of h rhGLP-1 Beinaglutide (BN) on adipose tissue (29). Potential explanations of this observation may be that the fat loss effect by semaglutide during the course of the experiment, might lower the degree of IR, leading to a lower expression of Glpr in mice, or the beneficial effects of GLP-1 are (32). Their findings indicated that exenatide induces the phosphorylation of AMPK which, in turn, activates SIRT1 by regulating NAD+ concentration, triggering a lipolytic cycle. ...
Background and objectives:
Obesity is a global health problem with few pharmacologic options. Semaglutide is a glucagon-like peptide-1 (GLP-1) analogue that induces weight loss. Yet, the role of semaglutide in adipose tissue has not yet been examined. The following study investigated the mechanism of semaglutide on lipid metabolism by analyzing proteomics of epididymal white adipose tissue (eWAT) in obese mice.
Methods:
A total of 36 C57BL/6JC mice were randomly divided into a normal-chow diet group (NCD, n = 12), high-fat diet (HFD, n = 12), and HFD+semaglutide group (Sema, n = 12). Mice in the Sema group were intraperitoneally administered semaglutide, and the HFD group and the NCD group were intraperitoneally administered an equal volume of normal saline. Serum samples were collected to detect fasting blood glucose and blood lipids. The Intraperitoneal glucose tolerance test (IPGTT) was used to measure the blood glucose value at each time point and calculate the area under the glucose curve. Tandem Mass Tag (TMT) combined with liquid chromatography-tandem mass spectrometry (LC-MS/MS) were used to study the expression of eWAT, while cellular processes, biological processes, corresponding molecular functions, and related network molecular mechanisms were analyzed by bioinformatics.
Results:
Compared with the model group, the semaglutide-treated mice presented 640 differentially expressed proteins (DEPs), including 292 up-regulated and 348 down-regulated proteins. Bioinformatics analysis showed a reduction of CD36, FABP5, ACSL, ACOX3, PLIN2, ANGPTL4, LPL, MGLL, AQP7, and PDK4 involved in the lipid metabolism in the Sema group accompanied by a decrease in visceral fat accumulation, blood lipids, and improvement in glucose intolerance.
Conclusion:
Semaglutide can effectively reduce visceral fat and blood lipids and improve glucose metabolism in obese mice. Semaglutide treatment might have beneficial effects on adipose tissues through the regulation of lipid uptake, lipid storage, and lipolysis in white adipose tissue.
... Representative agents, such as glucagon-like peptide-1 (GLP-1) analog or GLP-1 receptor agonists, reduce weight by acting on the nervous system causing loss of appetite, 9,10 gastrointestinal tract by delaying gastric emptying to reduce food intake, 11,12 and white fat browning for reducing weight. 13 Liraglutide, a widely used long-acting GLP-1 analog, has been confirmed to aid weight loss in the Liraglutide Effect and Action Diabetes (LEAD) study [14][15][16][17][18][19] as well as in the clinical practice. [20][21][22][23][24][25][26][27] Nonetheless, its weight loss effect was highly heterogeneous in different patients and had no effect in some cases in the clinical setting. ...
... The weight loss effect of liraglutide is achieved by suppressing appetite, delaying gastric evacuation, controlling food intake by directly affecting the nervous system, 10,35-38 and browning of white fat. 13,39,40 . In the LEAD series of studies, LEAD-2 15 and LEAD-4 17 reported that weight loss caused by liraglutide treatment was dosedependent. ...
Background
Liraglutide can effectively reduce the weight of patients with type 2 diabetes. Nonetheless, its weight loss effect was highly heterogeneous in different patients in the clinical practice.
Objective
To identify the factors most associated with the weight loss effect of liraglutide in obese or overweight patients with type 2 diabetes with poorly controlled oral medication in northeast China.
Design
A prospective study.
Methods
A prospective study was performed in subjects with type 2 diabetes who were taking oral medication and had a body mass index (BMI) of ⩾24 kg/m ² . Liraglutide was administered for at least 12 weeks, while the original hypoglycemic regimen was kept unchanged (Phase I). Later, liraglutide treatment was continued or stopped as necessary or as subjects thought fit in the 13–52 weeks that followed (Phase II), and the potential factors affecting the effect of weight loss of liraglutide were analyzed.
Results
Of the 127 recruited subjects, 90 had comprehensive follow-up data at week 12. In Phase I, the subjects’ blood sugar levels and weight decreased significantly( P < 0.001). Among all the significant factors, the gastrointestinal adverse reactions score (GARS) was more correlated with BMI change (ΔBMI; r = 0.43) and waist circumference change (ΔWC; r = 0.32) than the baseline BMI (BMI 0 ) and WC (WC 0 ). At week 12, linear regression showed that BMI 0 independently affected ΔBMI and ΔWC, whereas WC 0 only affected ΔWC. The GARS was significantly associated with ΔBMI and ΔWC, and this association continued until week 52, even after most subjects had discontinued liraglutide treatment.
Conclusion
The degree of obesity and gastrointestinal adverse reactions were the most promising predictors of weight loss in liraglutide treatment.
