Valerie Espinal Abreu , Rachel Barnes , Vishnupriya Borra, Jennifer Schurdak, Diego Perez-Tilve
{"title":"Chemogenetic engagement of different GPCR signaling pathways segregates the orexigenic activity from the control of whole-body glucose metabolism by AGRP neurons","authors":"Valerie Espinal Abreu , Rachel Barnes , Vishnupriya Borra, Jennifer Schurdak, Diego Perez-Tilve","doi":"10.1016/j.molmet.2024.102079","DOIUrl":"10.1016/j.molmet.2024.102079","url":null,"abstract":"<div><h3>Objective</h3><div>The control of energy balance involves neural circuits in the central nervous system, including AGRP neurons in the arcuate nucleus of the hypothalamus (ARC). AGRP neurons are crucial for energy balance and their increased activity during fasting is critical to promote feeding behavior. The activity of these neurons is influenced by multiple signals including those acting on G-protein coupled receptors (GPCR) activating different intracellular signaling pathways. We sought to determine whether discrete G-protein mediated signaling in AGRP neurons, promotes differential regulation of feeding and whole-body glucose homeostasis.</div></div><div><h3>Methods</h3><div>To test the contribution of Gαq/11 or Gαs signaling, we developed congenital mouse lines expressing the different DREADD receptors (i.e., hM3q and rM3s), in AGRP neurons. Then we elicited chemogenetic activation of AGRP neurons in these mice during the postprandial state to determine the impact on feeding and glucose homeostasis.</div></div><div><h3>Results</h3><div>Activation of AGRP neurons via hM3q and rM3s promoted hyperphagia. In contrast, only hM3q activation of AGRP neurons of the hypothalamic arcuate nucleus during the postprandial state enhanced whole-body glucose disposal by reducing sympathetic nervous system activity to the pancreas and liver, promoting glucose-stimulated insulin secretion, glycogen deposition and improving glucose tolerance.</div></div><div><h3>Conclusions</h3><div>These data indicate that AGRP neurons regulate food intake and glucose homeostasis through distinct GPCR-dependent signaling pathways and suggest that the transient increase in AGRP neuron activity may contribute to the beneficial effects of fasting on glycemic control.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"91 ","pages":"Article 102079"},"PeriodicalIF":7.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11699438/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142792084","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}
Renata T. Da Costa , Anna Nichenko , Matheus M. Perez , Malgorzata Tokarska-Schlattner , Sheida Kavehmoghaddam , Vedangi Hambardikar , Ernest R. Scoma , Erin L. Seifert , Uwe Schlattner , Joshua C. Drake , Maria E. Solesio
{"title":"Mammalian mitochondrial inorganic polyphosphate (polyP) and cell signaling: Crosstalk between polyP and the activity of AMPK","authors":"Renata T. Da Costa , Anna Nichenko , Matheus M. Perez , Malgorzata Tokarska-Schlattner , Sheida Kavehmoghaddam , Vedangi Hambardikar , Ernest R. Scoma , Erin L. Seifert , Uwe Schlattner , Joshua C. Drake , Maria E. Solesio","doi":"10.1016/j.molmet.2024.102077","DOIUrl":"10.1016/j.molmet.2024.102077","url":null,"abstract":"<div><div>Inorganic polyphosphate (polyP) is an evolutionary and ancient polymer composed by orthophosphate units linked by phosphoanhydride bonds. In mammalian cells, polyP shows a high localization in mammalian mitochondria, and its regulatory role in various aspects of bioenergetics has already been demonstrated, via molecular mechanism(s) yet to be fully elucidated. In recent years, a role for polyP in signal transduction, from brain physiology to the bloodstream, has also emerged.</div></div><div><h3>Objective</h3><div>In this manuscript, we explored the intriguing possibility that the effects of polyP on signal transduction could be mechanistically linked to those exerted on bioenergetics.</div></div><div><h3>Methods</h3><div>To conduct our studies, we used a combination of cellular and animal models.</div></div><div><h3>Results</h3><div>Our findings demonstrate for the first time the intimate crosstalk between the levels of polyP and the activation status of the AMPK signaling pathway, via a mechanism involving free phosphate homeostasis. AMPK is a key player in mammalian cell signaling, and a crucial regulator of cellular and mitochondrial homeostasis. Our results show that the depletion of mitochondrial polyP in mammalian cells downregulates the activity of AMPK. Moreover, increased levels of polyP activate AMPK. Accordingly, the genetic downregulation of AMPKF0611 impairs polyP levels in both SH-SY5Y cells and in the brains of female mice.</div></div><div><h3>Conclusions</h3><div>This manuscript sheds new light on the regulation of AMPK and positions polyP as a potent regulator of mammalian cell physiology beyond mere bioenergetics, paving the road for using its metabolism as an innovative pharmacological target in pathologies characterized by dysregulated bioenergetics.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"91 ","pages":"Article 102077"},"PeriodicalIF":7.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11696858/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142769991","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}
Marie K. Holt , Natalia Valderrama , Maria J. Polanco , Imogen Hayter , Ellena G. Badenoch , Stefan Trapp , Linda Rinaman
{"title":"Modulation of stress-related behaviour by preproglucagon neurons and hypothalamic projections to the nucleus of the solitary tract","authors":"Marie K. Holt , Natalia Valderrama , Maria J. Polanco , Imogen Hayter , Ellena G. Badenoch , Stefan Trapp , Linda Rinaman","doi":"10.1016/j.molmet.2024.102076","DOIUrl":"10.1016/j.molmet.2024.102076","url":null,"abstract":"<div><div>Stress-induced behaviours are driven by complex neural circuits and some neuronal populations concurrently modulate diverse behavioural and physiological responses to stress. Glucagon-like peptide-1 (GLP-1)-producing preproglucagon (PPG) neurons within the lower brainstem caudal nucleus of the solitary tract (cNTS) are particularly sensitive to stressful stimuli and are implicated in multiple physiological and behavioural responses to interoceptive and psychogenic threats. However, the afferent inputs driving stress-induced activation of PPG neurons are largely unknown, and the role of PPG neurons in anxiety-like behaviour is controversial. Through chemogenetic manipulations we reveal that cNTS PPG neurons have the ability to moderately increase anxiety-like behaviours in mice in a sex-dependent manner. Using an intersectional approach, we show that input from the paraventricular nucleus of the hypothalamus (PVN) drives activation of both the cNTS as a whole and PPG neurons in particular in response to acute restraint stress, but that while this input is rich in corticotropin-releasing hormone (CRH), PPG neurons do not express significant levels of receptors for CRH and are not activated following lateral ventricle delivery of CRH. Finally, we demonstrate that cNTS-projecting PVN neurons are necessary for the ability of restraint stress to suppress food intake in male mice. Our findings reveal sex differences in behavioural responses to PPG neural activation and highlight a hypothalamic-brainstem pathway in stress-induced hypophagia.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"91 ","pages":"Article 102076"},"PeriodicalIF":7.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11667184/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142739913","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}
{"title":"Intestinal butyric acid-mediated disruption of gut hormone secretion and lipid metabolism in vasopressin receptor-deficient mice","authors":"Kazuki Harada , Eiji Wada , Yuri Osuga , Kie Shimizu , Reiko Uenoyama , Masami Yokota Hirai , Fumihiko Maekawa , Masao Miyazaki , Yukiko K. Hayashi , Kazuaki Nakamura , Takashi Tsuboi","doi":"10.1016/j.molmet.2024.102072","DOIUrl":"10.1016/j.molmet.2024.102072","url":null,"abstract":"<div><h3>Objectives</h3><div>Arginine vasopressin (AVP), known as an antidiuretic hormone, is also crucial in metabolic homeostasis. Although AVP receptor-deficient mice exhibit various abnormalities in glucose and lipid metabolism, the mechanism underlying these symptoms remains unclear. This study aimed to explore the involvement of the gut hormones including glucagon-like peptide-1 (GLP-1) and microbiota as essential mediators.</div></div><div><h3>Methods</h3><div>We used the mouse GLP-1-secreting cell line, GLUTag, and performed live cell imaging to examine the contribution of V1a and V1b vasopressin receptors (V1aR and V1bR, respectively) to GLP-1 secretion. We next investigated the hormone dynamics of <em>V1aR</em>-deficient mice (<em>V1aR</em><sup><em>−/−</em></sup> mice), <em>V1bR</em>-deficient mice (<em>V1bR</em><sup><em>−/−</em></sup> mice), and <em>V1aR</em>/<em>V1bR</em>-double deficient mice (<em>V1aR</em><sup><em>−/−</em></sup> <em>V1bR</em><sup><em>−/−</em></sup>mice).</div></div><div><h3>Results</h3><div>AVP induced the increase in intracellular Ca<sup>2+</sup> levels and GLP-1 secretion from GLUTag cells in a V1aR and V1bR-dependent manner. AVP receptor-deficient mice, particularly <em>V1aR</em><sup><em>−/−</em></sup><em>V1bR</em><sup><em>−/−</em></sup> mice, demonstrated impaired secretion of GLP-1 and peptide YY secreted by enteroendocrine L cells. <em>V1aR</em><sup><em>−/−</em></sup><em>V1bR</em><sup><em>−/−</em></sup>mice also exhibited abnormal lipid accumulation in the brown adipose tissue and skeletal muscle. We discovered that <em>V1aR</em><sup><em>−/−</em></sup> <em>V1bR</em><sup><em>−/−</em></sup> mice showed increased Paneth cell-related gene expression in the small intestine, which was attributed to increased fecal butyric acid levels. Exposure to butyric acid reduced GLP-1 secretion in L cell line. Additionally, human Paneth cell-related gene expressions negatively correlated with that of V1 receptor genes.</div></div><div><h3>Conclusions</h3><div>The deficiency in V1 receptor genes may increase gut butyric acid levels and impair the function of L cells, thus dysregulating lipid homeostasis in the brown adipose tissue and skeletal muscle. This study highlights the importance of appropriate control of the gut microbiota and its metabolites, including butyric acid, for the optimum functioning of enteroendocrine cells.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"91 ","pages":"Article 102072"},"PeriodicalIF":7.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11728074/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142818469","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}
William Roell , Tamer Coskun , Teayoun Kim , Libbey O’Farrell , Jennifer A. Martin , Shelly Nason , Jasmin Hernandez-Alamillo , Saidharshana Dhantu , Daniel J. Drucker , Kyle W. Sloop , James P. Steele , Jorge Alsina-Fernandez , Kirk M. Habegger
{"title":"Characterization of LY3324954 a long-acting glucagon-receptor agonist","authors":"William Roell , Tamer Coskun , Teayoun Kim , Libbey O’Farrell , Jennifer A. Martin , Shelly Nason , Jasmin Hernandez-Alamillo , Saidharshana Dhantu , Daniel J. Drucker , Kyle W. Sloop , James P. Steele , Jorge Alsina-Fernandez , Kirk M. Habegger","doi":"10.1016/j.molmet.2024.102073","DOIUrl":"10.1016/j.molmet.2024.102073","url":null,"abstract":"<div><h3>Objective</h3><div>Glucagon is a crucial regulator of glucose and lipid metabolism as well as whole-body energy balance. Thus, modulation of glucagon receptor (GCGR) activity in the context of single-molecule multi-receptor co-agonists has become an emerging therapeutic target against obesity and obesity-associated metabolic dysfunction. To better elucidate the role of GCGR-signaling when paired with incretin receptor signaling or on its own, we developed, LY3324954, a GCGR agonist with improved potency and selectivity as compared to the native glucagon peptide.</div></div><div><h3>Methods</h3><div>LY3324954 was administered to DIO mice, rats, dogs, and monkeys to evaluate pharmacokinetic (PK) profile. Biweekly treatments were conducted in lean and DIO mice to characterize LY3324954-effects on glucose homeostasis and energy balance. Single dose studies were also conducted in liver <em>Gcgr</em>-deficient mice to establish receptor specificity.</div></div><div><h3>Results</h3><div>LY3324954 also exhibited extended PK profile in DIO mice, rats, dogs, and monkeys. When administered every 72 h, LY3324954 treatment stimulated transient glucose and insulin excursions in lean mice. In diet-induced obese mice, LY3324954 treatment stimulates energy expenditure, weight loss, and a reduction of adiposity in a dose-dependent manner. Benefit to whole-body lipid homeostasis was likewise observed in these mice.</div></div><div><h3>Conclusions</h3><div>Taken together, these studies characterize a long-acting and potent GCGR-agonist and its regulation of glucose and lipid metabolism as well as whole-body energy balance following both acute and chronic treatment in mice.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"91 ","pages":"Article 102073"},"PeriodicalIF":7.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11696851/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142739909","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}
Cecilia Hes , Lu Ting Gui , Alexandre Bay , Fernando Alvarez , Pierce Katz , Tanushree Paul , Nadejda Bozadjieva-Kramer , Randy J. Seeley , Ciriaco A. Piccirillo , Paul V. Sabatini
{"title":"GDNF family receptor alpha-like (GFRAL) expression is restricted to the caudal brainstem","authors":"Cecilia Hes , Lu Ting Gui , Alexandre Bay , Fernando Alvarez , Pierce Katz , Tanushree Paul , Nadejda Bozadjieva-Kramer , Randy J. Seeley , Ciriaco A. Piccirillo , Paul V. Sabatini","doi":"10.1016/j.molmet.2024.102070","DOIUrl":"10.1016/j.molmet.2024.102070","url":null,"abstract":"<div><h3>Objective</h3><div>Growth differentiation factor 15 (GDF15) acts on the receptor dimer of GDNF family receptor alpha-like (GFRAL) and Rearranged during transfection (RET). While <em>Gfral</em>-expressing cells are known to be present in the area postrema and nucleus of the solitary tract (AP/NTS) located in the brainstem, the presence of Gfral-expressing cells in other sites within the central nervous system and peripheral tissues is not been fully addressed. Our objective was to thoroughly investigate whether GFRAL is expressed in peripheral tissues and in brain sites different from the brainstem.</div></div><div><h3>Methods</h3><div>From <em>Gfral</em>:eGFP mice we collected tissue from 12 different tissues, including brain, and used single molecule <em>in-situ</em> hybridizations to identify cells within those tissues expressing <em>Gfral</em>. We then contrasted the results with human <em>Gfral</em>-expression by analyzing publicly available single-cell RNA sequencing data.</div></div><div><h3>Results</h3><div>In mice we found readably detectable <em>Gfral</em> mRNA within the AP/NTS but not within other brain sites. Within peripheral tissues, we failed to detect any <em>Gfral</em>-labelled cells in the vast majority of examined tissues and when present, were extremely rare. Single cell sequencing of human tissues confirmed <em>GFRAL</em>-expressing cells are detectable in some sites outside the AP/NTS in an extremely sparse manner. Importantly, across the utilized methodologies, smFISH, genetic <em>Gfral</em> reporter mice and scRNA-Seq, we failed to detect <em>Gfral</em>-labelled cells with all three.</div></div><div><h3>Conclusions</h3><div>Through highly sensitive and selective technologies we show <em>Gfral</em> expression is overwhelmingly restricted to the brainstem and expect that GDF15 and GFRAL-based therapies in development for cancer cachexia will specifically target AP/NTS cells.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"91 ","pages":"Article 102070"},"PeriodicalIF":7.0,"publicationDate":"2024-11-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142750866","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}
Xiaomin Luo , Fang Liu , Lijun Zhu , Caizhi Liu , Ruhui Shen , Xiaoyin Ding , Yufan Wang , Xiaofang Tang , Yongde Peng , Zhijian Zhang
{"title":"Leupaxin promotes hepatic gluconeogenesis and glucose metabolism by coactivation with hepatic nuclear factor 4α","authors":"Xiaomin Luo , Fang Liu , Lijun Zhu , Caizhi Liu , Ruhui Shen , Xiaoyin Ding , Yufan Wang , Xiaofang Tang , Yongde Peng , Zhijian Zhang","doi":"10.1016/j.molmet.2024.102075","DOIUrl":"10.1016/j.molmet.2024.102075","url":null,"abstract":"<div><h3>Background</h3><div>As the primary source of glucose during fasting, hepatic gluconeogenesis is rigorously regulated to maintain euglycemia. Abnormal gluconeogenesis in the liver can lead to hyperglycemia, a key diagnostic marker and the primary pathological contributor to type 2 diabetes (T2D) and metabolic disorders. Hepatic nuclear factor-4 (HNF4α) is an important regulator of gluconeogenesis. In this study, we identify leupaxin (LPXN) as a novel coactivator for HNF4α. Although previous studies have shown that LPXN is highly correlated with cancer types such as B-cell differentiation and hepatocellular carcinoma progression, the role of LPXN in gluconeogenesis remains unknown.</div></div><div><h3>Methods</h3><div>We initially used protein pull-down assays, mass spectrometry and luciferase assays to identify the coactivator that interacts with HNF4α in gluconeogenesis. We further leveraged cell cultures and mouse models to validate the functional importance of molecular pathway during gluconeogenesis by using adenovirus-mediated overexpression and adeno-associated virus shRNA–mediated knockdown both <em>in vivo</em> and <em>ex vivo,</em> such as in ob/db/DIO mice, HepG2 and primary hepatocytes. Following, we used CUT&Tag and chip qPCR to identify the LPXN-mediated mechanisms underlying the observed abnormal gluconeogenesis. Additionally, we assessed the translational relevance of our findings using human liver tissues from both healthy donors and patients with obesity/type 2 diabetes.</div></div><div><h3>Results</h3><div>We found that LPXN interacts with HNF4α to participate in gluconeogenesis. Knockdown of LPXN expression in the liver effectively enhanced glucose metabolism, while its overexpression in the liver effectively inhibited it. Mechanistically, LPXN could translocate into the nucleus and was essential for regulating gluconeogenesis by binding to the PEPCK promoter, which controlled the expression of an enzyme involved in gluconeogenesis, mainly through the Gcg-cAMP-PKA pathway. Additionally, LPXN expression was found to be increased in the livers of patients with steatosis and diabetes, supporting a pathological role of LPXN.</div></div><div><h3>Conclusions</h3><div>Taken together, our study provides evidence that LPXN plays a critical role in modulating hepatic gluconeogenesis, thereby reinforcing the fact that targeting LPXN may be a potential approach for the treatment of diabetes and metabolic disorders.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"91 ","pages":"Article 102075"},"PeriodicalIF":7.0,"publicationDate":"2024-11-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142739911","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}
Philippe Zizzari , Ashley Castellanos-Jankiewicz , Selma Yagoub , Vincent Simon , Samantha Clark , Marlene Maître , Nathalie Dupuy , Thierry Leste-Lasserre , Delphine Gonzales , Kristina Schoonjans , Valérie S. Fénelon , Daniela Cota
{"title":"TGR5 receptors in SF1-expressing neurons of the ventromedial hypothalamus regulate glucose homeostasis","authors":"Philippe Zizzari , Ashley Castellanos-Jankiewicz , Selma Yagoub , Vincent Simon , Samantha Clark , Marlene Maître , Nathalie Dupuy , Thierry Leste-Lasserre , Delphine Gonzales , Kristina Schoonjans , Valérie S. Fénelon , Daniela Cota","doi":"10.1016/j.molmet.2024.102071","DOIUrl":"10.1016/j.molmet.2024.102071","url":null,"abstract":"<div><h3>Objective</h3><div>Steroidogenic factor-1 (SF1) neurons of the ventromedial hypothalamus play key roles in the regulation of food intake, body weight and glucose metabolism. The bile acid receptor Takeda G protein-coupled receptor 5 (TGR5) is expressed in the hypothalamus, where it determines some of the actions of bile acids on food intake and body weight through still poorly defined neuronal mechanisms. Here, we examined the role of TGR5 in SF1 neurons in the regulation of energy balance and glucose metabolism.</div></div><div><h3>Methods</h3><div>We used a genetic approach combined with metabolic phenotyping and molecular analyses to establish the effect of TGR5 deletion in SF1 neurons on meal pattern, body weight, body composition, energy expenditure and use of energy substrates as well as on possible changes in glucose handling and insulin sensitivity.</div></div><div><h3>Results</h3><div>Our findings reveal that TGR5 in SF1 neurons does not play a major role in the regulation of food intake or body weight under standard chow, but it is involved in the adaptive feeding response to the acute exposure to cold or to a hypercaloric, high-fat diet, without changes in energy expenditure. Notably, TGR5 in SF1 neurons hinder glucose metabolism, since deletion of the receptor improves whole-body glucose uptake through heightened insulin signaling in the hypothalamus and in the brown adipose tissue.</div></div><div><h3>Conclusions</h3><div>TGR5 in SF1 neurons favours satiety by differently modifying the meal pattern in response to specific metabolic cues. These studies also reveal a novel key function for TGR5 in SF1 neurons in the regulation of whole-body insulin sensitivity, providing new insight into the role played by neuronal TGR5 in the regulation of metabolism.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"91 ","pages":"Article 102071"},"PeriodicalIF":7.0,"publicationDate":"2024-11-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142738778","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}
Jordan Wean, Allison Ho Kowalsky, Rhianna Laker, Sarah Will, Daniel J Drucker, Christopher J Rhodes, Randy J Seeley
{"title":"Specific loss of GIPR signaling in GABAergic neurons enhances GLP-1R agonist-induced body weight loss.","authors":"Jordan Wean, Allison Ho Kowalsky, Rhianna Laker, Sarah Will, Daniel J Drucker, Christopher J Rhodes, Randy J Seeley","doi":"10.1016/j.molmet.2024.102074","DOIUrl":"10.1016/j.molmet.2024.102074","url":null,"abstract":"<p><strong>Objectives: </strong>Dual incretin agonists are among the most effective pharmaceutical treatments for obesity and type 2 diabetes to date. Such therapeutics can target two receptors, such as the glucagon-like peptide-1 (GLP-1) receptor and the glucose-dependent insulinotropic polypeptide (GIP) receptor in the case of tirzepatide, to improve glycemia and reduce body weight. Regarding body weight effects, GIPR signaling is thought to involve at least two relevant mechanisms: the enhancement of food intake reduction and the attenuation of aversive effects caused by GLP-1R agonists. Although it is known that dual GLP-1R-GIPR agonism produces greater weight loss than GLP-1R agonism alone, the precise mechanism is unknown.</p><p><strong>Methods: </strong>To address this question, we used mice lacking GIPR in the whole body, GABAergic neurons, or glutamatergic neurons. These mice were given various combinations of GLP-1R and GIPR agonist drugs with subsequent food intake and conditioned taste aversion measurements.</p><p><strong>Results: </strong>A GIPR knockout in either the whole body or selectively in inhibitory GABAergic neurons protects against diet-induced obesity, whereas a knockout in excitatory glutamatergic neurons had a negligible effect. Furthermore, we found that GIPR in GABAergic neurons is essential for the enhanced weight loss efficacy of dual incretin agonism, yet, surprisingly, its removal enhances the effect of GLP-1R agonism alone. Finally, GIPR knockout in GABAergic neurons prevents the anti-aversive effects of GIPR agonism.</p><p><strong>Conclusions: </strong>Our findings are consistent with GIPR research at large in that both enhancement and removal of GIPR signaling are metabolically beneficial. Notably, however, our findings suggest that future obesity therapies designed to modulate GIPR signaling, whether by agonism or antagonism, would be best targeted towards GABAergic neurons.</p>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":" ","pages":"102074"},"PeriodicalIF":7.0,"publicationDate":"2024-11-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142755419","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}
Fangzhen Xia , Ziteng Zhang , Zhen Qian , Xiaoyu Fang , Junxue Wang , Yan Wang , Guoting Sun , Yuefeng Yu , Ninjian Wang , Junke Zhen , Yan Liu , Yingli Lu
{"title":"The immune checkpoint molecule B7-H4 regulates β-cell mass and insulin secretion by modulating cholesterol metabolism through Stat5 signalling","authors":"Fangzhen Xia , Ziteng Zhang , Zhen Qian , Xiaoyu Fang , Junxue Wang , Yan Wang , Guoting Sun , Yuefeng Yu , Ninjian Wang , Junke Zhen , Yan Liu , Yingli Lu","doi":"10.1016/j.molmet.2024.102069","DOIUrl":"10.1016/j.molmet.2024.102069","url":null,"abstract":"<div><h3>Objective</h3><div>B7-H4 (B7S1, B7x, VTCN1) is an important immune checkpoint molecule that maintains immune homeostasis and is also expressed in pancreatic β cells. The polymorphism of B7-H4 influences the prevalence of Type 2 diabetes (T2D), suggesting a potential role of B7-H4 in the physiological function of pancreatic β cells and the pathogenesis of T2D.</div></div><div><h3>Methods</h3><div>β-cell-specific B7-H4 knockout mice (B7-H4 cKO mice) and their wild-type littermates were used to investigate the <em>in vivo</em> effects of B7-H4 on pancreatic β-cell morphology and function. AAV2/8-ins2-B7H4 and a control virus were infused via the pancreatic intraduct into high-fat diet (HFD)-treated mice to elucidate the therapeutic effect of B7-H4. RNA sequencing was conducted on primary islets. A Luminex assay was used to quantify cytokine changes in B7-H4 cKO mice. Electron microscopy imaging was used to observe insulin secretory vesicles in pancreatic β cells.</div></div><div><h3>Results</h3><div>Lesion of B7-H4 in β cells results in glucose intolerance due to reduced β-cell mass and deficient insulin secretion, whereas overexpression of B7-H4 in β cells ameliorates glucose intolerance in HFD-fed mice. Mechanistically, B7-H4 deficiency activates signal transducer and activator of transcription 5 (Stat5) signalling, which inhibits the expression of apolipoprotein F (Apof), leading to reduced cholesterol efflux and accumulated cholesterol in β cells, thereby impairing insulin processing and secretion. Overexpression of Apof in β cells or intraperitoneal injection of a Stat5 inhibitor reverses the metabolic phenotype and insulin secretion deficiency in B7-H4 cKO mice.</div></div><div><h3>Conclusion</h3><div>Our study demonstrated that B7-H4 plays an important role in regulating β-cell mass and insulin secretion, which may shed new light on the development of novel strategies for T2D treatment.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"91 ","pages":"Article 102069"},"PeriodicalIF":7.0,"publicationDate":"2024-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142687731","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}