Search Results (98)

Obesity is a multifaceted disorder influenced by various factors, with heredity being a significant contributor. Bariatric surgery is the most effective long-term intervention for morbid obesity and associated comorbidities, while outcomes vary significantly across individuals. Recent studies indicate that genetic and molecular determinants, particularly alterations in the leptin–melanocortin signalling pathway involving the fat mass and obesity-associated gene (FTO), pro-opiomelanocortin (POMC), melanocortin 4 receptor (MC4R), leptin (LEP), and leptin receptor (LEPR), influence the efficacy of weight loss and metabolic adaptations post-surgery. This narrative review consolidates evidence from peer-reviewed papers available in PubMed and Scopus until July 2025. The emphasis was on novel research and systematic reviews examining genetic polymorphisms, gene–environment interactions, and outcomes following bariatric procedures such as Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy (SG). Recent research emphasised the integration of genetic screening and precision medicine models into clinical bariatric workflows. Variants in FTO (e.g., rs9939609), MC4R (e.g., rs17782313), LEPR, and POMC are associated with diminished weight loss post-surgery, an increased likelihood of weight regain, and reduced metabolic enhancement. Patients with bi-allelic mutations in MC4R, POMC, or LEPR exhibited poor long-term outcomes despite receiving effective physical interventions. Furthermore, genes regulating mitochondrial metabolism (such as PGC1A), adipokine signalling (such as ADIPOQ), and glucose regulation (such as GLP1R) have been demonstrated to influence the body’s response to sugar and the extent of weight gain or loss. Two recent systematic reviews elucidate that candidate gene investigations are beneficial; however, larger genome-wide association studies (GWAS) and machine learning techniques are necessary to enhance predictive accuracy. Integrating genetic and molecular screening with bariatric surgery planning possesses significant therapeutic potential. Genotyping can assist in patient selection, procedural decisions, and medication additions, particularly for those with variants that influence appetite regulation or metabolic flexibility. Advancements in precision medicine, including the integration of polygenic risk scores, omics-based profiling, and artificial intelligence, will enhance the customisation of surgical interventions and extend the lifespan of individuals with severe obesity. The epigenetic regulators of energy balance DNA methylation, histone changes, and microRNAs that may affect individual differences in weight-loss patterns after bariatric surgery are also briefly contextualised. We discuss the concept that epigenetic modulation of gene expression, mediated by microRNAs in response to food and exercise, may account for variations in metabolic outcomes post-surgery. Full article

The early developmental transition from endogenous to exogenous feeding is a critical period in carnivorous fish larvae, often associated with high mortality rates in aquaculture. Although trypsin, a key protease in protein digestion, is hypothesized to play a pivotal role in initiating exogenous feeding, the expression dynamics and functional contributions of trypsin and isoforms during early development remain poorly characterized in carnivorous species. This study explores the critical role of trypsin in the early feeding process of carnivorous fish, using mandarin fish (Siniperca chuatsi) as a model, which is a commercially valuable species that faces significant challenges during this phase due to its strict dependence on live prey and underdeveloped digestive system. Phylogenetic analysis indicates that, compared to herbivorous and omnivorous fish, carnivorous fish have evolved a greater number of trypsins, with a distinct branch specifically dedicated to try. RNA-seq data revealed the expression profiles of 13 trypsins during the early developmental stages of the mandarin fish. Most trypsins began to be expressed in large quantities with the appearance of the pancreas, reaching a peak prior to feeding. In situ hybridization revealed the spatiotemporal expression pattern of trypsins, starting from the pancreas in early development and later extending to the intestines. Furthermore, inhibition of trypsins activity successfully suppressed early oral feeding in mandarin fish, which was achieved by increasing the expression of cholecystokinin 2 (CCK2) and proopiomelanocortin (POMC) to suppress appetite. These findings enhance our understanding of the adaptive relationship between the ontogeny of the digestive enzyme system and feeding behavior in carnivorous fish. This research may help alleviate bottleneck issues in aquaculture production by improving the survival rate and growth performance of carnivorous fish during critical early life stages. Full article

Melanocortin receptors (MCRs) are responsible for various functions ranging from skin pigmentation, regulation of appetite, stress response and cognition, steroid synthesis, and energy balance to cellular regeneration and immunomodulation. The genetic polymorphism with tissue distribution ranging from the brain, limbic system, and adrenal cortex to neutrophils, monocytes, and macrophages is evident in MCRs. The mutations in MC1R, MC2R, MC3R, and MC4R genes are associated with risk of melanoma, familial glucocorticoid deficiency, obesity, and type 2 diabetes mellitus, respectively. Meanwhile, MC1R, MC2R, and MC5R genes are involved in the risk of major depressive disorder. Melanocortin receptors are involved in different inflammatory disorders, i.e., atopic dermatitis, autoimmune uveitis, sarcoidosis, respiratory diseases, multiple sclerosis, scleroderma, inflammatory bowel disease, amyotrophic lateral sclerosis, Alzheimer’s disease, arthritis, and reperfusion injury. Several newer therapeutic agents related to MCRs have numerous advantages over the current anti-inflammatory drugs, demonstrating therapeutic relevance. Among them, α-MSH analogs play a role in atopic dermatitis and scleroderma, and MC1R agonist Dersimelagon has shown effectiveness in systemic sclerosis. The FDA has recently approved the repository corticotropin injection (RCI) to treat sarcoidosis. The FDA has also approved various melanocortin agonists, i.e., Bremelanotide, Afamelanotide, and Setmelanotide, for the treatment of hypoactive sexual desire disorder, Erythropoietic protoporphyria, and obesity, due to pro-opiomelanocortin and leptin receptor deficiency, respectively. Therefore, this review aims to summarize the function and genetic polymorphism of melanocortin receptors, regulatory pathways involving MCRs, and the existing evidence of the prime effect of MCRs on inflammatory responses via different mechanisms and their potential therapeutic use in inflammatory diseases. Full article

Leptin, an adipocyte-derived hormone, plays a central role in the regulation of energy homeostasis by acting on distinct hypothalamic nuclei. This review explores recent advances in our understanding of leptin’s region-specific actions within the arcuate nucleus, ventromedial hypothalamus, dorsomedial hypothalamus, and lateral hypothalamus, highlighting their contributions to appetite regulation, energy expenditure, and neuroendocrine function. In the hypothalamic arcuate nucleus, leptin’s differential regulation of pro-opiomelanocortin and agouti-related peptide/neuropeptide Y neurons is now complemented by the identification of novel leptin-responsive neuronal populations—such as those expressing prepronociceptin, basonuclin 2, and Pirt—as well as a growing array of cellular and molecular modulators, including secreted factors like angiopoietin-like growth factor, zinc-α2-glycoprotein, and spexin, intracellular regulators such as Rap1, growth factor receptor-bound protein 10, and spliced X-box binding protein 1. In the ventromedial hypothalamus, leptin integrates with both peripheral (e.g., cholecystokinin) and central (e.g., pituitary adenylate cyclase-activating polypeptide) signals, while epigenetic mechanisms, such as those mediated by Jumonji domain-containing protein D3, regulate leptin receptor expression and sensitivity. The dorsomedial hypothalamus is increasingly recognized for coordinating leptin’s effects on metabolism, circadian rhythms, and respiration through distinct neuronal populations, including a subset of neurons co-expressing GLP-1 receptors that mediate leptin’s metabolic effects. In the lateral hypothalamus, leptin modulates reward-driven feeding via GABAergic neuronal populations—circuits that are particularly susceptible to disruption following early life trauma. Together, these insights reveal a sophisticated neurobiological framework through which leptin orchestrates systemic physiology. Understanding the heterogeneity of leptin signaling opens new avenues for restoring leptin sensitivity and developing personalized therapeutic strategies to combat obesity and related metabolic disorders. Full article

Background: Gold nanoparticles (AuNPs) have several beneficial properties that make them effective as intracellular drug carriers, and their potential for various diagnostic and therapeutic applications is gaining recognition. Depending on their size and shape, AuNPs can cross the central nervous system (CNS) through the blood–brain barrier (BBB). In the CNS, they can exert a variety of influences on neuronal and glial cells, which can be both supportive—promoting cell health and function—and cytotoxic, potentially leading to cellular damage. The hypothalamus (HT) is the first region where nanoparticles (NPs) interact, as this neuroendocrine center is particularly sensitive to factors in the systemic circulation due to its function and location. This area is affected by systemic factors, including pro-opiomelanocortin (POMC) neurons, which regulate metabolic function and maintain homeostasis. The activity of mitochondria within these cells influences their response to both external factors and the presence of AuNPs, thereby facilitating a complex interplay between nanoparticle interactions and cellular metabolism in this vital brain region. Aims: This study investigates how AuNPs, at different concentrations and exposure times under in vitro conditions, affect the mitochondrial activity of POMC neurons, aiming to provide a comprehensive understanding of the mechanisms in the HT. Methods: The study investigates the effect of varying gold nanoparticle concentrations on the mitochondrial activity of POMC neurons over treatment periods of 1, 15, 24, and 48 h. Mitochondrial activity was measured using a Seahorse XFp Analyzer to provide high-resolution insights. Additionally, mitochondrial functionality was assessed through the detection of reactive oxygen species (ROS) and cell viability. Results: The findings indicated that the effects of gold nanoparticles on mitochondrial activity depend significantly on their concentration and exposure time. Specifically, exposure leads to an increase in early response systems, the citric acid cycle, and proton efflux, ultimately resulting in the inhibition of mitochondrial function and ATP production in POMC cells. This disruption may affect hypothalamic regulation and energy metabolism. Full article

Pituitary pars intermedia dysfunction (PPID) is a common, slowly progressive, neurodegenerative disorder of the older horse. Oxidative damage to the hypothalamic periventricular neurons results in loss of dopaminergic inhibition of the pars intermedia region of the pituitary gland. Consequently, there is increased production of the pro-opiomelanocortin (POMC)-derived hormones normally produced by this region, as well as initial melanocyte hypertrophy and hyperplasia, followed by adenomatous change. Clinical signs that are highly suggestive of the disease are generalised and regional hypertrichosis and delayed/abnormal coat shedding. Numerous clinical signs provide a moderate clinical suspicion, including hyperhidrosis, abnormal fat distribution/regional adiposity, epaxial muscle atrophy/loss of topline, laminitis, weight loss, recurrent infections, behavioural changes/lethargy, polyuria and polydipsia, a pot-bellied appearance, bulging supraorbital fat pads, reduced wound healing, lordosis and infertility. In all animals, a diagnosis of PPID is made based on the signalment, clinical signs and results of further diagnostic tests, with age being a crucial factor to consider. Currently recommended further diagnostic tests are measurement of basal adrenocorticotrophic hormone (ACTH) concentrations (all year) and evaluation of the ACTH response to thyrotrophin-releasing hormone (TRH) using seasonally adjusted references intervals (non-autumn). Animals should also be tested for insulin dysregulation, as laminitis risk in PPID is associated with hyperinsulinaemia. PPID can be managed but not cured; it is a lifelong condition. The individual clinical signs can be managed, e.g., clipping the excessive haircoat and providing unrestricted access to water for individuals with polydipsia. Alternatively, pharmacological management can be employed, and the dopamine-2 receptor agonist pergolide is licensed/approved for the treatment of equine PPID. This should be prescribed in combination with dietary recommendations based on the body condition score and insulin sensitivity status of the individual animal. Full article

Obesity remains a major global health challenge with limited therapeutic options. Bromelain, a proteolytic enzyme complex derived from pineapple, has been recognized for its natural anti-inflammatory, anti-edematous, and appetite-suppressing properties. This study aimed to investigate the effects of bromelain on hypothalamic neuropeptides and metabolic markers in a high-fat diet (HFD)-induced obesity model in rats. Thirty-six male Wistar albino rats were randomly divided into four groups: standard diet (SD), standard diet with bromelain (SDBro), high-fat diet (HFD), and high-fat diet with bromelain (HFDBro). Obesity was induced by a 3-month HFD regimen, followed by bromelain supplementation (200 mg/kg/day, orally) for one month. Hypothalamic tissues were analyzed via ELISA for neuropeptide Y (NPY), pro-opiomelanocortin (POMC), glucose transporter 2 (GLUT2), fibroblast growth factor 2 (FGF2), and insulin-like growth factor 1 receptor (IGF1R). While NPY levels showed no significant changes, POMC increased in the HFD and was normalized with bromelain. GLUT2 was downregulated in the HFD and significantly restored by bromelain. FGF2 levels remained unchanged. IGF1R was upregulated in the HFD but reduced by bromelain, with an unexpected increase in SDBro. Overall, bromelain partially reversed HFD-induced disruptions in hypothalamic energy-regulating pathways, particularly affecting GLUT2 and POMC. These findings highlight bromelain’s potential role in central metabolic regulation under dietary stress. Full article

Pulsed radiofrequency (PRF) current applied to peripheral nerves is a modality used in interventional pain medicine, but its underlying mechanisms remain unclear. This study aimed to investigate whether ex vivo exposure of human monocytic THP-1 cells to PRF current or to heat induces β-endorphin production. Methods: THP-1 cells were exposed to PRF current for 15 min or incubated at elevated temperatures (42 °C to 50 °C) for 3 or 15 min. Flow cytometry was used to assess cell viability, and β-endorphin concentrations in culture supernatants were quantified by ELISA. In a separate experiment, cells were stimulated with lipopolysaccharide (LPS) to compare its effects on β-endorphin release. Results: A 3 min exposure to temperatures ≥ 46 °C reduced THP-1 cell viability, whereas a 15 min exposure to PRF current or to heat at 42 °C did not impair viability. Both PRF current and mild heat significantly enhanced β-endorphin release. β-Endorphin levels in the supernatant of LPS-stimulated cells were comparable to those of cells exposed to PRF current. Conclusions: Ex vivo application of PRF current or mild heat enhanced β-endorphin production from THP-1 cells without significant cytotoxicity. These preliminary findings warrant further investigation using primary human monocytes and in vivo models to assess therapeutic potential. Full article

The hypothalamus is the advanced center that regulates visceral activities under the cerebral cortex. It plays some key roles, such as regulating body temperature, assessing feed intake, and balancing blood glucose and endocrine gland activities. Heat stress is known to trigger a series of detrimental consequences, prominently featuring a reduction in feed intake, an elevation in body temperature, and other related phenomena. To understand the mechanisms of how heat stress affects the function of the hypothalamus, broilers were allocated to three groups: the normal control (NC) group, the heat-stress (HS) group, and the pair-fed (PF) group. The PF group was established with the aim of eliminating the confounding effect of reduced feed intake. The trial lasted for two weeks, from the age of 28 to 42 d. A total of 280 differential expressed genes (DEGs) were identified (p_adj < 0.05, |log₂(FC)| ≥ 1) among three groups, including 3 up-regulated and 112 down-regulated genes in the HS group compared to the NC group, and 3 up-regulated and 13 down-regulated genes between the PF and NC groups. Compared with the HS group, a total of 149 genes were identified in the PF group, of which 125 genes were up-regulated and 24 genes were down-regulated. Gene Ontology enrichment indicated that a subset of DEGs was involved in brain development, the central nervous system (CNS), nerve signal transduction, and calcium homeostasis. The solute carrier family 1 member A6 and solute carrier family 6 member 13, identified as down-regulated genes (p_adj < 0.05) in the HS group, were considered as key genes in Gamma-aminobutyric acid (GABA) transportation, the normal expression of which ensures that extracellular GABA is maintained at a certain level and provides the amino acids needed for metabolism. Simultaneously, the solute carrier family 13 member 4 and solute carrier family 16 member 8 were also identified as down-regulated, which indicated that heat stress resulted in disorder and physiologic derangement in the hypothalamus. Meanwhile, the anorexigenic part of pro-opiomelanocortin genes was up-regulated significantly in the HS group. The transcriptome sequencing results can help us understand the regulatory mechanism of feed intake decline in broilers under heat stress at the genetic level. Full article

Genetic obesity results from loss-of-function mutations, including those affecting the leptin–melanocortin system, which regulates body weight. Pro-opiomelanocortin (POMC)-derived neurohormones act as ligands for melanocortin receptors (MCRs), regulating the leptin–melanocortin pathway through protein–protein interactions. Loss-of-function mutations in the genes encoding POMC, MC3R, and MC4R can lead to the dysregulation of energy expenditure and feeding balance, early-onset obesity, and developmental dysregulation. Recent studies have identified new genetic regulatory mechanisms and potential biomarker regions for the POMC gene and MC4R secondary messenger pathway associated with obesity. Recent advances in crystal structure studies have enhanced our understanding of the protein interactions in this pathway. This narrative review focuses on recent developments in two key areas related to POMC regulation and the leptin–melanocortin pathway: (1) genetic variations in and functions of POMC, and (2) MC3R and MC4R variants that lead to genetic obesity in humans. Understanding these novel mutations in POMC and MC4R/MC3R, as well as their structural and intracellular mechanisms, may help identify strategies for the treatment and diagnosis of obesity, particularly childhood obesity. Full article

Gastric inhibitory polypeptide (GIP) contributes to energy metabolism regulation. We investigated differences in GIP receptor expression in the brain by feeding status among lean and obese mice and the effect of acute central GIP administration on the expression of appetite-regulating hypothalamic neuropeptides. We divided the mice into four groups: fed/lean, fasted/lean, fed/obese, and fasted/obese. The arcuate nucleus (ARC), paraventricular nucleus of the hypothalamus, and nucleus of the solitary tract in the brainstem were harvested. GIP (6 nmol) or saline was injected for the acute intracerebroventricular administration test, followed by the collection of hypothalamic tissue after 2 h. Fed/obese mice had higher ARC GIP receptor mRNA levels than fasted/obese and lean mice. This difference was not observed among lean mice by feeding status. Obese mice had higher blood GIP levels than lean mice. Fed/obese mice had higher blood GIP levels than fasted/obese mice. This difference was not observed among lean mice by feeding status. GIP administration significantly increased proopiomelano-cortin (Pomc) mRNA levels (GIP: 7.59 ± 0.14; saline: 3.44 ± 1.38 arbitrary units; p = 0.030). Increased GIP receptor expression in the ARC in obese mice indicates its central nervous system involvement in energy balance regulation. GIP potentially regulates POMC-mediated appetite regulation in the hypothalamus. It is possible that POMC neurons are targets of GIP action in the brain. Full article

Diverse feeding habits in teleosts involve a wide range of appetite-regulating factors. As an appetite-suppressing gene, the polymorphisms of POMCa in largemouth bass (Micropterus salmoides) were validated via sequencing and high-resolution melting (HRM). The frequency distribution of different POMCa genotypes were analyzed in two populations, and physiological responses of different POMCa genotypes to feed domestication were investigated. The indel of an 18 bp AU-rich element (ARE) in the 3′ UTR and four interlocked SNP loci in the ORF of 1828 bp of POMCa cDNA sequence were identified in largemouth bass and constituted three genotypes of POMC-A I, II, and III, respectively. POMC-A I and Allele I had increased frequencies in the selection population than in the non-selection population (p < 0.01), 63.55% vs. 43.33% and 0.7850 vs. 0.6778, respectively. POMC-A I possessed the lowest value of POMCa mRNA during fasting (p < 0.05) and exhibited growth and physiological advantages under food deprivation and refeeding according to the levels of body mass and four physiological indicators, i.e., cortisol (Cor), growth hormone (GH), insulin-like growth factor-1 (IGF-1), and glucose (Glu). The identification of three POMCa genotypes, alongside their varying physiological responses during feed domestication, suggests a selective advantage that could be leveraged in molecular marker-assisted breeding of largemouth bass that are adapted to feeding on formula diet. Full article

Excessive consumption of vegetable oils such as soybean and canolla oils containing ω-6 polyunsaturated fatty acids is considered one of the most important epidemiological factors leading to the progression of lifestyle-related diseases. However, the underlying mechanism of vegetable-oil-induced organ damage is incompletely elucidated. Since proopiomelanocortin (POMC) neurons in the hypothalamus are related to the control of appetite and energy expenditure, their cell degeneration/death is crucial for the occurrence of obesity. In patients with metabolic syndrome, saturated fatty acids, especially palmitate, are used as an energy source. Since abundant reactive oxygen species are produced during β-oxidation of the palmitate in mitochondria, an increased amount of 4-hydroxy-2-nonenal (4-HNE) is endogenously generated from linoleic acids constituting cardiolipin of the inner membranes. Further, due to the daily intake of deep-fried foods and/or high-fat diets cooked using vegetable oils, exogenous 4-HNE being generated via lipid peroxidation during heating is incorporated into the blood. By binding with atheromatous and/or senile plaques, 4-HNE inactivates proteins via forming hybrid covalent chemical addition compounds and causes cellular dysfunction and tissue damage by the specific oxidation carbonylation. 4-HNE overstimulates G-protein-coupled receptors to induce abnormal Ca²⁺ mobilization and µ-calpain activation. This endogenous and exogenous 4-HNE synergically causes POMC neuronal degeneration/death and obesity. Then, the resultant metabolic disorder facilitates degeneration/death of hippocampal neurons, pancreatic β-cells, and hepatocytes. Hsp70.1 is a molecular chaperone which is crucial for both protein quality control and the stabilization of lysosomal limiting membranes. Focusing on the monkey hippocampus after ischemia, previously we formulated the ‘calpain–cathepsin hypothesis’, i.e., that calpain-mediated cleavage of carbonylated Hsp70.1 is a trigger of programmed neuronal death. This review aims to report that in diverse organs, lysosomal cell degeneration/death occurs via the calpain–cathepsin cascade after the consecutive injections of synthetic 4-HNE in monkeys. Presumably, 4-HNE is a root substance of lysosomal cell death for lifestyle-related diseases. Full article

Background: The biologics derived from human amniotic membranes (AMs) demonstrate potential pain-inhibitory effects in clinical settings. However, the molecular basis underlying this therapeutic effect remains elusive. HC-HA/PTX3 is a unique water-soluble regenerative matrix that is purified from human AMs. We examined whether HC-HA/PTX3 can modulate the gene networks and transcriptional signatures in the dorsal root ganglia (DRG) neurons transmitting peripheral sensory inputs to the spinal cord. Methods: We conducted bulk RNA-sequencing (RNA-seq) of mouse DRG neurons after treating them with HC-HA/PTX3 (15 µg/mL) for 10 min and 24 h in culture. Differential gene expression analysis was performed using the limma package, and Gene Ontology (GO) and protein–protein interaction (PPI) analyses were conducted to identify the networks of pain-related genes. Western blotting and in vitro calcium imaging were used to examine the protein levels and signaling of pro-opiomelanocortin (POMC) in DRG neurons. Results: Compared to the vehicle-treated group, 24 h treatment with HC-HA/PTX3 induced 2047 differentially expressed genes (DEGs), which were centered on the ATPase activity, receptor–ligand activity, and extracellular matrix pathways. Importantly, PPI analysis revealed that over 50 of these DEGs are closely related to pain and analgesia. Notably, HC-HA/PTX3 increased the expression and signaling pathway of POMC, which may affect opioid analgesia. Conclusions: HC-HA/PTX3 induced profound changes in the gene expression in DRG neurons, centered around various neurochemical mechanisms associated with pain modulation. Our findings suggest that HC-HA/PTX3 may be an important biological active component in human AMs that partly underlies its pain inhibitory effect, presenting a new strategy for pain treatment. Full article

Recent clinical trials using synthetic incretin hormones, glucagon-like peptide 1 (GLP-1), and glucose-dependent insulinotropic polypeptide (GIP) receptor agonists have demonstrated that these treatments ameliorated many complications related to obesity, emphasizing the significant impact of body weight on overall health. Incretins are enteroendocrine hormones secreted by gut endothelial cells triggered by nutrient ingestion. The phenomenon that oral ingestion of glucose elicits a much higher insulin secretion than intra-venous injection of equimolar glucose is known as the incretin effect. This also alludes to the thesis that food intake is the root cause of insulin resistance. Synthetic GLP-1 and GIP agonists have demonstrated unprecedented glucoregulation and body weight reduction. Also, randomized trials have shown their ability to prevent complications of obesity, including development of diabetes from prediabetes, reducing cardiovascular disease risks and renal complications in diabetic patients. Moreover, the benefits of these agonists persist among the patients who are already on metformin or insulin. The ultimate question is “Are these benefits of incretin agonism sustainable?” Chronic agonism of pancreatic β-cells may decrease the number of receptors and cause β-cell exhaustion, leading to β-cell failure. Unfortunately, the long-term effects of these drugs are unknown at the present because the longest duration in randomized trials is 3 years. Additionally, manipulation of the neurohormonal axis to control satiety and food intake may hinder the long-term sustainability of these treatments. In this review, we will discuss the incretins’ mechanism of action, challenges, and future directions. We will briefly review other molecules involved in glucose homeostasis such as amylin and glucagon. Amylin is co-expressed with insulin from the pancreas β-cells but does not have insulinotropic function. Amylin suppresses glucagon secretion, slowing gastric emptying and suppressing the reward center in the central nervous system, leading to weight loss. However, amylin can self-aggregate and cause serious cytotoxicity and may cause β-cell apoptosis. Glucagon is secreted by pancreatic α-cells and participates in glucose homeostasis in a glucose-dependent manner. In hypoglycemia, glucagon increases the blood glucose level by glycogenolysis and gluconeogenesis and inhibits glycogenesis in the liver. Several triple agonists, in combination with dual incretins and glucagon, are being developed. Full article