Semaglutide Alleviates Ovary Inflammation via the AMPK/SIRT1/NF­κB Signaling Pathway in Polycystic Ovary Syndrome Mice.

Background: GLP-1 receptor agonists (GLP-1 RA) have been proven to treat several metabolic diseases; however, the effects of GLP-1 RA on polycystic ovary syndrome (PCOS) remain unclear. Here, we aimed to investigate whether semaglutide, a novel GLP-1 RA, could alleviate ovarian inflammation in PCOS mice. Methods: Female C57BL/6J mice were subcutaneously injected with dehydroepiandrosterone for 21 days to establish the PCOS model. Then the mice were randomly divided into three groups: PCOS group (n = 6), S-0.42 group (semaglutide 0.42 mg/kg/w, n = 6), and S-0.84 group (semaglutide 0.84 mg/kg/w, n = 6). The remaining six mice were used as controls (NC). After 28 days of intervention, serum sex hormones and inflammatory cytokine levels were measured. Hematoxylin and eosin staining was used to observe the ovarian morphology. Immunohistochemical staining was used to detect the relative expression of CYP19A1, TNF-α, IL-6, IL-1ß, and NF-κB in ovaries. CYP17A1 and StAR were detected using immunofluorescence staining. Finally, the relative expressions of AMPK, pAMPK, SIRT1, NF-κB, IκBα, pIκBα, TNF-α, IL-6, and IL-1ß were measured using Western blotting. Results: First, after intervention with semaglutide, the weight of the mice decreased, insulin resistance improved, and the estrous cycle returned to normal. Serum testosterone and IL-1ß levels decreased significantly, whereas estradiol and progestin levels increased significantly. Follicular cystic dilation significantly improved. The expression of TNF-α, IL-6, IL-1ß, NF-κB, CYP17A1, and StAR in the ovary was significantly downregulated, whereas CYP19A1 expression was upregulated after the intervention. Finally, we confirmed that semaglutide alleviates ovarian tissue inflammation and improves PCOS through the AMPK/SIRT1/NF-κB signaling pathway. Conclusion: Semaglutide alleviates ovarian inflammation via the AMPK/SIRT1/NF­κB signaling pathway in PCOS mice.

Impact of Selected Glucagon-like Peptide-1 Receptor Agonists on Serum Lipids, Adipose Tissue, and Muscle Metabolism-A Narrative Review.

Glucagon-like peptide-1 receptor agonists (GLP-1 RA) are novel antihyperglycemic agents. By acting through the central nervous system, they increase satiety and reduce food intake, thus lowering body weight. Furthermore, they increase the secretion of insulin while decreasing the production of glucagon. However, recent studies suggest a more complex metabolic impact through the interaction with various other tissues. In our present review, we aim to provide a summary of the effects of GLP-1 RA on serum lipids, adipose tissue, and muscle metabolism. It has been found that GLP-1 RA therapy is associated with decreased serum cholesterol levels. Epicardial adipose tissue thickness, hepatic lipid droplets, and visceral fat volume were reduced in obese patients with cardiovascular disease. GLP-1 RA therapy decreased the level of proinflammatory adipokines and reduced the expression of inflammatory genes. They have been found to reduce endoplasmic reticulum stress in adipocytes, leading to better adipocyte function and metabolism. Furthermore, GLP-1 RA therapy increased microvascular blood flow in muscle tissue, resulting in increased myocyte metabolism. They inhibited muscle atrophy and increased muscle mass and function. It was also observed that the levels of muscle-derived inflammatory cytokines decreased, and insulin sensitivity increased, resulting in improved metabolism. However, some clinical trials have been conducted on a very small number of patients, which limits the strength of these observations.

Mechanisms of action and therapeutic applications of GLP-1 and dual GIP/GLP-1 receptor agonists.

Glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) are two incretins that bind to their respective receptors and activate the downstream signaling in various tissues and organs. Both GIP and GLP-1 play roles in regulating food intake by stimulating neurons in the brain's satiety center. They also stimulate insulin secretion in pancreatic ß-cells, but their effects on glucagon production in pancreatic α-cells differ, with GIP having a glucagonotropic effect during hypoglycemia and GLP-1 exhibiting glucagonostatic effect during hyperglycemia. Additionally, GIP directly stimulates lipogenesis, while GLP-1 indirectly promotes lipolysis, collectively maintaining healthy adipocytes, reducing ectopic fat distribution, and increasing the production and secretion of adiponectin from adipocytes. Together, these two incretins contribute to metabolic homeostasis, preventing both hyperglycemia and hypoglycemia, mitigating dyslipidemia, and reducing the risk of cardiovascular diseases in individuals with type 2 diabetes and obesity. Several GLP-1 and dual GIP/GLP-1 receptor agonists have been developed to harness these pharmacological effects in the treatment of type 2 diabetes, with some demonstrating robust effectiveness in weight management and prevention of cardiovascular diseases. Elucidating the underlying cellular and molecular mechanisms could potentially usher in the development of new generations of incretin mimetics with enhanced efficacy and fewer adverse effects. The treatment guidelines are evolving based on clinical trial outcomes, shaping the management of metabolic and cardiovascular diseases.

The benefits of GLP-1 drugs beyond obesity.

Glucagon-like peptide-1-based medicines have weight loss-independent actions.

GLP-1 increases preingestive satiation via hypothalamic circuits in mice and humans.

Glucagon-like peptide-1 (GLP-1) receptor agonists (GLP-1RAs) are effective antiobesity drugs. However, the precise central mechanisms of GLP-1RAs remain elusive. We administered GLP-1RAs to patients with obesity and observed a heightened sense of preingestive satiation. Analysis of human and mouse brain samples pinpointed GLP-1 receptor (GLP-1R) neurons in the dorsomedial hypothalamus (DMH) as candidates for encoding preingestive satiation. Optogenetic manipulation of DMHGLP-1R neurons caused satiation. Calcium imaging demonstrated that these neurons are actively involved in encoding preingestive satiation. GLP-1RA administration increased the activity of DMHGLP-1R neurons selectively during eating behavior. We further identified that an intricate interplay between DMHGLP-1R neurons and neuropeptide Y/agouti-related peptide neurons of the arcuate nucleus (ARCNPY/AgRP neurons) occurs to regulate food intake. Our findings reveal a hypothalamic mechanism through which GLP-1RAs control preingestive satiation, offering previously unexplored neural targets for obesity and metabolic diseases.

A novel approach to exploit Small-Molecule glucagon-like Peptide-1 receptor agonists with high potency.

Small-molecule glucagon-like peptide-1 receptor (GLP-1R) agonists are recognized as promising therapeutics for type 2 diabetes mellitus (T2DM) and obesity. Danuglipron, an investigational small-molecule agonist, has demonstrated high efficacy in clinical trials. However, further development of danuglipron is challenged by a high rate of gastrointestinal adverse events. While these effects may be target-related, it is plausible that the carboxylic acid group present in danuglipron may also play a role in these outcomes by affecting the pharmacokinetic properties and dosing regimen of danuglipron, as well as by exerting direct gastrointestinal irritation. Therefore, this study aims to replace the problematic carboxylic acid group by exploring the internal binding cavity of danuglipron bound to GLP-1R using a water molecule displacement strategy. A series of novel triazole-containing compounds have been designed and synthesized during the structure-activity relationship (SAR) study. These efforts resulted in the discovery of compound 2j with high potency (EC50 = 0.065 nM). Moreover, docking simulations revealed that compound 2j directly interacts with the residue Glu387 within the internal cavity of GLP-1R, effectively displacing the structural water previously bound to Glu387. Subsequent in vitro and in vivo experiments demonstrated that compound 2j had comparable efficacy to danuglipron in enhancing insulin secretion and improving glycemic control. Collectively, this study offers a practicable approach for the discovery of novel small-molecule GLP-1R agonists based on danuglipron, and compound 2j may serve as a lead compound to further exploit the unoccupied internal cavity of danuglipron's binding pocket.

Contemporary Management of Obesity: A Comparison of Bariatric Metabolic Surgery and Novel Incretin Mimetic Drugs.

The global prevalence of obesity has risen sharply during the past half-century, reaching pandemic proportions and creating a public health crisis. Obesity is a recognized risk factor for the development of diabetes, atherosclerosis, hypertension, hepatic steatosis, and many other cardiometabolic disorders with significant resultant morbidity and mortality. Though treatment of obesity can prevent or slow the progression of the aforementioned illnesses, efforts to help patients achieve reliable and sustainable weight loss have had limited success. Improving nutrition and increasing physical activity results in a host of health benefits; however, the weight loss achieved with lifestyle interventions alone is modest and difficult to sustain. Early attempts at medical and surgical treatment of obesity were plagued with adverse effects and complications. Moreover, these approaches failed to demonstrate long-term health benefits, even when weight loss was achieved. Recently, novel incretin-based therapies targeting glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptors have gained popularity because of their effectiveness in achieving substantial weight loss in patients both with and without diabetes. Following many successful clinical trials, there are now multiple GLP-1 receptor agonists and one dual GLP-1-GIP receptor agonist approved by the Food and Drug Administration for chronic weight management. Advancements in laparoscopic surgical technique and refinements in procedure selection have similarly improved the safety and efficacy of bariatric metabolic surgery for patients with obesity. In this review, we discuss the advantages and disadvantages of contemporary pharmacologic and surgical weight management strategies. We review the data regarding expected weight loss, glycemic control, cardiometabolic benefits, and potential adverse effects of various treatment approaches. As obesity rates continue to rise worldwide, it is imperative that clinicians keep these considerations in mind in order to better care for patients.

Effects of glucagon-like peptide-1 receptor agonists on spermatogenesis-related gene expression in mouse testis and testis-derived cell lines.

Glucagon-like peptide-1 (GLP-1) is an incretin released into the gastrointestinal tract after food ingestion, and stimulates insulin secretion from the beta cells of the pancreatic islets. Incretins have recently been reported to have extrapancreatic actions, and they are anticipated to have potential efficacy for conditions such as male infertility as well as diabetes. However, the effects of incretins on male reproductive function remain unclear. In this study, GLP-1 receptor expression and the effects of GLP-1 on spermatogenesis-associated genes were investigated using mouse testes and testis-derived cultured cell lines. Glp1r mRNA and GLP-1 protein were expressed in mouse testes at levels comparable to or greater than those in positive control adipose tissue, and the liver and intestine, and also in a Sertoli cell line (TM4) and a Leydig cell line (MA-10) as well as the GC-1 spg and GC-2 spd (ts) germ cell lines. TM4 cells treated with the GLP-1 receptor agonist exenatide showed transiently and significantly upregulated Kitl, Pdgfa, and Glp1r mRNA expression. Furthermore, at 1 hr post-exenatide administration to male mice, Kitl and Glp1r mRNA expression levels were significantly increased, and Pdgfa mRNA expression level also showed a tendency toward increase. TM4 cells were treated with various cell-activating agents, and bucladesine elicited significantly increased Glp1r mRNA expression. We suggest that GLP-1 provides acute stimulation of Sertoli cells in the mouse testis and has a stimulatory effect on the expression of spermatogenesis-related genes.

Impact of Glucagon-Like Peptide 1 Receptor Agonists on Biochemical Markers of the Initiation of Atherosclerotic Process.

Atherosclerosis stands out as one of the leading causes of global mortality. The inflammatory response against vascular wall components plays a pivotal role in the atherogenic process. The initiation of this process is notably driven by oxidized low-density lipoprotein (oxLDL) and a range of pro-inflammatory cytokines, with interleukin-1ß (Il-1ß) and tumor necrosis factor α (TNFα) emerging as particularly significant in the early stages of atherosclerotic plaque formation. In recent years, researchers worldwide have been diligently exploring innovative therapeutic approaches for metabolic diseases, recognizing their impact on the atherogenesis process. Our study aimed to investigate the influence of glucagon-like peptide 1 receptor agonists (GLP-1RA) on cytokine concentrations associated with the initiation of atherosclerotic plaque formation in a group of patients with type 2 diabetes and dyslipidemia. The study encompassed 50 subjects aged 41-81 (mean: 60.7), all diagnosed with type 2 diabetes, dyslipidemia and confirmed atherosclerosis based on B-mode ultrasound. Following a 180-day treatment with dulaglutide or semaglutide, we observed a statistically significant reduction in biochemical markers (oxLDL, TNFα and Il-1ß) associated with the initiation of the atherosclerotic process (p < 0.001) within our study group. In addition to the already acknowledged positive effects of GLP-1RA on the metabolic parameters of treated patients, these drugs demonstrated a notable reduction in proinflammatory cytokine concentrations and may constitute an important element of therapy aimed at reducing cardiovascular risk.

Highway to the danger zone? A cautionary account that GLP-1 receptor agonists may be too effective for unmonitored weight loss.

Glucagon-like peptide 1 (GLP-1) receptor agonists are revolutionizing obesity and type 2 diabetes treatment, delivering remarkable weight loss outcomes. These medications, leveraging the effects of the insulin-regulating hormone GLP-1 via actions on peripheral and central nervous system targets, have raised hopes with their bariatric surgery-rivaling results. However, questions remain about their long-term safety and efficacy. Drawing from our expertise in obesity medicine and psychiatry, we reflect upon our experiences with the clinical use of these medications and delve into the nuanced challenges and risks they pose, particularly for those prone to disordered eating or those diagnosed with rare genetic diseases of obesity. We contend that effectively managing weight loss within this "danger zone" necessitates (1) proactive screening and continuous monitoring for disordered eating, (2) vigilant monitoring for appetite-related maladaptive responses, including food aversion and dehydration, and (3) ongoing assessment for broader health impacts. A multifaceted, interdisciplinary approach that melds medical, psychological, dietary, and behavioral strategies is crucial to delivering tailored and thorough care to each patient.

Impact of a dual glucose-dependent insulinotropic peptide/glucagon-like peptide-1 receptor agonist tirzepatide on heart rate among patients with type 2 diabetes: A systematic review and pairwise and network meta-analysis.

AIMS: To evaluate the impact of a dual glucose-dependent insulinotropic peptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist tirzepatide (TZP), and its potential dose-response effect, on heart rate. METHODS: Articles were searched from PubMed, Web of Science, Embase, Cochrane Library, and clinical trials registries (ClinicalTrials.gov) databases. Randomized controlled trials (RCTs) comparing TZP at doses of 5, 10 and 15 mg in adults with type 2 diabetes were included. Six study arms were summarized from original research (TZP 5, 10 and 15 mg, GLP-1 receptor agonists [GLP-1RAs], insulin, placebo). The GLP-1RA and non-GLP-1RA groups were combined to form a control group. Two reviewers independently extracted data and assessed the quality of each study. Mean differences (MDs) were calculated as effect estimates for continuous outcomes. Pairwise meta-analyses and network meta-analyses were conducted. The study protocol was prospectively registered (PROSPERO ID: CRD42023418551). RESULTS: Eight articles were included in this systematic review and meta-analysis. The mean baseline heart rate ranged from 65.2 to 75.7 beats per minute. Pairwise meta-analysis showed that, compared with combined the control group, there were significantly greater increases in heart rates in the TZP group (MD 1.82, 95% confidence interval [CI] 0.75, 2.89). Similar significant rises were identified when comparing TZP with GLP-1RAs and non-GLP-1RAs (GLP-1 RAs: MD 2.29, 95% CI 1.00, 3.59; non-GLP-1RAs: MD 1.58, 95% CI 0.26, 2.91). TZP 5 mg was associated with smaller increases in heart rates compared to TZP 10 mg and TZP 15 mg (TZP 10 mg: MD -0.97, 95% CI -1.79, -0.14; TZP 15 mg: MD -2.57, 95% CI -3.79, -1.35). TZP 10 mg increased heart rate less than TZP 15 mg (MD -1.5, 95% CI -2.38, -0.82). Network meta-analysis indicated that TZP 15 mg was associated with significant increases in heart rate compared with TZP 5 mg (MD 2.53, 95% CI 1.43, 3.62), TZP 10 mg (MD 1.44, 95% CI 0.35, 2.53), GLP-1RAs (MD 3.46, 95% CI 1.67, 5.25), insulin (MD 2.86, 95% CI 1.32, 4.41) and placebo (MD 2.96, 95% CI 1.36, 4.57). CONCLUSIONS: Our study showed not only that there was a greater increase in heart rate in the TZP group than in the control, GLP-1RA and non-GLP-1RA groups, but also that the 15-mg dose of TZP had the strongest impact on increasing heart rates compared with the other five inventions, with a TZP dose-response impact on heart rate. Further research on the effects of TZP treatment-related increases in heart rate is required.

Use of glucagon-like peptide-1 receptor agonists in eating disorder populations.

Glucagon-like peptide-1 receptor agonists (GLP-1As) are being used as approved or off-label treatments for weight loss. As such, there has been increasing concern about the potential for GLP-1As to impact eating disorder (ED) symptomatology. This article seeks to (1) review the current state of knowledge regarding GLP-1As and ED symptomatology; (2) provide recommendations for future research; and (3) guide ED clinicians in how to discuss GLP-1As in clinical practice. Although evidence is limited, it is possible that GLP-1As could exacerbate, or contribute to the development of, ED pathology and negatively impact ED treatment. Preliminary research on the use of GLP-1As to treat binge eating has been conducted; however, studies have design limitations and additional research is needed. Therefore, at the current time there is not sufficient evidence to support the use of GLP-1s to treat ED symptoms. In summary, more research is required before negative or positive conclusions can be drawn about the impact of GLP-1As on EDs psychopathology. Herein, we provide specific recommendations for future research and a guide to help clinicians navigate discussions with their clients about GLP-1As. A client handout is also provided. PUBLIC SIGNIFICANCE: Despite glucagon-like peptide-1 receptor agonists (GLP-1As; e.g., semaglutide) increasingly being the topic of clinical and public discourse, little is known about their potential impact on ED symptoms. It is possible that GLP-1As could maintain, worsen, or improve ED symptoms. This article reviews the limited literature on GLP-1As and ED symptoms, recommends future research, and provides clinicians with a guide for discussing GLP-1As with ED clients.