Molecular Metabolism最新文献

{"title":"Transcriptomic Signatures of Cold Acclimated Adipocytes Reveal CXCL12 as a Brown Autocrine and Paracrine Chemokine.","authors":"Marina Agueda-Oyarzabal, Marie S Isidor, Kaja Plucińska, Lars R Ingerslev, Oksana Dmytriyeva, Patricia S S Petersen, Sara Laftih, Axel B Pontoppidan, Jo B Henningsen, Kaja Rupar, Erin L Brown, Thue W Schwartz, Romain Barrès, Zachary Gerhart-Hines, Camilla C Schéele, Brice Emanuelli","doi":"10.1016/j.molmet.2025.102102","DOIUrl":"https://doi.org/10.1016/j.molmet.2025.102102","url":null,"abstract":"<p><p>Besides its thermogenic capacity, brown adipose tissue (BAT) performs important secretory functions that regulate metabolism. However, the BAT microenvironment and factors involved in BAT homeostasis and adaptation to cold remain poorly characterized. We therefore aimed to study brown adipocyte-derived secreted factors that may be involved in adipocyte function and/or may orchestrate intercellular communications. For this, mRNA levels in mature adipocytes from mouse adipose depots were assessed using RNA sequencing upon chronic cold acclimation, and bioinformatic analysis was used to identify secreted factors. Among 858 cold-sensitive transcripts in BAT adipocytes were 210 secreted factor-encoding genes, and Cxcl12 was the top brown adipocyte-enriched cytokine. Cxcl12 mRNA expression analysis by RT-qPCR and fluorescence in situ hybridization specified Cxcl12 distribution in various cell types, and indicated its enrichment in cold-acclimated brown adipocytes. We found that CXCL12 secretion from BAT was increased after chronic cold, yet its level in plasma remained unchanged, suggesting a local/paracrine function. Cxcl12 knockdown in mature brown adipocytes impaired thermogenesis, as assessed by norepinephrine (NE)-induced glycerol release and mitochondrial respiration. However, knockdown of Cxcl12 did not impact β-adrenergic signaling, suggesting that CXCL12 regulates adipocyte function downstream of the β-adrenergic pathway. Moreover, we provide evidence for CXCL12 to exert intercellular cross-talk via its capacity to promote macrophage chemotaxis and neurite outgrowth. Collectively, our results indicate that CXCL12 is a brown adipocyte-enriched, cold-induced secreted factor involved in adipocyte function and the BAT microenvironment communication network.</p>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":" ","pages":"102102"},"PeriodicalIF":7.0,"publicationDate":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143028889","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Timing of exercise differentially impacts adipose tissue gain in male adolescent rats.","authors":"Y Kutsenko, L P Iñiguez, A Barreda, L Pardo-Marín, A Toval, D Garrigos, M Martínez-Morga, S Pujante, B Ribeiro Do-Couto, K Y Tseng, J J Cerón, M Garaulet, M B Wisniewska, M Irimia, J L Ferran","doi":"10.1016/j.molmet.2025.102100","DOIUrl":"https://doi.org/10.1016/j.molmet.2025.102100","url":null,"abstract":"<p><p>Circadian rhythms of metabolic, hormonal, and behavioral fluctuations and their alterations can impact health. An important gap in knowledge in the field is whether the time of the day of exercise and the age of onset of exercise exert distinct effects at the level of whole-body adipose tissue and body composition. The goal of the present study was to determine how exercise at different times of the day during adolescence impacts the adipose tissue transcriptome and content in a rodent model. Rats were subjected to one of four conditions during their adolescence: early active phase control or exercise (EAC or EAE; ZT13), and late active phase control or exercise (LAC or LAE; ZT23). The effects of exercise timing were assessed at the level of subcutaneous and visceral adipose tissue transcriptome, body composition, hypothalamic expression of orexigenic and anorexigenic genes, blood serum markers and 24-hour core body temperature patterns. We found that late active phase exercise (ZT23) greatly upregulated pathways of lipid synthesis, glycolysis and NADH shuttles in LAE rats, compared to LAC or EAE. Conversely, LAE rats showed notably lower content of adipose tissue. In addition, LAE rats showed signs of impaired FGF21-adiponectin axis compared to other groups. Finally, LAE rats showed higher post-exercise core body temperature compared to other groups. Our results thus indicate that our exercise protocol induced an unusual effect characterized by enhanced lipid synthesis but reduced adipose tissue content in late active phase but not early active phase exercise during adolescence.</p>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":" ","pages":"102100"},"PeriodicalIF":7.0,"publicationDate":"2025-01-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143008438","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Endothelial Autophagy-related gene 7 Contributes to High Fat Diet-Induced Obesity.","authors":"Guang Ren, Sushant Bhatnagar, Martin E Young, Timmy Lee, Jeong-A Kim","doi":"10.1016/j.molmet.2025.102099","DOIUrl":"https://doi.org/10.1016/j.molmet.2025.102099","url":null,"abstract":"<p><strong>Objective: </strong>Obesity-associated metabolic dysfunction is a major public health concern worldwide. Endothelial dysfunction is a hallmark of metabolic dysfunction, and endothelial cells affect metabolic functions. Because autophagy-related gene 7 (ATG7) is involved in various cellular physiology, we investigated the roles of endothelial cell-ATG7 (EC-ATG7) on high-fat diet-induced obesity and its related metabolic dysfunction.</p><p><strong>Methods: </strong>We generated an endothelial-specific Atg7 knock-out mouse by breeding Atg7^flox/flox mouse with the Chd5-Cre mouse, and investigated the metabolic phenotypes associated with high-fat diet (HFD)-induced obesity. Body weight, food intake, glucose tolerance, insulin sensitivity, and liver fat accumulation were measured in endothelial Atg7 deficient (Atg7^ΔEnd) and control mice (Atg7^f/f). Adipose tissue inflammation was assessed by measuring the expression of pro-inflammatory genes. Furthermore, we performed indirect calorimetry and examined the insulin signaling pathway molecules.</p><p><strong>Results: </strong>We found that deletion of EC-Atg7 ameliorated HFD-induced weight gain, fatty liver, and adipocyte hypertrophy and inflammatory response in adipose tissue, and improved insulin sensitivity without changing glucose tolerance. These metabolic effects seem to be due to the reduced food intake because there were no differences in energy expenditure, energy excretion to feces, and physical activity. Interestingly, the deletion of EC-Atg7 protected from HFD-induced vascular rarefaction, and the knock-down of Atg7 in endothelial cells protected from fatty acid-induced cell death.</p><p><strong>Conclusions: </strong>Our results suggest that EC-Atg7 deletion ameliorates HFD-induced obesity and its related metabolic dysfunction, such as insulin resistance and fatty liver by attenuating appetite and vascular rarefaction. The EC-Atg7 deletion may protect the endothelial cells from lipotoxicity and impaired angiogenesis, which preserves the endothelial function in metabolic tissues. These findings may have implications for developing new therapeutic strategies for preventing and treating obesity and its associated health risks.</p>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":" ","pages":"102099"},"PeriodicalIF":7.0,"publicationDate":"2025-01-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143008437","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Bioenergetic adaptations of small intestinal epithelial cells reduce cell differentiation enhancing intestinal permeability in obese mice.","authors":"Thomas Guerbette, Vincent Ciesielski, Manon Brien, Daniel Catheline, Roselyne Viel, Mégane Bostoen, Jean-Baptiste Perrin, Agnès Burel, Régis Janvier, Vincent Rioux, Annaïg Lan, Gaëlle Boudry","doi":"10.1016/j.molmet.2025.102098","DOIUrl":"https://doi.org/10.1016/j.molmet.2025.102098","url":null,"abstract":"<p><strong>Background: </strong>Obesity and overweight are associated with low-grade inflammation induced by adipose tissue expansion and perpetuated by altered intestinal homeostasis, including increased epithelial permeability. Intestinal epithelium functions are supported by intestinal epithelial cells (IEC) mitochondria function.</p><p><strong>Methods and results: </strong>Here, we report that diet-induced obesity (DIO) in mice induces lipid metabolism adaptations favoring lipid storage in IEC together with reduced number, altered dynamics and diminished oxidative phosphorylation activity of IEC mitochondria. Using the jejunal epithelial cell line IPEC-J2, we showed that IEC lipid metabolism and oxidative stress machinery adaptations preceded mitochondrial bioenergetic ones. Moreover, we unraveled the intricate link between IEC energetic status and proliferation/differentiation balance since enhancing mitochondrial function with the AMPK activator AICAR in jejunal organoids reduced proliferation and initiated IEC differentiation and conversely. We confirmed that the reduced IEC mitochondrial function observed in DIO mice was associated with increased proliferation and reduced differentiation, promoting expression of the permissive Cldn2 in the jejunal epithelium of DIO mice.</p><p><strong>Conclusions: </strong>Our study provides new insights into metabolic adaptations of IEC in obesity by revealing that excess lipid intake diminishes mitochondrial number in IEC, reducing IEC differentiation that contribute to increased epithelial permeability.</p>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":" ","pages":"102098"},"PeriodicalIF":7.0,"publicationDate":"2025-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143008090","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hypoxia inducible factor-dependent upregulation of Agrp in glomus type I cells of the carotid body.","authors":"Luis Leon-Mercado, Ivan Menendez-Montes, Jonathan Tao, Bandy Chen, David P Olson, C Mackaaij, C G J Cleypool, Laurent Gautron","doi":"10.1016/j.molmet.2025.102095","DOIUrl":"10.1016/j.molmet.2025.102095","url":null,"abstract":"<p><p>Agouti-related peptide (AgRP) is a well-established potent orexigenic peptide primarily expressed in hypothalamic neurons. Nevertheless, the expression and functional significance of extrahypothalamic AgRP remain poorly understood. In this study, utilizing histological and molecular biology techniques, we have identified a significant expression of Agrp mRNA and AgRP peptide production in glomus type I cells within the mouse carotid body (CB). Furthermore, we have uncovered evidence supporting the expression of the AgRP receptor melanocortin receptor 3 (Mc3r) in adjacent sympathetic neurons, suggesting a potential local paracrine role for AgRP within the CB. Importantly, AgRP immunoreactivity was also identified in glomus type I cells of the human CB. Given the unexpected abundance of AgRP in glomus type I cells, a chemoreceptor cell specialized in oxygen sensing, we proceeded to investigate whether Agrp expression in the CB is regulated by hypoxemia and associated oxygen-sensing molecular mechanisms. In vitro luciferase assays reveal that hypoxia stimulates the human and mouse Agrp promoters in a Hypoxia Inducible Factor (HIF1/2)-dependent manner. Our in vivo experiments further demonstrate that exposure to environmental hypoxia (10%) robustly induces Agrp expression in type I glomus cells of mice. Furthermore, these findings collectively highlight the hitherto unknown source of AgRP in murine and human type I glomus cells and underscore the direct control of Agrp transcription by HIF signaling.</p>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":" ","pages":"102095"},"PeriodicalIF":7.0,"publicationDate":"2025-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142964702","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"LGR4 is essential for maintaining β-cell homeostasis through suppression of RANK.","authors":"Joanna Filipowska, Zelda Cisneros, Sneha S Varghese, Nancy Leon-Rivera, Peng Wang, Randy Kang, Geming Lu, Yate-Ching Yuan, Hung-Ping Shih, Supriyo Bhattacharya, Sangeeta Dhawan, Adolfo Garcia-Ocaña, Nagesha Guthalu Kondegowda, Rupangi C Vasavada","doi":"10.1016/j.molmet.2025.102097","DOIUrl":"10.1016/j.molmet.2025.102097","url":null,"abstract":"<p><strong>Objective: </strong>Loss of functional β-cell mass is a major cause of diabetes. Thus, identifying regulators of β-cell health is crucial for treating this disease. The Leucine-rich repeat-containing G-protein-coupled receptor (GPCR) 4 (LGR4) is expressed in β-cells and is the fourth most abundant GPCR in human islets. Although LGR4 has regenerative, anti-inflammatory, and anti-apoptotic effects in other tissues, its functional significance in β-cells remains unknown. We have previously identified Receptor Activator of Nuclear Factor Kappa B (NFκB) (RANK) as a negative regulator of β-cell health. In this study, we assessed the regulation of Lgr4 in islets, and the role of LGR4 and LGR4/RANK stoichiometry in β-cell health under basal and stress-induced conditions, in vitro and in vivo.</p><p><strong>Methods: </strong>We evaluated Lgr4 expression in mouse and human islets in response to acute (proinflammatory cytokines), or chronic (high fat fed mice, db/db mice, and aging) stress. To determine the role of LGR4 we employed in vitro Lgr4 loss and gain of function in primary rodent and human β-cells and examined its mechanism of action in the rodent INS1 cell line. Using Lgr4^fl/fl and Lgr4^fl/fl/Rank^fl/fl × Ins1-Cre mice we generated _{β-cell-specific} conditional knockout (cko) mice to test the role of LGR4 and its interaction with RANK in vivo under basal and stress-induced conditions.</p><p><strong>Results: </strong>Lgr4 expression in rodent and human islets was reduced by multiple stressors. In vitro, Lgr4 knockdown decreased proliferation and survival in rodent β-cells, while overexpression protected against cytokine-induced cell death in rodent and human β-cells. Mechanistically, LGR4 protects β-cells by suppressing RANK- Tumor necrosis factor receptor associated factor 6 (TRAF6) interaction and subsequent activation of NFκB. Lgr4cko mice exhibit normal glucose homeostasis but increased β-cell death in both sexes and decreased β-cell proliferation and maturation only in females. Male Lgr4cko mice under stress displayed reduced β-cell proliferation and a further increase in β-cell death. The impaired β-cell phenotype in Lgr4cko mice was rescued in Lgr4/Rank double ko (dko) mice. Upon aging, both male and female Lgr4cko mice displayed impaired β-cell homeostasis, however, only female mice became glucose intolerant with decreased plasma insulin.</p><p><strong>Conclusions: </strong>These data demonstrate a novel role for LGR4 as a positive regulator of β-cell health under basal and stress-induced conditions, through suppressing the negative effects of RANK.</p>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":" ","pages":"102097"},"PeriodicalIF":7.0,"publicationDate":"2025-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142951382","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Chronic GIPR agonism results in pancreatic islet GIPR functional desensitisation.","authors":"Iona Davies, Alice E Adriaenssens, William R Scott, David Carling, Kevin G Murphy, James S Minnion, Stephen R Bloom, Ben Jones, Tricia M-M Tan","doi":"10.1016/j.molmet.2025.102094","DOIUrl":"10.1016/j.molmet.2025.102094","url":null,"abstract":"<p><strong>Objectives: </strong>There is renewed interest in targeting the glucose-dependent insulinotropic polypeptide receptor (GIPR) for treatment of obesity and type 2 diabetes. G-protein coupled receptor desensitisation is suggested to reduce the long-term efficacy of glucagon-like-peptide 1 receptor (GLP-1R) agonists and may similarly affect the efficacy of GIPR agonists. We explored the extent of pancreatic GIPR functional desensitisation with sustained agonist exposure.</p><p><strong>Methods: </strong>A long-acting GIPR agonist, GIP108, was used to probe the effect of sustained agonist exposure on cAMP responses in dispersed pancreatic islets using live cell imaging, with rechallenge cAMP responses after prior agonist treatment used to quantify functional desensitisation. Receptor internalisation and β-arrestin-2 activation were investigated in vitro using imaging-based assays. Pancreatic mouse GIPR desensitisation was assessed in vivo via intraperitoneal glucose tolerance testing.</p><p><strong>Results: </strong>GIP108 treatment led to weight loss and improved glucose homeostasis in mice. Prolonged exposure to GIPR agonists produced homologous functional GIPR desensitisation in isolated islets. GIP108 pre-treatment in vivo also reduced the subsequent anti-hyperglycaemic response to GIP re-challenge. GIPR showed minimal agonist-induced internalisation or β-arrestin-2 activation.</p><p><strong>Conclusions: </strong>Although GIP108 chronic treatment improved glucose tolerance, it also resulted in partial desensitisation of the pancreatic islet GIPR. This suggests that ligands with reduced desensitisation tendency might lead to improved in vivo efficacy. Understanding whether pancreatic GIPR desensitisation affects the long-term benefits of GIPR agonists in humans is vital to design effective metabolic pharmacotherapies.</p>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":" ","pages":"102094"},"PeriodicalIF":7.0,"publicationDate":"2025-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142951458","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cannabinoid type-1 receptors in CaMKII neurons drive impulsivity in pathological eating behavior.","authors":"Elena Martin-Garcia, Laura Domingo-Rodriguez, Beat Lutz, Rafael Maldonado, Inigo Ruiz de Azua","doi":"10.1016/j.molmet.2025.102096","DOIUrl":"10.1016/j.molmet.2025.102096","url":null,"abstract":"<p><strong>Objectives: </strong>Overconsumption of palatable food and energy accumulation are evolutionary mechanisms of survival when food is scarce. These innate mechanisms becom detrimental in obesogenic environment promoting obesity and related comorbidities, including mood disorders. This study aims at elucidating the role of the endocannabinoid system in energy accumulation and hedonic feeding.</p><p><strong>Methods: </strong>We applied a genetic strategy to reconstitute cannabinoid type-1 receptor (CB1) expression at functional levels specifically in CaMKII+ neurons (CaMKII-CB1-RS) and adipocytes (Ati-CB1-RS), respectively, in a CB1 deficient background.</p><p><strong>Results: </strong>Rescued CB1 expression in CaMKII+ neurons, but not in adipocytes, promotes feeding behavior, leading to fasting-induced hyperphagia, increased motivation, and impulsivity to palatable food seeking. In a diet-induced obesity model, CB1 re-expression in CaMKII+ neurons, but not in adipocytes, compared to complete CB1 deficiency, was sufficient to largely restore weight gain, food intake without any effect on glucose intolerance associated with high-fat diet consumption. In a model of glucocorticoid-mediated metabolic syndrome, CaMKII-CB1-RS mice showed all metabolic alterations linked to the human metabolic syndrome except of glucose intolerance. In a binge-eating model mimicking human pathological feeding, CaMKII-CB1-RS mice showed increased seeking and compulsive behavior to palatable food, suggesting crucial roles in foraging and an enhanced susceptibility to addictive-like eating behaviors. Importantly, other contingent behaviors, including increased cognitive flexibility and reduced anxiety-like behaviors, but not depressive-like behaviors, were also observed.</p><p><strong>Conclusions: </strong>CB1 in CaMKII+ neurons is instrumental in feeding behavior and energy storage under physiological conditions. The exposure to risk factors (hypercaloric diet, glucocorticoid dysregulation) leads to obesity, metabolic syndrome, binge-eating and food addiction.</p>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":" ","pages":"102096"},"PeriodicalIF":7.0,"publicationDate":"2025-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142951447","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Roles for Prlhr/GPR10 and Npffr2/GPR74 in feeding responses to PrRP.","authors":"Yi Wang, Weiwei Qiu, Stace Kernodle, Carly Parker, Marc-Antonio Padilla, Jiaao Su, Abigail J Tomlinson, Stephanie Oldham, Joss Field, Elise Bernard, David Hornigold, Christopher J Rhodes, David P Olson, Randy J Seeley, Martin G Myers","doi":"10.1016/j.molmet.2024.102093","DOIUrl":"10.1016/j.molmet.2024.102093","url":null,"abstract":"<p><strong>Objective: </strong>Several groups of neurons in the NTS suppress food intake, including Prlh-expressing neurons (NTS^Prlh cells). Not only does the artificial activation of NTS^Prlh cells decrease feeding, but also the expression of Prlh (which encodes the neuropeptide PrRP) and neurotransmission by NTS^Prlh neurons contributes to the restraint of food intake and body weight, especially in animals fed a high fat diet (HFD). We set out to determine roles for putative PrRP receptors in the response to NTS PrRP and exogenous PrRP-related peptides.</p><p><strong>Methods: </strong>We used animals lacking PrRP receptors GPR10 and/or GPR74 (encoded by Prlhr and Npffr2, respectively) to determine roles for each in the restraint of food intake and body weight by the increased expression of Prlh in NTS^Prlh neurons (NTS^PrlhOX mice) and in response to the anorectic PrRP analog, p52.</p><p><strong>Results: </strong>Although Prlhr played a crucial role in the restraint of food intake and body weight in HFD-fed control animals, the combined absence of Prlhr and Npffr2 was required to abrogate the restraint of food intake in NTS^PrlhOX mice. p52 suppressed feeding independently of both receptors, however.</p><p><strong>Conclusions: </strong>Hence, each receptor can participate in the NTS^Prlh-mediated suppression of food intake and body weight gain, while PrRP analog treatment can mediate its effects via distinct systems. While Prlhr plays a crucial role in the physiologic restraint of weight gain, the action of either receptor is capable of ameliorating obesity in response to enhanced NTS^Prlh signaling.</p>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":" ","pages":"102093"},"PeriodicalIF":7.0,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142927636","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Regulation of energy balance by leptin as an adiposity signal and modulator of the reward system.","authors":"Roshanak Asgari, Maria Caceres-Valdiviezo, Sally Wu, Laurie Hamel, Bailey E Humber, Sri Mahavir Agarwal, Paul J Fletcher, Stephanie Fulton, Margaret K Hahn, Sandra Pereira","doi":"10.1016/j.molmet.2024.102078","DOIUrl":"10.1016/j.molmet.2024.102078","url":null,"abstract":"<p><strong>Background: </strong>Leptin is an adipose tissue-derived hormone that plays a crucial role in body weight, appetite, and behaviour regulation. Leptin controls energy balance as an indicator of adiposity levels and as a modulator of the reward system, which is associated with liking palatable foods. Obesity is characterized by expanded adipose tissue mass and consequently, elevated concentrations of leptin in blood. Leptin's therapeutic potential for most forms of obesity is hampered by leptin resistance and a narrow dose-response window.</p><p><strong>Scope of review: </strong>This review describes the current knowledge of the brain regions and intracellular pathways through which leptin promotes negative energy balance and restrains neural circuits affecting food reward. We also describe mechanisms that hinder these biological responses in obesity and highlight potential therapeutic interventions.</p><p><strong>Major conclusions: </strong>Additional research is necessary to understand how pathways engaged by leptin in different brain regions are interconnected in the control of energy balance.</p>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":" ","pages":"102078"},"PeriodicalIF":7.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11696864/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142770159","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}