Regulation Of Food Intake Research Articles

The Possible Involvement of Glucagon-like Peptide-2 in the Regulation of Food Intake through the Gut-Brain Axis.

Food intake regulation is a complex mechanism involving the interaction between central and peripheral structures. Among the latter, the gastrointestinal tract represents one of the main sources of both nervous and hormonal signals, which reach the central nervous system that integrates them and sends the resulting information downstream to effector organs involved in energy homeostasis. Gut hormones released by nutrient-sensing enteroendocrine cells can send signals to central structures involved in the regulation of food intake through more than one mechanism. One of these is through the modulation of gastric motor phenomena known to be a source of peripheral satiety signals. In the present review, our attention will be focused on the ability of the glucagon-like peptide 2 (GLP-2) hormone to modulate gastrointestinal motor activity and discuss how its effects could be related to peripheral satiety signals generated in the stomach and involved in the regulation of food intake through the gut-brain axis. A better understanding of the possible role of GLP-2 in regulating food intake through the gut-brain axis could represent a starting point for the development of new strategies to treat some pathological conditions, such as obesity.

Globular adiponectin, acting via AdipoR1, regulates food intake of Siberian sturgeon (Acipenser baerii) in a mTOR dependent manner

Adiponectin (AdipoQ) is a hormone that regulates food intake and energy homeostasis in mammals. The globular adiponectin (gAd) has been reported involved in the regulation of appetite, but the regulatory role and mechanism in fish remains unelucidated. Using Siberian sturgeon as a model of Chondrostei, the recombinant gAd protein of Siberian sturgeon (SsgAd) was produced by Escherichia coli expression system and verified using western blotting. Intraperitoneal injection of recombinant SsgAd protein at 100 ng/g BW suppressed food intake 1 h after administration. Peripheral injection of SsgAd protein caused the upregulation of anorexigenic pyy expression in the valvula intestine, but did not affect cck expression in the valvula intestine and orexigenic ghrelin expression in the stomach. The SsgAd administration significantly increased the hypothalamic expressions of pomc and decreased npy, agrp, and cart expression. In addition, SsgAd recombinant protein promoted adipor1, ampkα2, akt, and mtor mRNA expressions within the hypothalamus, whereas inhibited ampkβ1, ampkβ2 and ampkγ2 mRNA expression, suggesting AMPK and mTOR signaling pathways might be related to SsgAd protein-mediated anorexia activity. Furthermore, the injection of an mTOR antagonist (rapamycin) reversed the reduced food intake and npy, agrp, and cart expression due to the peripheral injection of SsgAd, as well as the increased pomc expression induced by SsgAd, which were not observed after AMPK antagonist (dorsomorphin) treatment. In summary, the current study, for the first time, suggest that the anorexigenic function of SsgAd might bind with AdipoR1 and activate the mTOR signal pathway to affect the expression of hypothalamic appetite factors in Siberian sturgeon. This study provides new insight into the molecular mechanism of AdipoQ in feeding regulation in fish, and a basis for further exploration on physiological function of AdipoQ.

The effect of intraperitoneal injection of Glycyrrhizin on central regulation of food intake in broilers injected with LPS

ABSTRACT 1. Poultry farming faces challenges regarding correct hygiene and nutrition. One of the challenges is gram-negative bacteria that stimulate pro-inflammatory reactions through lipopolysaccharide (LPS) and cause disease and anorexia. Liquorice, a medicinal plant containing glycyrrhizin (Glz; a saponin and emulsifier compound) as its main active ingredient, was injected into broilers to investigate any beneficial effects on feed intake in LPS-injected broilers. 2. The study involved three experiments using 72 male broiler chickens in each, to examine the impact of Glz on feed intake, especially when challenged with lipopolysaccharide (LPS) by intra-peritoneal (IP) injection to cause inflammation (n = 24). Experiment 1 was conducted to examine the effects of intraperitoneal injection of Glz (12.5, 25 and 50 mg) on feed intake in chickens. In experiment 2, the effects of intracerebroventricular injections of LPS (6.25, 12.5 and 25 ng) were examined. The third experiment investigated the impact of IP injection of Glz on inflammation induced by LPS. 3. Injection of Glz significantly increased feed intake in a dose-dependent manner. Whereas LPS significantly reduced the feed intake in feed-deprived chickens (p < 0.05). 4. In conclusion, Glz can neutralise the feed intake reduction caused by inflammation in broilers, highlighting its potential role in modulating feed intake in broilers.

Paraventricular oxytocin neurons impact energy intake and expenditure: projections to the bed nucleus of the stria terminalis reduce sucrose consumption.

The part played by oxytocin and oxytocin neurons in the regulation of food intake is controversial. There is much pharmacological data to support a role for oxytocin notably in regulating sugar consumption, however, several recent experiments have questioned the importance of oxytocin neurons themselves. Here we use a combination of histological and chemogenetic techniques to investigate the selective activation or inhibition of oxytocin neurons in the hypothalamic paraventricular nucleus (OxtPVH). We then identify a pathway from OxtPVH neurons to the bed nucleus of the stria terminalis using the cell-selective expression of channel rhodopsin. OxtPVH neurons increase their expression of cFos after both physiological (fast-induced re-feeding or oral lipid) and pharmacological (systemic administration of cholecystokinin or lithium chloride) anorectic signals. Chemogenetic activation of OxtPVH neurons is sufficient to decrease free-feeding in Oxt Cre:hM3Dq mice, while inhibition in Oxt Cre:hM4Di mice attenuates the response to administration of cholecystokinin. Activation of OxtPVH neurons also increases energy expenditure and core-body temperature, without a significant effect on locomotor activity. Finally, the selective, optogenetic stimulation of a pathway from OxtPVH neurons to the bed nucleus of the stria terminalis reduces the consumption of sucrose. Our results support a role for oxytocin neurons in the regulation of whole-body metabolism, including a modulatory action on food intake and energy expenditure. Furthermore, we demonstrate that the pathway from OxtPVH neurons to the bed nucleus of the stria terminalis can regulate sugar consumption.

The role of receptor activity-modifying proteins in obesity and diabetes mellitus.

Receptor activity-modifying proteins (RAMPs) modulate the expression and activity of numerous G protein-coupled receptors, primarily those within class B1. These receptors have important physiological roles, including in the regulation of food intake, energy metabolism, and glucose homeostasis. Dysregulation of these pathways can lead to obesity and diabetes mellitus, which present an ever-expanding global challenge. Whilst the roles of class B1 receptors and their peptide agonists in obesity and diabetes have been investigated, the contribution of RAMPs is less well understood. This review summarises the results of RAMP knockout studies, highlighting the involvement of these proteins in the incidence of disease. It then moves to discuss how receptor, RAMP, and agonist expression changes in disease states, and the benefits (or detriments) of these agonists to the pathways implicated in disease pathophysiology. Whilst much of the data centres around the calcitonin family of receptors, as their interactions with RAMPs are well established, this review then discusses receptors whose role in obesity and diabetes is well founded, but the significance of whose interactions with RAMPs is more recently emerging. The conclusion of this study of the literature is, however, that the information surrounding RAMPs is conflicting and multifaceted, and more research is required to fully understand their contribution to obesity and diabetes.

Abstract 41: SerpinA3N in Leptin Receptor Neurons Regulates Metabolic Homeostasis and Cardiovascular Function

Obesity and associated conditions such as type 2 diabetes are among the most concerning health issues in the U.S. Leptin receptor (LepR) signaling in the brain plays a pivotal role in the regulation of food intake and energy expenditure. SerpinA3N is a serine protease inhibitor which is highly expressed in the arcuate nucleus of the hypothalamus, upregulated in diet-induced obesity and by leptin stimulation. However, the role of SerpinA3N in the LepR expressing cells in the control of body weight and glucose homeostasis remain unknown. RNAseq analysis confirmed that SerpinA3N mRNA levels were significantly upregulated in the hypothalamus of mice fed high fat high sucrose diet (HFHSD) for 12 weeks. Using immunofluorescence staining, we confirmed that SerpinA3N is expressed the LepR positive cells of the hypothalamus. Next, we investigated whether loss of SerpinA3N in LepR expressing neurons affects metabolic and glucose homeostasis. For this, we crossed mice harboring floxed alleles of the SerpinA3N gene (SerpinA3N fl/fl ) with mice expressing Cre recombinase driven by the LepR (LepRb Cre ). We found that female, but not male, conditional knockout (CKO, LepRb Cre /SerpinA3N fl/fl ) mice have significantly lower body weight when fed HFHSD. This lower body weight was due to decreased fat mass, measured by NMR. However, no alteration in food intake was observed between female CKO mice and controls, indicating that increased energy expenditure may account for the lower body weight in female CKO mice. Interestingly, CKO mice displayed exaggerated weight loss and anorectic response to leptin treatment (1 mg/g, twice daily, IP), indicating that loss of SerpinA3N enhances leptin sensitivity. Female CKO mice fed normal chow diet also exhibited enhanced insulin sensitivity compared to control animals. On the other hand, male CKO mice displayed significantly improved glucose handling, but no change in insulin sensitivity. Insulin-induced phosphorylation of AKT was elevated only in skeletal muscleof CKO mice relative to controls. Finally, systolic arterial blood pressure of CKO mice fed HFHSD trend to be lower during dark time compared to controls (142±6.4 vs 127.9±7.1 mmHg, p=0.06), although heart rate was not changed. These results demonstrate that SerpinA3N in LepRb-expressing neurons regulate energy and glucose homeostasis in a sex-dependent manner,and may protect from HFHSD induced hypertension.

Exposure to gestational diabetes mellitus in utero impacts hippocampal functional connectivity in response to food cues in children.

Intrauterine exposure to gestational diabetes mellitus (GDM) increases the risk of obesity in the offspring, but little is known about the underlying neural mechanisms. The hippocampus is crucial for food intake regulation and is vulnerable to the effects of obesity. The purpose of the study was to investigate whether GDM exposure affects hippocampal functional connectivity during exposure to food cues using functional magnetic resonance imaging (fMRI). Participants were 90 children age 7-11 years (53 females) who underwent an fMRI-based visual food cue task in the fasted state. Hippocampal functional connectivity (FC) was examined using generalized psychophysiological interaction in response to food versus non-food cues. Hippocampal FC was compared between children with and without GDM exposure, while controlling for possible confounding effects of age, sex and waist-to-hip ratio. In addition, the influence of childhood and maternal obesity were investigated using multiple regression models. While viewing high caloric food cues compared to non-food cure, children with GDM exposure exhibited higher hippocampal FC to the insula and striatum (i.e., putamen, pallidum and nucleus accumbens) compared to unexposed children. With increasing BMI, children with GDM exposure had lower hippocampal FC to the somatosensory cortex (i.e., postcentral gyrus). Intrauterine exposure to GDM was associated with higher food-cue induced hippocampal FC especially to reward processing regions. Future studies with longitudinal measurements are needed to clarify whether altered hippocampal FC may raise the risk of the development of metabolic diseases later in life.

Central regulation of feeding and body weight by ciliary GPR75.

Variants of the G protein-coupled receptor 75 (GPR75) are associated with a lower BMI in large-scale human exome-sequencing studies. However, how GPR75 regulates body weight remains poorly understood. Using random germline mutagenesis in mice, we identified a missense allele (Thinner) of Gpr75 that resulted in a lean phenotype and verified the decreased body weight and fat weight in Gpr75-knockout (Gpr75-/-) mice. Gpr75-/- mice displayed reduced food intake under high-fat diet (HFD) feeding, and pair-feeding normalized their body weight. The endogenous GPR75 protein was exclusively expressed in the brains of 3xFlag-tagged Gpr75-knockin (3xFlag-Gpr75) mice, with consistent expression across different brain regions. GPR75 interacted with Gαq to activate various signaling pathways after HFD feeding. Additionally, GPR75 was localized in the primary cilia of hypothalamic cells, whereas the Thinner mutation (L144P) and human GPR75 variants in individuals with a lower BMI failed to localize in the cilia. Loss of GPR75 selectively inhibited weight gain in HFD-fed mice but failed to suppress the development of obesity in leptin ob-mutant (Lepob-mutant) mice and adenylate cyclase 3-mutant (Adcy3-mutant) mice on a chow diet. Our data reveal that GPR75 is a ciliary protein expressed in the brain and plays an important role in regulating food intake.

Alx3 deficiency disrupts energy homeostasis, alters body composition, and impairs hypothalamic regulation of food intake

The coordination of food intake, energy storage, and expenditure involves complex interactions between hypothalamic neurons and peripheral tissues including pancreatic islets, adipocytes, muscle, and liver. Previous research shows that deficiency of the transcription factor Alx3 alters pancreatic islet-dependent glucose homeostasis. In this study we carried out a comprehensive assessment of metabolic alterations in Alx3 deficiency. We report that Alx3-deficient mice exhibit decreased food intake without changes in body weight, along with reduced energy expenditure and altered respiratory exchange ratio. Magnetic resonance imaging reveals increased adiposity and decreased muscle mass, which was associated with markers of motor and sympathetic denervation. By contrast, Alx3-deficient mice on a high-fat diet show attenuated weight gain and improved insulin sensitivity, compared to control mice. Gene expression analysis demonstrates altered lipogenic and lipolytic gene profiles. In wild type mice Alx3 is expressed in hypothalamic arcuate nucleus neurons, but not in major peripheral metabolic organs. Functional diffusion-weighted magnetic resonance imaging reveals selective hypothalamic responses to fasting in the arcuate nucleus of Alx3-deficient mice. Additionally, altered expression of proopiomelanocortin and melanocortin-3 receptor mRNA in the hypothalamus suggests impaired regulation of feeding behavior. This study highlights the crucial role for Alx3 in governing food intake, energy homeostasis, and metabolic nutrient partitioning, thereby influencing body mass composition.

Fasting-induced activity changes in MC3R neurons of the paraventricular nucleus of the thalamus.

The brain controls energy homeostasis by regulating food intake through signaling within the melanocortin system. Whilst we understand the role of the hypothalamus within this system, how extra-hypothalamic brain regions are involved in controlling energy balance remains unclear. Here we show that the melanocortin 3 receptor (MC3R) is expressed in the paraventricular nucleus of the thalamus (PVT). We tested whether fasting would change the activity of MC3R neurons in this region by assessing the levels of c-Fos and pCREB as neuronal activity markers. We determined that overnight fasting causes a significant reduction in pCREB levels within PVT-MC3R neurons. We then questioned whether perturbation of MC3R signaling, during fasting, would result in altered refeeding. Using chemogenetic approaches, we show that modulation of MC3R activity, during the fasting period, does not impact body weight regain or total food intake in the refeeding period. However, we did observe significant differences in the pattern of feeding-related behavior. These findings suggest that the PVT is a region where MC3R neurons respond to energy deprivation and modulate refeeding behavior.

Metabolism: Secretory autophagy balances nutrient supply and demand

The hormone leptin is critical for regulation of food intake, energy expenditure and overall metabolism. However, the mechanisms that promote leptin secretion from adipocytes in response to nutrient surplus and limit its secretion during nutrient scarcity are unclear. New work reveals that the autophagy protein Atg8/LC3 has a bidirectional role in leptin secretion, both facilitating and limiting its release.

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

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

Major clinical and metabomic approaches to childhood obesity: a systematic review

Introduction: In the context of childhood obesity, of children under 5 years of age in Brazil, 7% are overweight and 3% meet the criteria for obesity. Globally, according to a report from the World Health Organization (WHO), it is estimated that the total number of overweight and obese children in the world could reach 75 million by the year 2025. Objective: It was to carry out a systematic review to present the main approaches to clinical and metabolomics of childhood obesity. Methods: The PRISMA Platform systematic review rules were followed. The research was carried out from February to April 2024 in the Scopus, PubMed, Science Direct, Scielo and Google Scholar databases. The quality of the studies was based on the GRADE instrument and the risk of bias was analyzed according to the Cochrane instrument. Results and Conclusion: 110 articles were recruited for the initial evaluation. A total of 41 articles were evaluated and 19 were included in this systematic review. Considering the Cochrane tool for risk of bias, the overall assessment resulted in 28 studies with a high risk of bias and 28 studies that did not meet GRADE. Most studies showed homogeneity in their results, with X2=58.7%&gt;50%. It was concluded that miRNAs are potential biomarkers for the development of pathologies, such as obesity. A heterogeneous group of these molecules was found to be associated with obesity in children. miR-15b-5p, miR-486-5p and hsa-miR-122-5p were considered good candidates for childhood obesity biomarkers. MiRNA-dependent mechanisms regulate up to 60% of all human genes. MiRNAs influence multiple pathways, including insulin signaling, immune-mediated inflammation, adipokine expression, adipogenesis, lipid metabolism, and regulation of food intake.

Alpha-melanocyte-stimulating hormone contributes to an anti-inflammatory response to lipopolysaccharide

ObjectiveDuring infection, metabolism and immunity react dynamically to promote survival through mechanisms that remain unclear. Pro-opiomelanocortin (POMC) cleavage products are produced and released in the brain and in the pituitary gland. One POMC cleavage product, alpha-melanocyte-stimulating hormone (α-MSH), is known to regulate food intake and energy expenditure and has anti-inflammatory effects. However, it is not known whether α-MSH is required to regulate physiological anti-inflammatory responses. We recently developed a novel mouse model with a targeted mutation in Pomc (Pomctm1/tm1 mice) to block production of all α-MSH forms which are required to regulate metabolism. To test whether endogenous α-MSH is required to regulate immune responses, we compared acute bacterial lipopolysaccharide (LPS)-induced inflammation between Pomctm1/tm1 and wild-type Pomcwt/wt mice. MethodsWe challenged 10- to 14-week-old male Pomctm1/tm1 and Pomcwt/wt mice with single i.p. injections of either saline or low-dose LPS (100 μg/kg) and monitored immune and metabolic responses. We used telemetry to measure core body temperature (Tb), ELISA to measure circulating cytokines, corticosterone and α-MSH, and metabolic chambers to measure body weight, food intake, activity, and respiration. We also developed a mass spectrometry method to measure three forms of α-MSH produced in the mouse hypothalamus and pituitary gland. ResultsLPS induced an exaggerated immune response in Pomctm1/tm1 compared to Pomcwt/wt mice. Both groups of mice were hypoactive and hypothermic following LPS administration, but Pomctm1/tm1 mice were significantly more hypothermic compared to control mice injected with LPS. Pomctm1/tm1 mice also had reduced oxygen consumption and impaired metabolic responses to LPS compared to controls. Pomctm1/tm1 mice had increased levels of key proinflammatory cytokines at 2 h and 4 h post LPS injection compared to Pomcwt/wt mice. Lastly, Pomcwt/wt mice injected with LPS compared to saline had increased total α-MSH in circulation 2 h post injection. ConclusionsOur data indicate endogenous α-MSH contributes to the inflammatory immune responses triggered by low-dose LPS administration and suggest that targeting the melanocortin system could be a potential therapeutic for the treatment of sepsis or inflammatory disease.

Genetic Evidence of Endocannabinoid System on Perceived Stress and Restricted Food Intake: The Role of Variants rs324420 in FAAH Gene and rs1049353 in CNR1 Gene.

Background: The endocannabinoid system (ECS) is active in brain regions involved in stress, food intake, and emotional regulation. The CB1 receptor and the fatty acid amide hydrolase (FAAH) enzyme regulate the ECS. Genetic variants in the FAAH gene (rs324420) and in the CNR1 gene (rs1049353) have been involved in both chronic stress and obesity. As a maladaptive strategy to evade the stress, three dysfunctional eating patterns may appear: cognitive restriction, disinhibition, and emotional eating. Aim: To evaluate the association of variants rs324420 in the FAAH gene and rs1049353 in the CNR1 gene with perceived stress, dysfunctional eating patterns, and anthropometric and body composition variables. Methods: This cross-sectional study included 189 participants from western Mexico. The Spanish version of the Three-Factor Eating Questionnaire and the Perceived Stress Scale were applied. Genotyping was performed with TaqMan® probes. Results: It was found that subjects with CA/AA genotypes in FAAH had a higher risk of presenting high scores in stress perception than CC genotype carriers (odds ratio [OR] 1.85, 95% confidence interval [CI] 1.007-3.339; p = 0.048); in addition, the CC genotype of this genetic variant was related to higher body weight and body fat, but no association was found with dysfunctional eating patterns. As for the CNR1 single-nucleotide polymorphism, this variant showed no significant association with stress perception scores, but subjects with GA/AA genotypes in CNR1 had a lower risk of presenting high scores of restriction in food intake compared with GG genotype carriers (OR 0.11, 95% CI 0.046-0.322; p < 0.001). Therefore, this study suggests a differential role of the ECS genes FAAH and CNR1 in perceived stress and dysfunctional eating patterns, respectively. Further studies in other populations are required.

Nucleus accumbens ghrelin signaling controls anxiety-like behavioral response to acute stress

BackgroundAnxiety disorders are one of the most common mental disorders. Ghrelin is a critical orexigenic brain-gut peptide that regulates food intake and metabolism. Recently, the ghrelin system has attracted more attention for its crucial roles in psychiatric disorders, including depression and anxiety. However, the underlying neural mechanisms involved have not been fully investigated.MethodsIn the present study, the effect and underlying mechanism of ghrelin signaling in the nucleus accumbens (NAc) core on anxiety-like behaviors were examined in normal and acute stress rats, by using immunofluorescence, qRT-PCR, neuropharmacology, molecular manipulation and behavioral tests.ResultsWe reported that injection of ghrelin into the NAc core caused significant anxiolytic effects. Ghrelin receptor growth hormone secretagogue receptor (GHSR) is highly localized and expressed in the NAc core neurons. Antagonism of GHSR blocked the ghrelin-induced anxiolytic effects. Moreover, molecular knockdown of GHSR induced anxiogenic effects. Furthermore, injection of ghrelin or overexpression of GHSR in the NAc core reduced acute restraint stress-induced anxiogenic effects.ConclusionsThis study demonstrates that ghrelin and its receptor GHSR in the NAc core are actively involved in modulating anxiety induced by acute stress, and raises an opportunity to treat anxiety disorders by targeting ghrelin signaling system.

An atlas of GPCRs in dopamine neurons: Identification of the free fatty acid receptor 4 as a regulator of food and water intake

Midbrain dopaminergic neurons (DANs) are subject to extensive metabotropic regulation, but the repertoire of G protein-coupled receptors (GPCRs) present in these neurons has not been mapped. Here, we isolate DANs from Dat-eGFP mice to generate a GPCR atlas by unbiased qPCR array expression analysis of 377 GPCRs. Combined with data mining of scRNA-seq databases, we identify multiple receptors in DAN subpopulations with 38 of these receptors representing the majority of transcripts. We identify 41 receptors expressed in midbrain DANs but not in non-DAN midbrain cells, including the free fatty acid receptor 4 (FFAR4). Functional expression of FFAR4 is validated by exvivo Ca2+ imaging, and invivo experiments support that FFAR4 negatively regulates food and water intake and bodyweight. In addition to providing a critical framework for understanding metabotropic DAN regulation, our data suggest fatty acid sensing by FFAR4 as a mechanism linking high-energy intake to the dopamine-reward pathway.

Building the Glucagon-Like Peptide-1 Receptor Brick by Brick: Revisiting a 1993 Diabetes Classic by Thorens etal.

The glucagon-like peptide-1 receptor (GLP-1R) is a class B G protein-coupled receptor involved in the regulation of blood glucose levels and food intake. Stabilized agonists targeting GLP-1R are used in the treatment of type 2 diabetes and have recently become a breakthrough obesity therapy. Here, we revisit a classic article in Diabetes by Thorens etal. that described the cloning, sequencing, and functional expression of the human GLP-1R. The article also demonstrated that exendin4(1-39) was a full agonist of the human GLP-1R whereas exendin4(9-39) was a full antagonist. We discuss how the knowledge imparted by these studies has gone on to inform multiple strands of GLP-1R biology over the past three decades, including pharmacology, signaling, human genetics, structural biology, and chemical biology.

Examining the Potential Applicability of Orexigenic and Anorexigenic Peptides in Veterinary Medicine for the Management of Obesity in Companion Animals.

This review article comprehensively explores the role of orexigenic and anorexigenic peptides in the management of obesity in companion animals, with a focus on clinical applications. Obesity in domestic animals, particularly dogs and cats, is prevalent, with significant implications for their health and well-being. Factors contributing to obesity include overfeeding, poor-quality diet, lack of physical activity, and genetic predispositions. Despite the seriousness of this condition, it is often underestimated, with societal perceptions sometimes reinforcing unhealthy behaviors. Understanding the regulation of food intake and identifying factors affecting the function of food intake-related proteins are crucial in combating obesity. Dysregulations in these proteins, whether due to genetic mutations, enzymatic dysfunctions, or receptor abnormalities, can have profound health consequences. Molecular biology techniques play a pivotal role in elucidating these mechanisms, offering insights into potential therapeutic interventions. The review categorizes food intake-related proteins into anorexigenic peptides (inhibitors of food intake) and orexigenic peptides (enhancers of food intake). It thoroughly examines current research on regulating energy balance in companion animals, emphasizing the clinical application of various peptides, including ghrelin, phoenixin (PNX), asprosin, glucagon-like peptide 1 (GLP-1), leptin, and nesfatin-1, in veterinary obesity management. This comprehensive review aims to provide valuable insights into the complex interplay between peptides, energy balance regulation, and obesity in companion animals. It underscores the importance of targeted interventions and highlights the potential of peptide-based therapies in improving the health outcomes of obese pets.

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

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