Glucagon (GCG) like peptide 1 (GLP-1) has emerged as a powerful player in regulating metabolism and a promising therapeutic target for various chronic diseases. This review delves into the physiological roles of GLP-1, exploring its impact on glucose homeostasis, insulin secretion, and satiety. We examine the compelling evidence supporting GLP-1 receptor agonists (GLP-1RAs) in managing type 2 diabetes (T2D), obesity, and other diseases. The intricate molecular mechanisms underlying GLP-1RAs are explored, including their interactions with pathways like extracellular signal-regulated kinase 1/2 (ERK1/2), activated protein kinase (AMPK), cyclic adenine monophosphate (cAMP), mitogen-activated protein kinase (MAPK), and protein kinase C (PKC). Expanding our understanding, the review investigates the potential role of GLP-1 in cancers. Also, microribonucleic acid (RNA) (miRNAs), critical regulators of gene expression, are introduced as potential modulators of GLP-1 signaling. We delve into the link between miRNAs and T2D obesity and explore specific miRNA examples influencing GLP-1R function. Finally, the review explores the rationale for seeking alternatives to GLP-1RAs and highlights natural products with promising GLP-1 modulatory effects.

Glucagon-like peptide-1 (GLP-1) has been widely studied in the context of treating obesity and various forms of metabolic disease. Sepsis is a life-threatening medical emergency characterized by the widespread dysregulation of energy metabolism within cells. The potential for GLP-1 to improve sepsis patient outcomes through improvements in energy metabolism and inflammation has been a focus of growing research interest, with many studies of GLP-1 itself and related compounds, including GLP-1 receptor agonists (GLP-1RAs), and dipeptidyl peptidase-4 (DPP-4) inhibitors, having explored the impact on sepsis in cells and organs. Such studies require that attention be paid to both the physiological and potential pathological effects of GLP-1 in sepsis. In many reports, researchers have demonstrated that endogenous GLP-1, GLP-1RAs, or DPP-4 inhibitors (a GLP-1 depressant) can modulate glucose homeostasis, inflammatory activity, immune function, and organ dysfunction in studies of sepsis model systems in vitro and in vivo. To date, GLP-1-based treatments have yet to be specifically used to manage sepsis, but its pleiotropic effects suggest its significant potential in sepsis treatment. This review provides an overview of the relationship between GLP-1 and its related compounds with sepsis, aiming to offer novel perspectives for the diagnosis and treatment of this condition. It highlights that GLP-1 may serve as a new biomarker for assessing the severity and prognosis of sepsis, and potentially contribute to improving clinical outcomes in septic patients. Meanwhile, GLP-1 may function as a messenger of metabolic reprogramming, shifting cellular energy production from oxidative phosphorylation to glycolysis, thereby modulating immune responses and influencing inflammatory reactions to enhance the clearance of pathogens. However, GLP-1 may act as a double-edged sword, the enhanced inflammatory response can potentially induce cytotoxic and organ-damaging effects while exerting beneficial actions.

The systematic review was registered on the PROSPERO website (CRD42024558287). Our objective is to systematically summarise the clinical evidence of glucagon-like peptide-1 receptor agonists (GLP-1 RA) for obstructive sleep apnea (OSA) in patients with Obesity or/and type 2 Diabetes Mellitus (T2DM). This analysis was performed following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. 10 databases and registers Web of Science, Scopus, PubMed, APA PsycInfo, Embase, Ovid, Cochrane Library, CINAHL, Clinicaltrials.gov, and International Clinical Trials Registry Platform (ICTRP) were retrieved from the establishment to July 14, 2024 for related randomized controlled trials (RCT) and non-RCTs. Data were extracted by two investigators separately, and only the RCTs were included in the quantitative synthesis. The outcome was operated by Review Manager 5.4 and Stata 15.0. Ten studies containing eight RCTs and two non-RCTs were included. The efficacy of the GLP-1 RA group in reducing apnea-hypopnea index (AHI) was superior to that of the control group in patients with T2DM (MD = -5.68, 95%CI [-7.97, -3.38], P < 0.00001, I2 = 0%). GLP-1 RAs also possessed a tendency to reduce AHI in patients with obesity but more evidence is needed to support the findings due to the inconsistency. In consideration of the enhanced metabolic parameters observed with GLP-1 RAs, they may be recommended as useful hypoglycaemic medication for the management of T2DM with OSA. Patients with obesity and OSA may consider GLP-1 RA as a potential treatment option if the adverse events are deemed tolerable.

The incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP) have therapeutic effects in diabetes mellitus. Prior clinical studies suggest incretins are prognostic of adverse outcomes in critical illness. We investigated whether incretin levels indicate disease severity and clinical outcomes in patients with acute respiratory failure, a common cause of critical illness.

Retrospective cohort study.

ICUs in UPMC Health Systems hospitals within Western Pennsylvania.

Two hundred ninety-seven critically ill adults with acute respiratory failure.

None.

We measured GLP-1 and GIP levels in baseline samples collected at the time of study enrollment. We compared incretin levels across subgroups differing by severity of illness and investigated associations between incretins and markers of systemic host responses and intestinal permeability. In our primary analysis, we tested the association of each incretin level with 90-day mortality by logistic regression in unadjusted analyses and in analyses adjusted for age, Sequential Organ Failure Assessment score, and circulating interleukin-6 levels. GLP-1 levels were higher in nonsurvivors and patients with or at-risk for acute respiratory distress syndrome compared to those intubated for airway protection. GLP-1 levels also positively correlated with systemic immune response biomarkers but not with markers of intestinal permeability. GLP-1 levels positively correlated with mortality in unadjusted (odds ratio, 1.99 [1.55-2.56]; p < 0.01) and adjusted (2.02 [1.23-3.31]; p < 0.01) analyses. GIP levels were not associated with mortality or with host response biomarkers.

GLP-1 but not GIP levels were positively associated with systemic inflammation and mortality in critically ill patients with acute respiratory failure. Increased circulating GLP-1 levels may serve as prognostic biomarkers to identify patients who are likely to have worse outcomes.

The glucagon-like peptide-1 receptor (GLP-1R) plays an important role in regulating insulin secretion and reducing body weight, making it a prominent target in the treatment of type 2 diabetes and obesity. Extensive research on GLP-1R signaling has provided insights into the connection between receptor function and physiological outcomes, such as the correlation between Gs signaling and insulin secretion, yet the exact mechanisms regulating signaling remain unclear. Here, we explore the internalization pathway of GLP-1R, which is crucial for controlling insulin release and maintaining pancreatic beta-cell function. Utilizing a reliable and sensitive time-resolved fluorescence resonance energy transfer (TR-FRET) internalization assay, combined with HEK293-derived knockout cell lines, we were able to directly compare the involvement of different endocytic machinery in GLP-1R internalization. Our findings indicate that the receptor internalizes independently of arrestin and is dependent on Gs and Gi/o activation and G protein-coupled receptor kinase phosphorylation. Mechanistically, we observed that the receptor undergoes distinct clathrin- and caveolae-mediated internalization in HEK293 cells. This study also investigated the role of arrestins in GLP-1R function and regulation. These insights into key endocytic components that are involved in the GLP-1R internalization pathway could enhance the rational design of GLP-1R therapeutics for type 2 diabetes and other GLP-1R-related diseases.

Glucagon-like peptide-1 (GLP-1) is a fascinating target for the treatment of diabetes to avoid hypoglycemia. Kaempferiae Rhizoma (KR), the dried rhizomes of Kaempferia galanga, is a famous pungent medicine used for activating Qi, warming interior, removing digestion and relieving pain in China. In order to characterize the antidiabetic effects of KR, 21 previously undescribed O-linked diarylheptanoid dimers, kaemgalangins A1-A4 (1-4), B1-B13 (5-17) and C1-C4 (18-21), were isolated from the ethyl acetate fraction. Their structures were determined by extensive spectroscopic analyses, quantum computation and chemical methods. All compounds were tested for their GLP-1 stimulating effects on NCI-H716 cells, most of which showed obvious activity representing a new type of antidiabetic constituents. Especially, compounds 1, 2 and 16 showed spectacular GLP-1 stimulation with promoting rates of 146.6±31.1%, 159.0±16.6% and 142.9±2.7%, more potent than the positive control. Mechanism study manifested that kaemgalangin A1 (1) promoted GLP-1 secretion through up-regulating the mRNA expression of Gcg and Pc1/3, and the phosphorylation of PKA and CREB, but independent on TGR5 and GPR119 receptors. Furthermore, network pharmacology analysis suggested that the GLP-1 secretion induced by 1 was closely related to MAPK and PI3K-Akt signaling pathways. This investigation first revealed that KR was rich in diarylheptanoid dimers with GLP-1 promoting effects, which provides scientific basis for the antidiabetic application of K. galanga.

Incretin-based medicines have considerably impacted the treatment of type 2 diabetes mellitus (T2DM), providing considerable advantages in glycemic regulation, weight control, and cardiovascular results. This narrative review examines progress in incretin medicines, encompassing glucagon-like peptide-1 (GLP-1) receptor agonists, dual-receptor, and triple-receptor agonists, while emphasizing their therapeutic advantages, obstacles, and prospective developments. The examined articles were sourced from databases including PubMed and Google Scholar, concentrating on publications predominantly from 2010 to 2024. Selective foundational papers released before this timeline were incorporated to furnish critical historical context about incretin processes and their discovery. Incretin-based medicines, despite their therapeutic efficacy, encounter hurdles including elevated treatment costs, patient compliance difficulties, and variability in response attributable to genetic and physiological variables. Moreover, there are still deficiencies in comprehending the long-term cardiovascular safety and cancer risks linked to these medicines. Emerging dual- and triple-receptor agonists demonstrate potential in overcoming the shortcomings of conventional GLP-1 receptor agonists, providing enhanced metabolic results and broader uses in intricate disease profiles. Future research must concentrate on economic obstacles, streamlined regimens, customized medicine, the integration of artificial intelligence, patient stratification, as well as the safety and efficacy of incretin-based medicines for holistic management of T2DM.

Population aging is the most important social and medical demographic issue worldwide; therefore, healthy aging is important. The increasing prevalence of dementia and cognitive decline are major health concerns. Medium-chain triglycerides (MCTs) have been shown to improve cognitive decline. The present study investigated the effects and mechanisms of action of orally administered MCTs, including tricaprylin (TC8), tricaprin (TC10), and trilaurin (TC12), on cognitive function in mice fed a high-fat diet (HFD). The administration of TC8 and TC10 attenuated cognitive decline. A relationship has been reported between cognitive dysfunction and impaired glucose metabolism. The administration of TC8 and TC10 also reduced blood glucose levels in the glucose tolerance test. Cognitive improvements by MCTs are widely attributed to the ketogenic effect. In the present study, TC8 significantly increased blood ketone concentrations, whereas TC10 did not. On the other hand, TC10 increased the plasma concentration of glucagon-like peptide-1 (GLP-1), the hormone that promotes insulin secretion. The administration of the GLP-1 receptor antagonist, exendin(9-39), blocked the cognitive-enhancing effects of TC10. These results suggest that TC10 improved cognitive function via the GLP-1 receptor. The in vitro experiment indicated that 2-monocaprin (2-MC10), not TC10, stimulated the secretion of GLP-1 and decreased intracellular cAMP concentrations. In conclusion, we herein demonstrated that TC8 and TC10 attenuated cognitive decline through different mechanisms. This is the first study to suggest that TC10 attenuates cognitive decline via GLP-1.

Western-style dietary patterns have been linked with obesity and associated metabolic disorders and gut dysbiosis, whereas prudent dietary and snacking choices mitigate these predispositions. Using a multi-omics approach, we investigated how almond snacking counters gut imbalances linked to adiposity and an average American Diet (AAD). Fifteen adults with overweight or obesity underwent a randomized, crossover-controlled feeding trial comparing a 4-week AAD with a similar isocaloric diet supplemented with 42.5 g/day of almonds (ALD). Almond snacking increases functional gut microbes, including Faecalibacterium prausnitzii, while suppressing opportunistic pathogens, thereby favorably modulating gut microecological niches through symbiotic and microbe-metabolite interactions. Moreover, ALD elevates health-beneficial monosaccharides and fosters bacterial consumption of amino acids, owing to enhanced microbial homeostasis. Additionally, ALD enhances metabolic homeostasis through a ketosis-like effect, reduces inflammation, and improves satiety-regulating hormones. The findings suggest that prudent dietary choices, such as almond snacking, promote gut microbial homeostasis while modulating immune metabolic state.

Glucagon-like peptide-1 (GLP-1) agonists mimic the action of GLP-1, a hormone that regulates blood glucose levels via stimulation of insulin release and inhibition of glucagon secretion. After the burn, the current literature suggests that the use of GLP-1 agonists results in less insulin dependence with similar glucose control and hypoglycemic events to patients receiving a basal-bolus insulin regimen. Glucagon-like peptide-1 agonists may also promote wound healing through various mechanisms including angiogenesis and improved keratinocyte migration. Despite the potential benefits, GLP-1 agonists reduce gastrointestinal motility which impacts their widespread adoption in burn care. This dysmotility can result in inadequate nutrition delivery, unintentional weight loss, and is a potential aspiration risk. The net impact of these medications on patients with burns is unclear. Given their potential to demonstrate the safety, efficacy, and optimal dosing of various GLP-1 agonists in acute burn management.

Medications to treat substance use disorders (SUDs) remain suboptimal or, in the case of stimulants and cannabis, non-existent. Many factors have contributed to this paucity, including the biological complexity of addiction, regulatory challenges, and a historical lack of enthusiasm among pharmaceutical companies to commit resources to this disease space. Despite these headwinds, the recent opioid crisis has highlighted the devastating consequences of SUDs for both individuals and society, stimulating urgent efforts to identify novel treatment approaches. In addition, several neurobiological systems have been recently implicated in unique aspects of drug reward, opening the door to candidate medications with novel mechanisms of action. Here, we provide an overview of efforts to target several of these new systems, with a focus on those that are the subject of ongoing clinical trials as well as being areas of interest among the authors' research groups (MHJ, MTB, NAE). Specifically, we discuss new classes of medications targeting the serotonin 2A receptor (i.e., psychedelics), glucagon-like peptide 1 receptor, cannabidiol, dynorphin/kappa opioid receptor, orexin/hypocretin, and oxytocin receptor systems, as well as emergent approaches for modulating the more canonical dopaminergic system via agonist therapies for stimulant use disorders. Collectively, innovations in this space give reason for optimism for an improved therapeutic landscape for substance use disorders in the near future.

Obesity is a chronic condition demanding effective treatment strategies, among which pharmacotherapy plays a critical role. As glucagon-like peptide-1 (GLP-1) agonist approved by the Food and Drug Administration (FDA) for long-term weight management in adults with obesity, liraglutide and semaglutide have great weight loss effect through reducing food intake and delaying gastric emptying. The emergence of unimolecular polypharmacology, which utilizes single molecules to simultaneously target multiple receptors or pathways, marked a revolutionary improvement in GLP-1-based obesity pharmacotherapy. The dual agonist tirzepatide activates both GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) receptors and has shown enhanced potency for weight loss compared to conventional GLP-1 mono agonist. Furthermore, emerging data suggests that unimolecular GLP-1/glucagon (GCG) dual agonist, as well as GLP-1/GIP/GCG triple agonist, may offer superior weight loss efficacy over GLP-1 agonist. This review summarizes the comprehensive mechanisms underlying the pronounced advantages of GLP-1/GIP dual agonist, GLP-1/GCG dual agonist and GLP-1/GIP/GCG triple agonist over GLP-1 mono agonist in weight reduction in obese adults without type 2 diabetes. A deeper understanding of these unimolecular multitargeting GLP-1-based agonists will provide insights for their clinical application and guide the development of new drugs for obesity treatment.

Time-restricted feeding (TRF) is a lifestyle intervention that aims to maintain a consistent daily cycle of feeding and fasting to support robust circadian rhythms. Recently, it has gained scientific, medical, and public attention due to its potential to enhance body composition, extend lifespan, and improve overall health, as well as induce autophagy and alleviate symptoms of diseases like cardiovascular diseases, type 2 diabetes, neurodegenerative diseases, cancer, and ischemic injury. However, there is still considerable debate on the primary factors that contribute to the health benefits of TRF. Despite not imposing strict limitations on calorie intake, TRF consistently led to reductions in calorie intake. Therefore, while some studies suggest that the health benefits of TRF are primarily due to caloric restriction (CR), others argue that the key advantages of TRF arise not only from CR but also from factors like the duration of fasting, the timing of the feeding period, and alignment with circadian rhythms. To elucidate the roles and mechanisms of TRF beyond CR, this review incorporates TRF studies that did not use CR, as well as TRF studies with equivalent energy intake to CR, which addresses the previous lack of comprehensive research on TRF without CR and provides a framework for future research directions.

Obesity and its related complications are growing in prevalence worldwide, with increasing impact to individuals and healthcare systems alike. Currently, the leading treatment approaches for effective and sustained weight loss are bariatric surgery and gut peptide therapeutics. At a high level, both treatment strategies work by hijacking gut-brain axis signaling to reduce food intake. However, we predict that each modality has distinct neuronal mechanisms that are responsible for their success and complications. This review compares the neurobiology of feeding behavior between these two weight loss strategies via a discussion of both clinical and pre-clinical data. The most compelling evidence points to signaling within the hindbrain, hypothalamus, and reward circuits contributing to weight loss. Considerations for treatment, including differing complications between the two treatment approaches, will also be discussed. Based on the data, we pose the hypothesis that these two interventions are acting via distinct mechanisms to induce weight loss. Both interventions have variable degrees of weight loss across the patient population, thus, understanding these distinct mechanisms could help drive individualized medicine to optimize weight loss. This article is part of the Special Issue on "Food intake and feeding states".

Type 2 diabetes and obesity have some overlapping pathophysiology. This has allowed for the creation of therapies which are highly effective in treating both conditions. Weekly subcutaneous incretin agonists are preferred agents as they provide significant improvement in glycemic parameters, weight, and other comorbidities, like heart failure and reduce major adverse cardiovascular event. Bariatric surgery continues to show the most durable benefits for patients with both type 2 diabetes mellitus and obesity and should be considered in patients who are unable to meet goals with pharmacotherapy and lifestyle.

In the search for novel treatment strategies for alcohol use disorder (AUD), glucagon-like peptide-1 (GLP-1) receptor agonists (GLP-1RAs) approved for treating Type 2 diabetes and obesity have caught much attention. GLP-1 is a naturally occurring peptide produced in the small intestines and the brain, regulating plasma glucose levels and satiety. This focused review will report on the preclinical studies, case stories, register-based cohort studies, brain-imaging data and secondary analysis of clinical data supporting the role of GLP-1RAs as a novel treatment of AUD. Several clinical trials are ongoing, examining the potential effects of the GLP-1RA semaglutide in AUD.

Recent studies show that systemic administration of a glucagon-like peptide-1 receptor (GLP-1R) agonist is sufficient to attenuate cocaine seeking. However, the neural mechanisms mediating these effects and the role of endogenous central GLP-1 signaling in cocaine seeking remain unknown. Here, we show that voluntary cocaine taking decreased plasma GLP-1 levels in rats and that chemogenetic activation of GLP-1-producing neurons in the nucleus tractus solitarius that project to the ventral tegmental area (VTA) decreased cocaine seeking. Single-nuclei transcriptomics and FISH studies revealed that GLP-1Rs are expressed primarily on GABA neurons in the VTA. Using in vivo fiber photometry, we found that the efficacy of a systemic GLP-1R agonist to attenuate cocaine seeking was associated with increased activity of VTA GABA neurons and decreased activity of VTA dopamine neurons. Together, these findings suggest that targeting central GLP-1 circuits may be an effective strategy toward reducing cocaine relapse and highlight a functional role of GABAergic GLP-1R-expressing midbrain neurons in drug seeking.

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have emerged as groundbreaking therapeutic agents in managing a spectrum of metabolic disorders, demonstrating remarkable efficacy across multiple organ systems and disease states. These compounds are not only well-established in the treatment of type 2 diabetes (T2D) and obesity-conditions for which they have received widespread approval-but also exhibit promising potential in addressing cardiovascular disease (CVD) and Metabolic dysfunction-associated steatotic liver disease (MASLD). Recent investigations have begun to illuminate the utility of GLP-1RAs in the management of type 1 diabetes (T1D), as well as neurodegenerative disorders such as Alzheimer's and Parkinson's disease and various behavioral disorders. A plethora of clinical trials have consistently validated the capacity of GLP-1RAs to improve glycemic control, promote weight loss, and mitigate cardiovascular risk factors in individuals with T2D and obesity. While their application in T1D remains limited due to safety concerns-particularly regarding the risks of hypoglycemia and hyperglycemic ketoacidosis-emerging data suggest that GLP-1RAs may offer hepatoprotective benefits, potentially reducing liver fat content and decelerating the progression of MASLD. The neuroprotective attributes of GLP-1 RAs have garnered significant interest, with research indicating their potential to alleviate cognitive decline associated with neurodegenerative diseases. Furthermore, preliminary findings highlight the role of GLP-1 RAs in addressing behavioral disorders, emphasizing their extensive therapeutic promise. This comprehensive review synthesizes the current evidence supporting the diverse therapeutic applications of GLP-1RAs, positioning them as "magic drug" therapies for metabolic and neurological disorders. As ongoing research continues to explore innovative applications and combinations of GLP-1RAs, the landscape of disease management in metabolic and neurological contexts is poised for transformative advancements. This review will also critically assess safety considerations and underscore the need for personalized treatment strategies to optimize patient outcomes in these complex and often comorbid conditions.

To compare the risk of primary open-angle glaucoma (POAG) and ocular hypertension in patients with obesity taking glucagon-like peptide 1 receptor agonists (GLP-1RAs) versus alternative weight loss medications.

A retrospective cohort study of the TriNetX research network was conducted by analyzing international electronic health record data from January 2004 through December 2024.

Patients without diabetes who had a diagnosis of being overweight or obesity who were treated with either GLP-1RAs or alternative weight loss medications, including orlistat, phentermine-topiramate, bupropion-naltrexone, or setmelanotide.

Patients were assessed for outcomes at 3 and 5 years. Propensity score matching (PSM) was conducted between cohorts matched for baseline demographics, comorbidities, and medication use. Risk ratios (RR) and 95% confidence intervals (CIs) were calculated subsequently.

Risk of POAG and ocular hypertension.

After PSM, both cohorts comprised 61 057 patients. The risk of both POAG and ocular hypertension were significantly lower in the GLP-1RA group at both 3 and 5 years of follow-up. A 50.4% lower risk at 3 years (RR, 0.496; 95% CI, 0.371-0.664) and a 58.5% lower risk at 5 years (RR, 0.415; 95% CI, 0.316-0.545) for POAG developing was noted. Lower risks of 55.9% at 3 years (RR, 0.441; 95% CI, 0.318-0.611) and 65.8% at 5 years (RR, 0.342; 95% CI, 0.250-0.466) for ocular hypertension developing were noted.

In patients without diabetes, the use of GLP-1RAs exhibited a significantly lower risk of POAG and ocular hypertension compared with alternative weight loss therapy at 3-year and 5-year intervals.

Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Obesity and overweight have become increasingly significant conditions, affecting more than 70% of the adult population in the United States. These conditions are caused by a combination of factors, including genetic, behavioral, environmental, and medical influences. Obesity is a major risk factor for cardiovascular and metabolic diseases. A comprehensive treatment plan for individuals with obesity must recognize the chronic nature of the condition and offer strategies for weight reduction and long-term cardiometabolic benefits. Over the past several decades, multiple therapeutic options have been implemented to address weight loss, appetite regulation, and caloric expenditure, with the goal of reducing the burden of obesity and improving cardiovascular outcomes. Pharmacological treatment of obesity has focused primarily on the central regulation of appetite and food intake behavior. The introduction of incretin agonists for obesity treatment has ushered in a new era of cardiometabolic health, with a multitargeted mechanism that achieves weight loss, glycemic control, decreased cardiovascular mortality, and other metabolic benefits. This review explores the current pharmacological options and the future of obesity treatment.

This case report is interesting because it highlights a direction for the treatment of comorbid obesity and cocaine use disorder, which is an increasing clinical condition from an epidemiological point of view, and allows us to identify the possibility of a new strategy to address the problem of substance craving, particularly for cocaine.

This case report discusses the efficacy of semaglutide in a 54-year-old Caucasian patient with a history of cocaine abuse and obesity. Subcutaneous semaglutide was administered, as per guidelines, with a progressive weekly increase for a total of 12 weeks. The patient was monitored with respect to clinical parameters, as well as psychodiagnostic ones. The patient demonstrated significant weight loss and a marked reduction in cocaine craving.

The action of semaglutide on the hunger and reward centers offers a new approach to the treatment of patients with obesity and concomitant substance use disorders. By targeting glucagon-like peptide-1 receptors involved in both metabolic regulation and reward processing, semaglutide could potentially reduce both food intake and drug craving, thereby improving outcomes for these patients. The findings suggest that semaglutide may be a promising therapeutic option for the management of substance abuse in patients with comorbid obesity.

Glucagon-like peptide-1 (GLP-1), derived from enteroendocrine cells, is a pivotal hormone crucial for blood glucose regulation. Menin, encoded by the MEN1 gene and known for its tumor suppressor role, is abundantly expressed in the intestine. Previous research has demonstrated that acute Men1 excision reverses preexisting glucose intolerance in high-fat diet-fed mice. However, its impact on GLP-1 expression in enteroendocrine cells has not been investigated. In the present study, both the knockdown of Men1 and the administration of the MI-463 menin inhibitor increased GLP-1 expression in glucose-stimulated STC-1 cells. Additionally, administering MI-463 to obese mice significantly elevated GLP-1 levels in both ileal epithelial cells and serum. Mechanistically, menin inhibition enhanced the nuclear accumulation of β-catenin, allowing it to bind TCF7L2, thereby increasing glucagon gene (Gcg) transcription. Furthermore, compared with control mice, mice with intestinal epithelial cell-specific Men1 knockdown exhibited significant improvements in glucose tolerance under fat challenge, which was correlated with elevated GLP-1 levels. These findings suggest that menin-mediated regulation of GLP-1 expression may be an important mechanism through which menin inhibiton alleviates type 2 diabetes.

This letter comments on a study by Jin et al, published recently in the World Journal of Diabetes. Hypoglycemia is a significant complication of diabetes, with primary defense mechanisms involving the stimulation of glucagon secretion in α-cells and the inhibition of insulin secretion in pancreatic β-cells, which are often compromised in type 1 diabetes mellitus (T1DM) and advanced type 2 diabetes mellitus. Recurrent hypoglycemia predisposes the development of impaired hypoglycemia awareness, a condition underpinned by complex pathophysiological processes, encompassing central nervous system adaptations and several hormonal interactions, including a potential role for glucagon-like peptide-1 (GLP-1) in paracrine and endocrine vias. Experimental evidence indicates that GLP-1 may impair hypoglycemic counterregulation by disrupting the sympathoadrenal system and promoting somatostatin release in pancreatic δ-cells, which inhibits glucagon secretion from neighboring α-cells. However, current trials evaluating GLP-1 receptor agonists (GLP-1 RAs) in T1DM patients have shown promising benefits in reducing insulin requirements and body weight, without increasing the risk of hypoglycemia. Further research is essential to elucidate the specific roles of GLP-1 and GLP-1 RAs in modulating glucagon secretion and the sympathetic-adrenal reflex, and their impact on hypoglycemia unawareness in T1DM patients.

G-protein coupled receptors (GPCRs), the largest family of integral membrane proteins, enable cells to sense and appropriately respond to the environment through mediating extracellular signaling to intercellular messenger molecules. GPCRs' pairing with a diverse array of G protein subunits and related downstream secondary messengers, combined with their ligand versatility-from conventional peptide hormone to numerous bioactive metabolites, allow GPCRs to comprehensively regulate metabolism and physiology. Consequently, GPCRs have garnered significant attention for their therapeutic potential in metabolic diseases. This review focuses on six GPCRs, GPR40, GPR120, GLP-1R, and ß-adrenergic receptors (ADRB1, ADRB2, and ADRB3), with GLP-1R recognized as a prominent regulator of system-level metabolism, while the roles of GPR40, GPR120 and ß-adrenergic receptors in central carbon metabolism and energy homeostasis are increasingly appreciated. Here, we discuss their physiological functions in metabolism, the current pharmacological landscape, and the intricacies of their signaling pathways via G protein and ß-arrestin activation. Additionally, we discuss the limitations of existing GPCR-targeted strategies for treating metabolic diseases and offer insights into future perspectives for advancing GPCR pharmacology.

Available knowledge shows that obesity is associated with an impaired endothelial function and an increase in cardiovascular risk, but the mechanisms of this association are not yet fully understood. Adipose tissue dysfunction, adipocytokines production, along with systemic inflammation and associated comorbidities (e.g., diabetes and hypertension), are regarded as the primary physiological and pathological factors. Various strategies are now available for the control of excess body weight. Dietary regimens alone, or in association with bariatric surgery when indicated, are now widely used. Of particular interest is the understanding of the effect of these interventions on endothelial homeostasis in relation to cardiovascular health. Substantial weight loss resulting from both diet and bariatric surgery decreases circulating biomarkers and improves endothelial function. Extensive clinical trials and meta-analyses show that bariatric surgery (particularly gastric bypass) has more substantial and long-lasting effect on weight loss and glucose regulation, as well as on distinct circulating biomarkers of cardiovascular risk. This review summarizes the current understanding of the distinct effects of diet-induced and surgery-induced weight loss on endothelial function, focusing on the key mechanisms involved in these effects.

Clinically effective pharmacological treatment(s) for metabolic dysfunction-associated steatotic liver disease (MASLD) and its progressive form metabolic dysfunction-associated steatohepatitis (MASH) represent a largely unmet need in medicine. Since glucagon-like peptide-1 receptor agonists (GLP-1RAs) have been licensed for the treatment of type 2 diabetes mellitus and obesity, they were one of the first drug classes to be examined in individuals with MASLD/MASH. Successful phase 2 randomised clinical trials with these agents have resulted in progression to phase 3 clinical trials (principally testing the long-term efficacy of subcutaneous semaglutide). Over the last few years, in addition to GLP-1RAs, newer agents with glucose-dependent insulinotropic peptide and/or glucagon receptor agonist functions have been tested, with increasing evidence from phase 2 randomised clinical trials of histological improvements in MASLD/MASH, as well as benefits on MASLD-related extrahepatic complications. Based on this background of evidence, single, dual or triple incretin receptor agonists are becoming an attractive and promising treatment option for MASLD or MASH, particularly in individuals with coexisting obesity or type 2 diabetes mellitus. In this narrative review, we examine the rapidly expanding body of clinical evidence supporting a role of incretin-based pharmacotherapies in delaying or reversing MASH progression. We also discuss the biology of incretins and the putative hepatoprotective mechanisms of incretin-based pharmacotherapies for managing MASLD or MASH.

Both continuous aerobic training (CAT) and high-intensity interval training (HIIT) are recommended to promote health and prevent diseases. Exercise-induced circulating extracellular vesicles (EX-EVs) have been suggested to play essential roles in mediating organ crosstalk, but corresponding molecular mechanisms remain unclear. To assess and compare the systemic effects of CAT and HIIT, five healthy male volunteers were assigned to HIIT and CAT, with a 7-day interval between sessions. Plasma EVs were collected at rest or immediately after each training section, prior to proteomics and miRNA profile analysis. We found that the differentially expressed (DE) miRNAs in EX-EVs were largely involved in the regulation of transcriptional factors, while most of the DE proteins in EX-EVs were identified as non-secreted proteins. Both CAT and HIIT play common roles in neuronal signal transduction, autophagy, and cell fate regulation. Specifically, CAT showed distinct roles in cognitive function and substrate metabolism, while HIIT was more associated with organ growth, cardiac muscle function, and insulin signaling pathways. Interestingly, the miR-379 cluster within EX-EVs was specifically regulated by HIIT, involving several biological functions, including neuroactive ligand-receptor interaction. Furthermore, EX-EVs likely originate from various tissues, including metabolic tissues, the immune system, and the nervous system. Our study provides molecular insights into the effects of CAT and HIIT, shedding light on the roles of EX-EVs in mediating organ crosstalk and health promotion.

Recent studies demonstrated that glucagon-like peptide-1 receptor agonists (GLP-1RA) have promising prospects in promoting wound healing. In this study, we intend to investigate the pro-healing effect and potential molecular mechanism of topical administration of GLP-1RA liraglutide on wounds in normoglycemic mice. Two full-thickness wounds were created on the back of the C57BL/6 mice. The "lower" wounds were topically infiltrated with liraglutide every day after injury; while the "upper" wounds were infiltrated with saline solution. Wound area was measured daily during the 10-day study period. The wound tissue was stained with H&E and immunofluorescence. Western blotting was performed to detect the markers in macrophages. The results showed that topical administration of liraglutide resulted in a rapid reduction of wound size. The capillary density and the expression of vascular endothelial growth factor (VEGF)-A were significantly increased in liraglutide-treated wounds. Findings from immunofluorescence and Western blotting revealed that liraglutide promoted phenotypic polarization of macrophages from M1 to M2. We further identified that M2a macrophages predominantly presented in the early and middle stages of inflammation phase and M2d macrophages presented in the middle and late stages. Our study suggested that GLP-1RA liraglutide could promote wound healing in normoglycemic mice, which is partly attributed to the modulation of the macrophage polarization from M1 subtype to M2 subtype.

Understanding the detailed mechanism of action of glucagon-like peptide 1 receptor (GLP-1R) agonists on distinct topographic and genetically defined brain circuits is critical for improving the efficacy and mitigating adverse side effects of these compounds. In this mini-review, we propose that the central nucleus of the amygdala (CeA) is a critical mediator of GLP-1R agonist-driven hypophagia. Here, we review the extant literature demonstrating CeA activation via GLP-1R agonists across multiple species and through multiple routes of administration. The precise role of GLP-1Rs within the CeA is unclear but the site-specific GLP-1Rs may mediate distinct behavioral and physiological hallmarks of GLP-1R agonists on food intake. Thus, we propose important novel directions and methods to test the role of the CeA in mediating GLP-1R actions.

Diabetes mellitus is a chronic disorder that progressively induces complications, compromising daily independence. Among these, diabetic neuropathy is particularly prevalent and contributes to substantial neuromuscular impairments in both types 1 and 2 diabetes. This condition leads to structural damage affecting both the central and peripheral nervous systems, resulting in a significant decline in sensorimotor functions. Alongside neuropathy, diabetic myopathy also contributes to muscle impairment and reduced motor performance, intensifying the neuromuscular decline. Diabetic neuropathy typically implicates neurogenic muscle atrophy, motoneuron loss and clustering of muscle fibres as a result of aberrant denervation-reinervation processes. These complications are associated with compromised neuromuscular junctions, where alterations occur in pre-synaptic vesicles, mitochondrial content and post-synaptic signalling. Neural damage is intensified by chronic hyperglycaemia and oxidative stress, exacerbating vascular dysfunction and reducing oxygen delivery. These complications imply a severe decline in neuromuscular performance, evidenced by reductions in maximal force and power output, rate of force development and muscle endurance. Furthermore, diabetes-related complications are compounded by age-related degenerative changes in long-term patients. Aerobic and resistance training offer promising approaches for managing blood glucose levels and neuromuscular function. Aerobic exercise promotes mitochondrial biogenesis and angiogenesis, supporting metabolic and cardiovascular health. Resistance training primarily enhances neural plasticity, muscle strength and hypertrophy, which are crucial factors for mitigating sarcopenia and preserving functional independence. This topical review examines current evidence on the physiological mechanisms underlying diabetic neuropathy and the potential impact of physical activity in counteracting this decline.

A number of studies have suggested that pancreatic α cells produce intact GLP-1, thereby constituting a gut-independent paracrine incretin system. However, the debate on whether human α cells contain intact GLP-1 and whether this relates to the presence of diabetes is still ongoing. This study aimed to determine the presence of proglucagon-derived peptides, including GLP-1 isoforms, in pancreas biopsies obtained during partial pancreatectomy from metabolically profiled human donors, stratified according to pre-surgery glucose tolerance.

We enrolled 61 individuals with no known history of type 2 diabetes (31F/30M, age 64.6 ± 10.6 yrs., BMI 24.2 ± 3.68 kg/m2) scheduled for partial pancreatectomy for periampullary neoplasm. Differences in glucose tolerance and insulin secretion/sensitivity were assessed using preoperative 2 h OGTT, 4 h-Mixed Meal Test and Hyperinsulinemic Euglycemic Clamp. Subjects were subsequently classified as normal glucose tolerant (NGT, n = 19), impaired glucose tolerant (IGT, n = 20) or newly diagnosed diabetes (DM) (n = 22). We measured total GLP-1, intact GLP-1, glucagon, insulin, and C-peptide in pancreas biopsies and plasma from these subjects and correlated the results with their secretory and metabolic parameters.

Extractable levels of total GLP-1 were 23.9 ± 2.66 pmol/g, while intact GLP-1 levels were 1.15 ± 0.18 pmol/g. When we examined proglucagon derived peptides (adjusted for glucagon levels), in subjects classified according to glucose tolerance, we observed similar levels of total GLP-1, however, intact GLP-1 was significantly increased in IGT and DM groups and inversely associated with beta cell glucose sensitivity and insulin secretion in vivo.

Our data show that development of glucose intolerance and beta cell dysfunction are significantly associated with increased levels of intra-islet intact GLP-1, a potentially beneficial adaptation of the paracrine regulation of insulin secretion in type 2 diabetes.

Glucagon-like peptide-1 receptor agonist (GLP-1RA) therapies are increasingly used for the treatment of type 2 diabetes mellitus and obesity. Despite growing awareness of potentially increased risk of pulmonary aspiration due to delayed gastric emptying, the risks and benefits of their perioperative use in patients undergoing cardiac procedures remains unexplored. A scoping review was performed to investigate the perioperative GLP-1RA use in patients undergoing cardiac procedures and recommendations.

PubMed and Ovid MEDLINE were searched up to April 2024 to identify English-language studies on the perioperative use of weekly and daily dosed GLP-1RAs in adult patients undergoing cardiac procedures (including cardiac surgery, trans-oesophageal echocardiograms, and cardiac catheterisation procedures).

Three studies were identified, which investigated daily dosed GLP-1RAs in patients undergoing cardiac surgery. No studies were found investigating GLP-1RA use in cardiac catheterisation or trans-oesophageal echocardiograms procedures, and none which specifically examined risk of pulmonary aspiration in patients using GLP-1RAs undergoing cardiac procedures.

GLP-1RAs are beneficial for perioperative weight loss, glycaemic control, and cardiovascular health. Existing guidelines and consensus recommendations are highly contradictory on perioperative GLP-1RA management. Although no known published case reports exist to date of pulmonary aspiration in patients using GLP-1RAs undergoing cardiac procedures, non-cardiac surgical literature strongly suggests that patients are at theoretical risk and a cautious approach is advised in the absence of robust evidence informing recommendations for optimal withholding periods.

Glucagon-like peptide-1 (GLP-1), a hormone released from enteroendocrine cells in the distal small and large intestines in response to nutrients and other stimuli, not only controls eating and insulin release, but is also involved in drinking control as well as renal and cardiovascular functions. Moreover, GLP-1 functions as a central nervous system peptide transmitter, produced by preproglucagon (PPG) neurons in the hindbrain. Intestinal GLP-1 inhibits eating by activating vagal sensory neurons directly, via GLP-1 receptors (GLP-1Rs), but presumably also indirectly, by triggering the release of serotonin from enterochromaffin cells. GLP-1 enhances glucose-dependent insulin release via a vago-vagal reflex and by direct action on beta cells. Finally, intestinal GLP-1 acts on the kidneys to modulate electrolyte and water movements, and on the heart, where it provides numerous benefits, including anti-inflammatory, antiatherogenic, and vasodilatory effects, as well as protection against ischemia/reperfusion injury and arrhythmias. Hindbrain PPG neurons receive multiple inputs and project to many GLP-1R-expressing brain areas involved in reward, autonomic functions, and stress. PPG neuron-derived GLP-1 is involved in the termination of large meals and is implicated in the inhibition of water intake. This review details GLP-1's roles in these interconnected systems, highlighting recent findings and unresolved issues, and integrating them to discuss the physiological and pathological relevance of endogenous GLP-1 in coordinating these functions. As eating poses significant threats to metabolic, fluid, and immune homeostasis, the body needs mechanisms to mitigate these challenges while sustaining essential nutrient intake. Endogenous GLP-1 plays a crucial role in this "ingestive homeostasis."

Oral delivery of peptide drugs remains one of the most formidable challenges in the frontier of pharmaceutical research. Peptide drugs typically suffer from exceptionally low oral bioavailability, primarily attributed to rigorous enzymatic degradation within the gastrointestinal (GI) tract, limited ability to traverse the enterocyte barrier, and significant first-pass hepatic metabolism. Absorption of peptide drugs via the lymphatic route could potentially bypass intracellular lysosome degradation and hepatic first-pass metabolism. In this study, we present a strategy to enhance the lymphatic absorption of the model peptide leuprolide (LEU) by diverting its intracellular trafficking towards the endoplasmic-reticulum (ER)-Golgi pathway. Complexes were formed between LEU and lipophilic excipient and then formulated as an oral emulsion. We observed that the penetration of LEU in the emulsion across the Caco-2 cell monolayer model was diverted from the endosome-lysosome pathway, and LEU entered the bloodstream via the mesenteric lymph nodes (MLNs). The data obtained illustrates that the lipophilic LEU complexes could improve enterocyte permeability and bypass lysosomal degradation, and the change of absorption pathway may reduce hepatic first pass metabolism.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is currently a pressing public health issue associated with adverse outcomes such as cirrhosis, malignancy, transplantation, and mortality. Lifestyle modifications constitute the most effective and fundamental management approach, but they often pose challenges in sustaining long-term clinical benefits. Hence, there is a critical need to enhance our understanding through pharmacological management, which unfortunately remains limited. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have emerged as a leading treatment in the fields of diabetes and obesity, with recent preclinical and clinical studies indicating significant benefits in the management and treatment of MASLD. Our article begins by reviewing the beneficial therapeutic components of GLP-1RAs in MASLD. Subsequently, from a clinical research perspective, we concluded with the liver outcomes of current primary GLP-1RAs and co-agonists. Finally, we presented our insights on clinical concerns such as appropriate trial endpoints, management of comorbidities, and future developments. In conclusion, the benefits of GLP-1RAs in MASLD are promising, and background therapy involving metabolic modulation may represent one of the future therapeutic paradigms.

The present paper provides the first documentation and assessment of the capacity of chlorogenic acid to induce hormetic dose-response relationships. The findings suggest that chlorogenic acid may induce anabolic (i.e., growth) and catabolic (i.e., protective) hormetic dose responses in several cell types via a range of complementary and cross-talking pathways, affecting a spectrum of endpoints of biomedical and therapeutic importance. This paper also addresses the issue of whether the widely recognized beneficial effects of coffee consumption, as reported in multiple epidemiological studies, may be related to the hormetic effects of chlorogenic acid and its metabolites and their interactions. The present analysis suggests that some beneficial effects of coffee consumption may be due to the effects of chlorogenic acid and/or its metabolites on the gastrointestinal tract via their capacity to impact gastrointestinal integrity, structure, and functionality. These effects collectively contribute to the attenuation of the gastrointestinal tract and concurrent systemic oxidative stress, positively affecting a range of organ-specific effects.

Glucagon-like peptide-1 (GLP-1) is a 30-amino acid intestinal insulin-stimulating factor, which is mainly secreted by L cells in the distal ileum and colon. It has various physiological functions, such as promoting insulin secretion and synthesis, stimulating β-cell proliferation, inducing islet regeneration, inhibiting β-cell apoptosis and glucagon release, delaying gastric emptying and controlling appetite, etc. It plays a role through a specific GLP-1 receptor (GLP-1R) distributed in many organs or tissues and participates in the regulation of glucose homeostasis in the body. GLP-1 receptor agonists (GLP-1RAs) has the similar physiological function of GLP-1. Because of its structural difference from natural GLP-1, it is not easy to be degraded by dipeptidyl peptidase-4 (DPP-4), thus prolonging the action time. GLP-1RAs have been recognized as a new type of hypoglycemic drugs and widely used in the treatment of type 2 diabetes mellitus (T2DM). Compared with other non-insulin hypoglycemic drugs, it can not only effectively reduce blood glucose and glycosylated hemoglobin (HbA1c), but also protect cardiovascular system, nervous system and kidney function without causing hypoglycemia and weight gain. Therefore, GLP-1RAs has good application prospects and potential for further development.

Glucagon can increase the force of contraction (FOC) in, for example, canine hearts. Currently, whether glucagon can also increase the FOC via cAMP-increasing receptors in the human atrium is controversial discussed. Glucagon alone did not (up to 1 µM) raise the FOC in human right atrial preparations (HAP). Only in the additional presence of the phosphodiesterase (PDE) 3 inhibitor cilostamide (1 µM) or 1 nM isoprenaline did glucagon raise the FOC, starting at 1 µM. The positive inotropic effects of glucagon in HAP were attenuated by a glucagon receptor antagonist (1 µM SC203972), but not by 100 nM exendin(9-39), a glucagon-like peptide-1 receptor (GLP-1R) antagonist. Glucagon (in the presence of cilostamide) demonstrated a reduced efficacy in elevating the FOC in HAP when compared with isoprenaline. In contrast to glucagon, exenatide alone, a GLP-1R agonist, starting at 1 nM, increased the FOC and was more potent and effective than glucagon in raising the FOC in HAP. The effects of exenatide on the FOC were attenuated by exendin(9-39). Hence, glucagon and GLP-1R agonists act functionally via different receptors in the human right atrium. Clinically, these data suggest that endogenous or exogenous glucagon can stimulate glucagon receptors in the human atrium, but only in the presence of PDE inhibitors.

Alcohol use disorder (AUD) is a massive burden for the individual, relatives and society. Despite this, the treatment gap is wide compared with other mental health disorders. Treatment options are sparse, with only three Food and Drug Administration (FDA)-approved pharmacotherapies. Glucagon-like peptide-1 (GLP-1) receptor agonists have shown promising effects in reducing alcohol consumption in preclinical experiments, and clinical trials are in high demand to investigate these potentially beneficial effects in patients diagnosed with AUD.

The effects of the once-weekly GLP-1 receptor agonist semaglutide will be investigated in a 26-week, randomised, placebo-controlled, double-blinded clinical trial. 108 patients diagnosed with AUD and comorbid obesity (body mass index (BMI)≥30 kg/m2)) will be randomised to treatment with either semaglutide or placebo in combination with cognitive behavioural therapy. A subgroup of the patients will have structural, functional and neurochemical brain imaging performed at baseline and after 26 weeks of treatment. The primary endpoint is the reduction in heavy drinking days, defined as days with excess consumption of 48/60 g of alcohol per day (women and men, respectively). Secondary endpoints include changes from baseline to week 26 in alcohol consumption, smoking status, quality of life, fibrosis-4 score, plasma concentration of phosphatidylethanol, brain gamma-aminobutyric acid (GABA) levels, alcohol cue reactivity, functional connectivity and white matter tract integrity.

Recruitment started in June 2023.

The study is approved by the Ethics Committee of the Capital Region of Denmark, the Danish Board of Health and the Danish Data Protection Agency. All patients will sign the written consent form before being included in the trial. Results will be disseminated through peer-reviewed publications and conference presentations. After the results are published, all de-identified data will be available in the Mendeley database.

NCT05895643.

Overweight and obesity-chronic illnesses in which an increase in body fat promotes adipose tissue dysfunction and abnormal fat mass resulting in adverse metabolic, biomechanical, and psychosocial health consequences-negatively impact female fertility. Adverse conception outcomes are multifactorial, ranging from poor oocyte quality and implantation issues to miscarriages and fetal health issues. However, with the advent of novel pharmacologic agents, significant weight loss can be achieved, improving the chances of healthy pregnancies, and their use should be considered during periconceptual counseling. There are currently 6 FDA-approved medications for weight loss: 2 GLP1-receptor agonists (GLP1-RAs) liraglutide and semaglutide, 1 dual GLP-1 and gastric inhibitory peptide agonist (GLP1-GIP) tirzepatide, Contrave (naltrexone/bupropion), Qsymia (phentermine/Topamax), and Xenical (orlistat). GLP1-RAs reduce food cravings, appetite, and "food noise" and improve insulin sensitivity and satiety, all of which lead to significant weight loss, ranging from 6 to 30% of starting total body weight or greater, depending on the specific agent used. Their efficacy and relative safety should make them first-line options for women seeking to lose weight in the year before trying to conceive. Contrave, the combination of naltrexone and bupropion, seems to work most significantly for weight loss by inhibiting the rewarding and reinforcing effects of food consumption. Clinical trials report ~ 6% loss of starting total body weight with use of Contrave, as well as improvement in metabolic health factors. It may also improve a woman's ability to conceive by mitigating the effects of PCOS and endometriosis and reducing the drive for alcohol and smoking. Qsymia, the combination of phentermine and topiramate, results in more weight loss than Contrave but cannot be used in the acute preconception period, as its topiramate component is a known teratogen. Orlistat is another FDA-approved medication for weight loss; however, it is currently used much less often than other anti-obesity drugs because of its relatively lower efficacy and significant side effects. Bariatric surgery, which can lead to significant weight loss (25-50%), was previously regarded as the most durable method for weight loss, before the advent of GLP1-RAs. Given the inherent risks of surgery, the development of vitamin (i.e. B12, folate, vitamin D) and mineral (i.e. iron, copper, zinc) deficiencies, that may impact the health of the mother and fetus, as well as the recommended delay of 1-2 years prior to attempting pregnancy, bariatric surgery should not be considered first-line therapy for obesity management in women of reproductive age, especially for women who are hoping to conceive quickly or are nearing advanced maternal age.

Clinically significant and meaningful weight loss is achievable with pharmacotherapy to help enhance fertility in women of reproductive age who are overweight or obese. Current research supports the use of weight loss medications for enhancing spontaneous conception and response to ovulation induction. Further research on the effects upon live birth rates are warranted. For meaningful weight loss, GLP1-RAs can be considered for use in the preconception period, as long as they are stopped at least 2 months before conception. Contrave can be considered as well, though resulting in less weight loss. Phentermine and Qsymia are teratogenic but can be used with contraception for weight loss before trying to get pregnant.