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Analogs of the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP) have become mainstays of obesity and diabetes management. However, both the physiologic role of incretin hormones in the control of appetite and the pharmacologic mechanisms by which incretin-mimetic drugs suppress caloric intake remain incompletely understood. Hunger-promoting AgRP-expressing neurons are an important hypothalamic population that regulates food intake. Therefore, we set out to determine how incretins analogs affect their activity Show less

Obesity-related disability-adjusted life years (DALYs) are expected to increase by approximately 40% from 2020 to 2030. DALYs and mortality related to obesity are the consequence of multiple comorbidities such as cardiovascular (i.e., heart failure) and metabolic diseases (i.e. type 2 diabetes [T2D], metabolic dysfunction-associated steatotic liver disease [MASLD]). Lifestyle interventions represent the foundation of obesity treatment, yet an escalation to pharmacological and/or surgical interventions is often needed. Liraglutide, semaglutide and tirzepatide are incretin-based therapies currently approved by FDA for the management of obesity, while triple GIPR/GCGR/GLP-1R agonist retatrutide (LY3437943), the cagrilintide/semaglutide (CagriSema) 2.4 mg combination, high-dose oral semaglutide, and oral orforglipron are in advanced stages of development. Incretin-based therapies have been associated with a body weight (BW) reduction of ≥5% in at least half of patients in most randomized controlled trials (RCT) and real-world studies (RWS). Semaglutide and tirzepatide have also displayed a mean 60-69% 10-years relative risk reduction of T2D development. In line with evidence accrued in patients with T2D, incretin-based therapies produced a favorable effect on traditional cardiovascular risk factors, such as lipids and blood pressure, and even reduced the risk of major cardiovascular events and heart failure-related events in individuals with obesity, as recently demonstrated for the first time in the SELECT trial with semaglutide 2.4 mg once-weekly. Moreover, incretin-based therapies have also been proven beneficial on obesity-related comorbidities, such as knee osteoarthritis (KOA), obstructive sleep apnea (OSA) syndrome, and MASLD. Further research is needed to improve our understanding of their effects on obesity-related comorbidities and the underlying mechanism, whether involving direct effects on target tissues or mediated by improvement in BW, glucose levels and other CV risk factors. Show less

The dual activation of glucagon-like peptide-1 receptor (GLP-1R) and glucose-dependent insulinotropic polypeptide receptor (GIPR) has emerged as a promising therapeutic strategy for managing type 2 diabetes and obesity. Tirzepatide, a dual agonist peptide, has exhibited superior clinical efficacy in glycemic and weight control compared to selective GLP-1R agonists. Nevertheless, the structural basis of Tirzepatide's extended half-life, attributed to an acylation side chain on the parent peptide, raises questions regarding its partial agonistic activity. Employing molecular dynamics simulations, we explored the dynamic processes of peptide-receptor interactions. We uncovered a crucial salt bridge between parent peptide and GLP-1R/GIPR at K20, a feature not discernible in cryo-electron microscopy structures. Building upon these insights, we developed an optimization strategy based on the parent peptide which involved repositioning the acylation side chain. The results of both in vitro and in vivo experiments demonstrated that the optimized peptide has twofold to threefold increase in agonistic activity compared to Tirzepatide while maintaining its extended half-life in plasma. This led to the design of BGM0504, which proved to be more effective than its predecessor, Tirzepatide, in both laboratory and animal studies. Show less

Food-dependent Cushing's syndrome (FDCS) is a rare presentation of hypercortisolism from adrenal origin, mostly observed in primary bilateral macronodular adrenal hyperplasia (PBMAH) but also in some cases of unilateral adrenocortical adenoma. FDCS is mediated by the aberrant expression of glucose-dependent insulinotropic peptide (GIP) receptor (GIPR) in adrenocortical cells. GIP, secreted by duodenal K cells after food intake, binds to its ectopic adrenal receptor, and stimulates cortisol synthesis following meals. FDCS was first described more than 35 years ago, and its genetic cause in PBMAH has been recently elucidated: Show less

Type 2 diabetes mellitus (T2DM) is a worldwide health problem that has raised major concerns to the public health community. This chronic condition typically results from the cell's inability to respond to normal insulin levels. Glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) are the primary incretin hormones secreted from the intestinal tract. While clinical research has extensively explored the therapeutic potential of GLP-1R in addressing various T2DM-related abnormalities, the possibility of GIPR playing an important role in T2DM treatment is still under investigation. Evidence suggests that GIP is involved in the pathophysiology of T2DM. This chapter focuses on examining the role of GIP as a therapeutic molecule in combating T2DM, comparing the past, present, and future scenarios. Our goal is to delve into how GIP may impact pancreatic β-cell function, adipose tissue uptake, and lipid metabolism. Furthermore, we will elucidate the mechanistic functions of GIP and its receptors in relation to other clinical conditions like cardiovascular diseases, non-alcoholic fatty liver diseases, neurodegenerative diseases, and renal disorders. Additionally, this chapter will shed light on the latest advancements in pharmacological management for T2DM, highlighting potential structural modifications of GIP and the repurposing of drugs, while also addressing the challenges involved in bringing GIP-based treatments into clinical practice. Show less

Glucagon-like peptide-1 (GLP-1)-based drugs have been approved by the United States Food and Drug Administration (FDA) and are widely used to treat type 2 diabetes mellitus (T2DM) and obesity. More recent developments of unimolecular peptides targeting multiple incretin-related receptors ("multi-agonists"), including the glucose-dependent insulinotropic polypeptide (GIP) receptor (GIPR) and the glucagon (Gcg) receptor (GcgR), have emerged with the aim of enhancing drug benefits. In this study, we utilized human and mouse microglial cell lines, HMC3 and IMG, respectively, together with the human neuroblastoma SH-SY5Y cell line as cellular models of neurodegeneration. Using these cell lines, we studied the neuroprotective and anti-inflammatory capacity of several multi-agonists in comparison with a single GLP-1 receptor (GLP-1R) agonist, exendin-4. Our data demonstrate that the two selected GLP-1R/GIPR dual agonists and a GLP-1R/GIPR/GcgR triple agonist not only have neurotrophic and neuroprotective effects but also have anti-neuroinflammatory properties, as indicated by the decreased microglial cyclooxygenase 2 (COX2) expression, nitrite production, and pro-inflammatory cytokine release. In addition, our results indicate that these multi-agonists have the potential to outperform commercially available single GLP-1R agonists in neurodegenerative disease treatment. Show less

Obesity represents a global health crisis with significant patient burdens and healthcare costs. Despite the advances with glucagon-like peptide-1 (GLP-1) receptor agonists in treating obesity, unmet needs remain. This study characterizes a novel glucose-dependent insulinotropic polypeptide receptor (GIPR) peptide antagonist, AT-7687, evaluating its potential to enhance obesity treatment. We assessed the in vitro potency and pharmacokinetics of AT-7687, alongside its therapeutic effects when administered subcutaneously (SC) alone and in combination with liraglutide to high-fat-diet-fed obese non-human primates (NHP). The study spanned a 42-day treatment period and a 15-day washout period. AT-7687 demonstrated a subnanomolar cAMP antagonistic potency (pKB of 9.5) in HEK-293 cells and a 27.4 h half-life in NHPs. It effectively maintained weight stability in obese monkeys, whereas placebo recipients had an 8.6% weight increase by day 42 (P = 0.01). Monotherapy with liraglutide resulted in a 12.4% weight reduction compared to placebo (P = 0.03) and combining AT-7687 with liraglutide led to a 16.3% weight reduction (P = 0.0002). The combination therapy significantly improved metabolic markers, reducing insulin levels by 52% (P = 0.008), glucose by 30% (P = 0.02), triglycerides by 39% (P = 0.05), total cholesterol by 29% (P = 0.03), and LDL cholesterol by 48% (P = 0.003) compared to placebo. AT-7687 treatment was well tolerated and not associated with any side effects. This study underscores the potential of AT-7687 as a promising addition to current obesity treatments. Show less

The gut-derived peptide hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) play important physiological roles including glucose homeostasis and appetite suppression. Stabilized agonists of the GLP-1 receptor (GLP-1R) and dual agonists of GLP-1R and GIP receptor (GIPR) for the management of type 2 diabetes and obesity have generated widespread enthusiasm and have become blockbuster drugs. These therapeutics are refractory to the action of dipeptidyl peptidase-4 (DPP4), that catalyzes rapid removal of the two N-terminal residues of the native peptides, in turn severely diminishing their activity profiles. Here we report that a single atom change from carbon to nitrogen in the backbone of the entire peptide makes them refractory to DPP4 action while still retaining full potency and efficacy at their respective receptors. This was accomplished by use of aza-amino acids, that are bioisosteric replacements for α-amino acids that perturb the structural backbone and local side chain conformations. Molecular dynamics simulations reveal that aza-amino acid can populate the same conformational space that GLP-1 adopts when bound to the GLP-1R. The insertion of an aza-amino acid at the second position from the N-terminus in semaglutide and in a dual agonist of GLP-1R and GIPR further demonstrates its capability as a viable alternative to current DPP4 resistance strategies while offering additional structural variation that may influence downstream signaling. Show less

Primary bilateral macronodular adrenal hyperplasia (PBMAH) is a rare cause of Cushing's syndrome. Individuals with PBMAH and glucose-dependent insulinotropic polypeptide (GIP)-dependent Cushing's syndrome due to ectopic expression of the GIP receptor (GIPR) typically harbor inactivating KDM1A sequence variants. Primary unilateral macronodular adrenal hyperplasia (PUMAH) with concomitant glucocorticoid and androgen excess has never been encountered or studied. We investigated a woman with a large, heterogeneous adrenal mass and severe adrenocorticotropic hormone-independent glucocorticoid and androgen excess, a biochemical presentation typically suggestive of adrenocortical carcinoma. The patient presented during pregnancy (22nd week of gestation) and reported an 18-month history of oligomenorrhea, hirsutism, and weight gain. We undertook an exploratory study with detailed histopathological and genetic analysis of the resected adrenal mass and leukocyte DNA collected from the patient and her parents. Histopathology revealed benign macronodular adrenal hyperplasia. Imaging showed a persistently normal contralateral adrenal gland. Whole-exome sequencing of 4 representative nodules detected KDM1A germline variants, benign NM₀₀₁₀₀₉₉₉₉.3:c.136G > A:p.G46S, and likely pathogenic NM₀₀₁₀₀₉₉₉₉.3:exon6:c.865₈₆₆del:p.R289Dfs*7. Copy number variation analysis demonstrated an additional somatic loss of the KDM1A wild-type allele on chromosome 1p36.12 in all nodules. RNA sequencing of a representative nodule showed low/absent KDM1A expression and increased GIPR expression compared with 52 unilateral sporadic adenomas and 4 normal adrenal glands. Luteinizing hormone/chorionic gonadotropin receptor expression was normal. Sanger sequencing confirmed heterozygous KDM1A variants in both parents (father: p.R289Dfs*7 and mother: p.G46S) who showed no clinical features suggestive of glucocorticoid or androgen excess. We investigated the first PUMAH associated with severe Cushing's syndrome and concomitant androgen excess, suggesting pathogenic mechanisms involving KDM1A. Show less

The glucagon-like peptide 1 receptor (GLP-1R) is a class B G protein-coupled receptor (GPCR) that emerged as a pharmacologic target in cardiometabolic disease, including diabetes and obesity, over 30 years ago. The subsequent widespread clinical use of GLP-1R agonists, including exenatide, liraglutide, and semaglutide, has made the GLP-1R a preeminent model for understanding basic GPCR biology, including the emergent field of biased agonism. Recent data demonstrate that the dual GLP-1R/glucose dependent insulinotropic polypeptide receptor (GIPR) agonist tirzepatide exhibits a biased signaling profile characterized by preferential Gαs activation over β-arrestin recruitment, which appears to contribute to its insulinotropic and body-weight reducing effects in preclinical models. This constitutes a major finding in which nuanced, mechanistic receptor signaling dynamics in vitro mediate real-world clinical differentiation within a drug class. Because of the striking bench-top-to-bed side relevance of this biased signaling phenomenon, we have undertaken a review of the emerging data detailing biased agonism at the GLP-1R. In this review, we introduce the core concept of biased agonism followed by a detailed consideration of the key mechanisms, including ligand-mediated bias, receptor-mediated bias, and systems/cell-type bias. Current industry programs are largely, if not entirely, focused on developing biased ligands, and so we have dedicated a section of the review to a brief meta-analysis of compounds reported to drive biased signaling, with a consideration of the structural determinants of receptor-ligand interactions. In this work, we aim to assess the current knowledge regarding signaling bias at the GLP-1R and how these ideas might be leveraged in future optimization. Show less

Glucose-dependent insulinotropic polypeptide (GIP), a 42-aminoacid hormone, exerts multifaceted effects in physiology, most notably in metabolism, obesity, and inflammation. Its significance extends to neuroprotection, promoting neuronal proliferation, maintaining physiological homeostasis, and inhibiting cell death, all of which play a crucial role in the context of neurodegenerative diseases. Through intricate signaling pathways involving its cognate receptor (GIPR), a member of the G protein-coupled receptors, GIP maintains cellular homeostasis and regulates a defense system against ferroptosis, an essential process in aging. Our study, utilizing GIP-overexpressing mice and in vitro cell model, elucidates the pivotal role of GIP in preserving neuronal integrity and combating age-related damage, primarily through the Epac/Rap1 pathway. These findings shed light on the potential of GIP as a therapeutic target for the pathogenesis of ferroptosis in neurodegenerative diseases and aging. [BMB Reports 2024; 57(9): 417-423]. Show less

In humans, 15 genes encode the class B1 family of GPCRs, which are polypeptide hormone receptors characterized by having a large N-terminal extracellular domain (ECD) and receive signals from outside the cell to activate cellular response. For example, the insulinotropic polypeptide (GIP) stimulates the glucose-dependent insulinotropic polypeptide receptor (GIPR), while the glucagon receptor (GCGR) responds to glucagon by increasing blood glucose levels and promoting the breakdown of liver glycogen to induce the production of insulin. The glucagon-like peptides 1 and 2 (GLP-1 and GLP-2) elicit a response from glucagon-like peptide receptor types 1 and 2 (GLP1R and GLP2R), respectively. Since these receptors are implicated in the pathogenesis of diabetes, studying their activation is crucial for the development of effective therapies for the condition. With more structural information being revealed by experimental methods such as X-ray crystallography, cryo-EM, and NMR, the activation mechanism of class B1 GPCRs becomes unraveled. The available crystal and cryo-EM structures reveal that class B1 GPCRs follow a two-step model for peptide binding and receptor activation. The regions close to the C-termini of hormones interact with the N-terminal ECD of the receptor while the regions close to the N-terminus of the peptide interact with the TM domain and transmit signals. This review highlights the structural details of class B1 GPCRs and their conformational changes following activation. The roles of MD simulation in characterizing those conformational changes are briefly discussed, providing insights into the potential structural exploration for future ligand designs. Show less

The potential benefits of combining lifestyle changes with weight loss pharmacotherapies for obesity treatment are underexplored. Building on recent clinical observations, this study aimed to determine whether "lead-in" calorie restriction before administering clinically approved weight loss medications enhances the maximum achievable weight loss in preclinical models. Diet-induced obese mice (DIO) were exposed to 7 or 14 days of calorie restriction before initiating treatment with semaglutide (a glucagon-like peptide-1 receptor (GLP-1R) agonist), tirzepatide (a GLP-1R/glucose insulinotropic peptide receptor (GIPR) co-agonist), or setmelanotide (a melanocortin-4 receptor (MC4R) agonist). Follow-up assessments using indirect calorimetry determined the contributions of energy intake and expenditure linked to consecutive exposure to dieting followed by pharmacotherapy. Calorie restriction prior to treatment with semaglutide or tirzepatide enhanced the weight loss magnitude of both incretin-based therapies in DIO mice, reflected by a reduction in fat mass and linked to reduced energy intake and a less pronounced adaptive drop in energy expenditure. These benefits were not observed with the MC4R agonist, setmelanotide. Our findings provide compelling evidence that calorie restriction prior to incretin-based therapy enhances the achievable extent of weight loss, as reflected in a weight loss plateau at a lower level compared to that of treatment without prior calorie reduction. This work suggests that more intensive lifestyle interventions should be considered prior to pharmacological treatment, encouraging further exploration and discussion of the current standard of care. Show less

Aberrant G-protein coupled receptor (GPCR) expression is highly prevalent in cortisol-secreting primary bilateral macronodular adrenal hyperplasia (PBMAH) and unilateral adenomas. The aberrant expression of diverse GPCRs and their ligands play an important role in the over-function of various endocrine tumours. Examples include aberrant expression of MC2R, 5-HT4R, AVPR1A, LHCGR, and GnRHR in primary aldosteronism; GCGR, LHCGR, and 5-HT4R in phaeochromocytomas and paragangliomas; TRHR, GnRHR, GIPR, and GRP101 in pituitary somatotroph tumours; AVPR2, D2DR, and SSTR5 in pituitary corticotroph tumours; GLP1R, GIPR, and somatostatin receptors in medullary thyroid carcinoma; and SSTRs, GLP1R, and GIPR in other neuroendocrine tumours. The genetic mechanisms causing the ectopic expression of GIPR in cortisol-secreting PBMAHs and unilateral adenomas have been identified, but distinct mechanisms are implicated in other endocrine tumours. Development of functional imaging targeting aberrant GPCRs should be useful for identification and for specific therapies of this wide spectrum of tumours. The aim of this review is to show that the regulation of endocrine tumours by aberrant GPCR is not restricted to cortisol-secreting adrenal lesions, but also occurs in tumours of several other organs. Show less

Alzheimer's disease (AD) and Parkinson's disease (PD) are the most common neurodegenerative diseases. Their treatment options are rather limited, and no neuroprotective or disease-modifying treatments are available. Anti-diabetic drugs, such as glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) agonists, have been suggested as a potential therapeutic option. Assess AD, PD patients and healthy control subjects were included in the study. Cerebrospinal fluid (CSF) biomarkers of Alzheimer's disease were measured in AD patients, while cognitive impairment was evaluated in PD. All participants were genotyped for three SNPs: Show less

Anti-inflammatory effects of incretin signaling through the glucagon-like peptide-1 receptor (GLP-1R) and the glucose-dependent insulinotropic polypeptide receptor (GIPR) in mice have been reported. Therefore, we hypothesized that signaling through the endogenous GLP-1R and the GIPR individually decreases allergic airway inflammation and that the combination of GLP-1R and GIPR signaling together additively inhibits allergen-induced lung and airway inflammation. WT (C57BL/6J), GLP-1R knockout (KO), GIPR KO, and GLP-1R/GIPR double KO (DKO) mice were challenged intranasally with Alternaria alternata extract (Alt-Ext) or vehicle to evaluate the impact of signaling through these receptors on the innate allergen-induced inflammatory response that is primarily driven by group 2 innate lymphoid cells (ILC2). Alt-Ext-induced IL-33 release in the bronchoalveolar lavage fluid (BALF) was not different between the mouse strains, but thymic stromal lymphopoietin (TSLP) was significantly increased in GLP-1R/GIPR DKO mice challenged with Alt-Ext compared to the other strains. Furthermore, Alt-Ext-induced protein expression of IL-5, IL-13, CCL11, and CCL24 in the lung homogenates, the number of eosinophils, lymphocytes, and neutrophils in the BALF, and the number of lung GATA3+ ILC2 were significantly increased in GLP-1R/GIPR DKO mice compared to the other 3 strains. Furthermore, ICAM-1 expression on lung epithelial cells was increased in GLP-1R/GIPR DKO mice challenged with Alt-Ext compared to the other 3 strains. Deficiency of both GLP-1R and GIPR signaling together increased TSLP release, ILC2 activation, and early type 2 innate immune responses to aeroallergen exposure. Combined GLP-1R and GIPR signaling should be explored for the treatment of asthma. Show less

Obesity poses a significant global health challenge, with an alarming rise in prevalence rates. Traditional interventions, including lifestyle modifications, often fall short of achieving sustainable weight loss, ultimately leading to surgical interventions, which carry a significant burden and side effects. This necessitates the exploration of effective and relatively tolerable pharmacological alternatives. Among emerging therapeutic avenues, glucagon-based treatments have garnered attention for their potential to modulate metabolic pathways and regulate appetite. This paper discusses current research on the physiological mechanisms underlying obesity and the role of glucagon in energy homeostasis. Glucagon, traditionally recognized for its glycemic control functions, has emerged as a promising target for obesity management due to its multifaceted effects on metabolism, appetite regulation, and energy expenditure. This review focuses on the pharmacological landscape, encompassing single and dual agonist therapies targeting glucagon receptors (GcgRs), glucagon-like peptide-1 receptors (GLP-1Rs), glucose-dependent insulinotropic polypeptide receptors (GIPRs), amylin, triiodothyronine, fibroblast growth factor 21, and peptide tyrosine tyrosine. Moreover, novel triple-agonist therapies that simultaneously target GLP-1R, GIPR, and GcgR show promise in augmenting further metabolic benefits. This review paper tries to summarize key findings from preclinical and clinical studies, elucidating the mechanisms of action, safety profiles, and therapeutic potential of glucagon-based therapies in combating obesity and its comorbidities. Additionally, it explores ongoing research endeavors, including phase III trials, aimed at further validating the efficacy and safety of these innovative treatment modalities. Show less

Several new treatments have recently been shown to have heart and kidney protective benefits in people with diabetes. Because these treatments were developed in parallel, it is unclear how the different molecular pathways affected by the therapies may overlap. Here, we examined the effects of the mineralocorticoid receptor antagonist finerenone in mice with comorbid diabetes, focusing on the regulation of expression of the glucagon-like peptide-1 receptor (GLP-1R), gastric inhibitory polypeptide receptor (GIPR) and glucagon receptor (GCGR), which are targets of approved or investigational therapies in diabetes. Male C57BL/6J mice were fed a high fat diet for 26 weeks. Twelve weeks into the high fat diet feeding period, mice received an intraperitoneal injection of streptozotocin before being followed for the remaining 14 weeks (DMHFD mice). After 26 weeks, mice were fed a high fat diet containing finerenone (100 mg/kg diet) or high fat diet alone for a further 2 weeks. Cell culture experiments were performed in primary vascular smooth muscle cells (VSMCs), NRK-49 F fibroblasts, HK-2 cells, and MDCK cells. DMHFD mice developed albuminuria, glomerular mesangial expansion, and diastolic dysfunction (decreased E/A ratio). Glp1r and Gcgr were predominantly expressed in arteriolar VSMCs and distal nephron structures of mouse kidneys respectively, whereas Gipr was the predominant of the three transcripts in mouse hearts. Kidney Glp1r and Gcgr and cardiac Gipr mRNA levels were reduced in DMHFD mice and this reduction was negated or attenuated with finerenone. Mechanistically, finerenone attenuated upregulation of the profibrotic growth factor Ccn2 in DMHFD kidneys, whereas recombinant CCN2 downregulated Glp1r and Gcgr in VSMCs and MDCK cells respectively. Through its anti-fibrotic actions, finerenone reverses Glp1r and Gcgr downregulation in the diabetic kidney. Both finerenone and GLP-1R agonists have proven cardiorenal benefits, whereas receptor co-agonists are approved or under development. The current findings provide preclinical rationale for the combined use of finerenone with the GLP-1R agonist family. They also provide mechanism of action insights into the potential benefit of finerenone in people with diabetes for whom GLP-1R agonists or co-agonists may not be indicated. Show less

The use of incretin agonists for managing metabolic dysfunction-associated steatohepatitis (MASH) is currently experiencing considerable interest. However, whether these compounds have a direct action on MASH is still under debate. This study aims to investigate whether GLP-1R/GIPR agonists act directly in hepatocytes and hepatic stellate cells (HSCs). For this, human hepatocyte and HSCs lines, as well as primary human hepatocytes and HSCs treated with Liraglutide, Acyl-GIP or the GLP-1/GIP dual agonist (MAR709) were used. We show that the concentrations of each compound, which were effective in insulin release, did not induce discernible alterations in either hepatocytes or HSCs. In hepatocytes displaying elevated fatty acid content after the treatment with oleic acid and palmitic acid, none of the three compounds reduced lipid concentration. Similarly, in HSCs activated with transforming growth factor-β (TGFb), Liraglutide, Acyl-GIP and MAR709 failed to ameliorate the elevated expression of fibrotic markers. The three compounds were also ineffective in phosphorylating CREB, which mediates insulinotropic actions, in both hepatocytes and HSCs. These findings indicate that incretin agonists have no direct actions in human hepatocytes or hepatic stellate cells, suggesting that their beneficial effects in patients with MASH are likely mediated indirectly, potentially through improvements in body weight, insulin resistance and glycemic control. Show less

G-protein-coupled receptors (GPCRs) have emerged as critical regulators of bone development and remodeling. In this study, we aimed to identify specific GPCR mutations in osteoporotic patients via next-generation sequencing (NGS). We performed NGS sequencing of six genomic DNA samples taken from osteoporotic patients and two genomic DNA samples from healthy donors. Next, we searched for single-nucleotide polymorphisms (SNPs) in GPCR genes that are associated with osteoporosis. For three osteoporotic patients and one healthy donor, bone biopsies were used to generate patient-specific mesenchymal stem cell (MSC) lines, and their ability to undergo osteodifferentiation was analyzed. We found that MSCs derived from osteoporotic patients have a different response to osteoinductive factors and impaired osteogenic differentiation using qPCR and histochemical staining assays. The NGS analysis revealed specific combinations of SNPs in GPCR genes in these patients, where SNPs in Show less

Obesity is a heterogeneous, complex, and chronic disease that has a detrimental impact on disability-adjusted life years across the globe. Recent advancements in our understanding of gut-brain communication at the molecular level have driven the development of next-generation anti-obesity medications (AOMs). Glucagon-like peptide-1 receptor agonists (GLP1RAs) remain the front-runners in this rapidly evolving landscape of hormone-based AOMs. Two GLP1RAs, namely Liraglutide and Semaglutide, have been approved by the Food and Drug Administration (FDA) and European Medicine Agency (EMA) for use in clinical practice for weight loss. Three oral GLP1RAs, namely Semaglutide, Danuglipron, and Orforglipron, are undergoing advanced clinical trials in individuals with obesity. Amylin receptor agonist (AMYRA) Cagrilintide, when used alone or in combination with Semaglutide, has demonstrated substantial weight reduction in clinical trials. Tirzepatide, a dual agonist for the glucose-dependent insulinotropic polypeptide (GIP) and GLP-1 receptors, has been observed to be associated with a significant placebo-subtracted weight reduction of 17.8% in a 72-week randomized controlled trial. Novel approaches targeting glucagon signalling have also yielded promising preliminary results. Three long-acting GLP1R/glucagon receptor (GCGR) dual agonists, namely Survodutide, Mazdutide, and Pemvidutide, exhibited significant weight loss in clinical trials. Retatrutide, a GLP1R/GCGR/GIPR tri-agonist, has been associated with a placebo-subtracted weight reduction of -22.1% in a 48-week phase-II trial. As a note of caution, long-term data on such medications' safety and cardiovascular benefits is yet to be ascertained. Our review provides a comprehensive overview of the approved and emerging hormone-based AOMs, highlighting the diversity of options that might become available in the near future. Show less

Class B1 G protein-coupled receptors (GPCRs) are peptide hormone receptors and well validated therapeutic targets, however development of non-peptide drugs targeting this class of receptors is challenging. Recently, a series of isoquinoline-based derivates were reported in the patent literature as allosteric ligands for the glucagon receptor subfamily, and two compounds, LSN3451217 and LSN3556672, were used to facilitate structural studies with the glucagon-like peptide-1 receptor (GLP-1R) and glucose dependent insulinotropic peptide receptor (GIPR) bound to orthosteric agonists. Here we pharmacologically characterized stereoisomers of LSN3451217 and LSN3556672, across the class B1 GPCR family. This revealed LSN3556672 isomers are agonists for the glucagon receptor (GCGR), GLP-1R, GIPR and the calcitonin receptor (CTR), albeit the degree of agonism varied at each receptor. In contrast, LSN3451217 isomers were more selective agonists at the GLP-1R, with lower potency at the GCGR and CTR and no activity at the GIPR. All compounds also modulated peptide-mediated cyclic adenosine monophosphate (cAMP) signaling at the GIPR, and to a lesser extent the GLP-1R, in a probe-dependent manner, with modest positive allosteric modulation observed for some peptides, and negligible effects observed with other peptides. In contrast neutral or weak negative/positive allosteric modulation was observed with peptides assessed at the GCGR and CTR. This study expands our knowledge on class B1 GPCR allosteric modulation and may have implications for future structural and drug discovery efforts targeting the class B1 GPCR subfamily. Show less

Glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) are gut-derived peptide hormones that potentiate glucose-dependent insulin secretion. The clinical development of GIP receptor-GLP-1 receptor (GIPR-GLP-1R) multiagonists exemplified by tirzepatide and emerging GIPR antagonist-GLP-1R agonist therapeutics such as maritide is increasing interest in the extrapancreatic actions of incretin therapies. Both GLP-1 and GIP modulate inflammation, with GLP-1 also acting locally to alleviate gut inflammation in part through antiinflammatory actions on GLP-1R+ intestinal intraepithelial lymphocytes. In contrast, whether GIP modulates gut inflammation is not known. Here, using gain- and loss-of-function studies, we show that GIP alleviates 5-fluorouracil-induced (5FU-induced) gut inflammation, whereas genetic deletion of Gipr exacerbates the proinflammatory response to 5FU in the murine small bowel (SB). Bone marrow (BM) transplant studies demonstrated that BM-derived Gipr-expressing cells suppress 5FU-induced gut inflammation in the context of global Gipr deficiency. Within the gut, Gipr was localized to nonimmune cells, specifically stromal CD146+ cells. Hence, the extrapancreatic actions of GIPR signaling extend to the attenuation of gut inflammation, findings with potential translational relevance for clinical strategies modulating GIPR action in people with type 2 diabetes or obesity. Show less

From the pioneering moment in 1987 when the insulinotropic effect of glucagon-like peptide 1 (GLP-1) was first demonstrated in humans, to today's pharmaceutical gold rush for GLP-1-based treatments of obesity, the journey of GLP-1 pharmacology has been nothing short of extraordinary. The sequential conceptual developments of long-acting GLP-1 receptor (GLP-1R) mono-agonists, GLP-1R/glucose-dependent insulinotropic polypeptide receptor (GIPR) dual-agonists, and GLP-1R/GIPR/glucagon receptor (GcgR) triple agonists, have led to profound body weight-lowering capacities, with benefits that extend past obesity and towards obesity-associated diseases. The GLP-1R/GIPR dual-agonist tirzepatide has demonstrated a remarkable 23% body weight reduction in individuals with obesity over 72 weeks, eclipsing the average result achieved by certain types of bariatric surgery. Meanwhile, the GLP-1R/GIPR/GcgR triple-agonist retatrutide achieves similar body weight loss (∼25%) in just two-thirds of the time, potentially surpassing the efficacy of Roux-en-Y gastric bypass. These remarkable achievements rightfully raise the question whether and why there is still need for novel anti-obesity medications (AOMs) in the future. Show less

Class B1 G protein-coupled receptors (GPCRs) are important regulators of many physiological functions such as glucose homeostasis, which is mainly mediated by three peptide hormones, i.e., glucagon-like peptide-1 (GLP-1), glucagon (GCG), and glucose-dependent insulinotropic polypeptide (GIP). They trigger a cascade of signaling events leading to the formation of an active agonist-receptor-G protein complex. However, intracellular signal transducers can also activate the receptor independent of extracellular stimuli, suggesting an intrinsic role of G proteins in this process. Here, we report cryo-electron microscopy structures of the human GLP-1 receptor (GLP-1R), GCG receptor (GCGR), and GIP receptor (GIPR) in complex with G Show less

Glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like-peptide-1 (GLP-1) are incretin hormones that stimulate insulin secretion and improve glycemic control in individuals with type 2 diabetes (T2D). Data from several cardiovascular outcome trials for GLP-1 receptor (GLP-1R) agonists have demonstrated significant reductions in the occurrence of major adverse cardiovascular events in individuals with T2D. Although the cardiovascular actions attributed to GLP-1R agonism have been extensively studied, little is known regarding the cardiovascular consequences attributed to GIP receptor (GIPR) agonism. As there is now an increasing focus on the development of incretin-based co-agonist therapies that activate both the GLP-1R and GIPR, it is imperative that we understand the mechanism(s) through which these incretins impact cardiovascular function. This is especially important considering that cardiovascular disease represents the leading cause of death in individuals with T2D. With increasing evidence that perturbations in cardiac energy metabolism are a major contributor to the pathology of diabetes-related cardiovascular disease, this may represent a key component through which GLP-1R and GIPR agonism influence cardiovascular outcomes. Not only do GIP and GLP-1 increase the secretion of insulin, they may also modify glucagon secretion, both of which have potent actions on cardiac substrate utilization. Herein we will discuss the potential direct and indirect actions through which GLP-1R and GIPR agonism impact cardiac energy metabolism while interrogating the evidence to support whether such actions may account for incretin-mediated cardioprotection in T2D. Show less

Primary pigmented nodular adrenocortical disease (PPNAD) and bilateral macronodular adrenocortical disease (BMAD) are 2 forms of adrenocortical nodular diseases causing Cushing's syndrome but are 2 very distinct conditions. PPNAD, affecting mostly young patients with an almost constant severe Cushing's syndrome, is characterized by pigmented micronodules, usually less than 1 cm, not always visible on imaging. On the contrary, BMAD is predominantly diagnosed in the fifth and sixth decades, with highly variable degrees of cortisol excess, from mild autonomous cortisol secretion to overt Cushing's syndrome. BMAD presents as large bilateral adrenal macronodules, easily observed on imaging. Both diseases are often genetically determined: frequently PPNAD is observed in a multiple neoplasia syndrome, Carney complex, and a germline genetic defect is identified in around 80% of index cases, always affecting key actors of the cAMP/protein kinase A (PKA) pathway: mostly PRKAR1A, encoding the PKA 1-alpha regulatory subunit. On the other hand, BMAD appears mostly isolated, and 2 predisposing genes are known at present: ARMC5, accounting for around 20% of index cases, and the recently identified KDM1A, causing the rare presentation with food-dependent Cushing's syndrome, mediated by the ectopic expression of the glucose-dependent insulinotropic polypeptide receptor (GIPR) in adrenal nodules. GIPR was the first demonstrated receptor to illegitimately regulate cortisol secretion in nodular adrenocortical diseases, and a myriad of other receptors and paracrine signals were discovered afterward. The last 30 years were pivotal in the understanding of the genetics and pathophysiology of bilateral adrenocortical nodular diseases, leading to a personalized approach of these fascinating conditions. Show less