Pub Date : 2025-09-17DOI: 10.1016/j.molmet.2025.102253
Jeffery Bolte , Annie A. Smelter , Luke Norton
The global rise in obesity has underscored the critical importance of body composition, particularly the balance between fat mass and lean mass, in determining health outcomes. While excess fat mass is a well-established risk factor for numerous chronic diseases and reduced longevity, lean mass preservation has been widely considered essential for mitigating fall risk and maintaining functional independence. Recent advances in incretin-based weight loss therapies have shown remarkable efficacy in reducing body weight but have raised concerns about the concomitant loss of lean mass. However, emerging evidence suggests that muscle quality – rather than absolute muscle mass – is a more robust predictor of functional capacity and all-cause mortality. Intriguingly, these therapies may enhance muscle quality even while promoting lean mass loss, offering a nuanced perspective on their impact. This review aims to synthesize current evidence on body composition, muscle quality, and weight loss therapies to guide clinicians in tailoring weight loss strategies that optimize both metabolic health and patient outcomes.
{"title":"Are we giving too much weight to lean mass loss?","authors":"Jeffery Bolte , Annie A. Smelter , Luke Norton","doi":"10.1016/j.molmet.2025.102253","DOIUrl":"10.1016/j.molmet.2025.102253","url":null,"abstract":"<div><div>The global rise in obesity has underscored the critical importance of body composition, particularly the balance between fat mass and lean mass, in determining health outcomes. While excess fat mass is a well-established risk factor for numerous chronic diseases and reduced longevity, lean mass preservation has been widely considered essential for mitigating fall risk and maintaining functional independence. Recent advances in incretin-based weight loss therapies have shown remarkable efficacy in reducing body weight but have raised concerns about the concomitant loss of lean mass. However, emerging evidence suggests that muscle quality – rather than absolute muscle mass – is a more robust predictor of functional capacity and all-cause mortality. Intriguingly, these therapies may enhance muscle quality even while promoting lean mass loss, offering a nuanced perspective on their impact. This review aims to synthesize current evidence on body composition, muscle quality, and weight loss therapies to guide clinicians in tailoring weight loss strategies that optimize both metabolic health and patient outcomes.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"101 ","pages":"Article 102253"},"PeriodicalIF":6.6,"publicationDate":"2025-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145092167","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}
Pub Date : 2025-09-12DOI: 10.1016/j.molmet.2025.102251
Vindhya Chaganty , Ruey-Kuang Cheng , Kimberle Shen , Na Zhang , Gaynah Javier Doblado , Sarah Ong , Sandra Tan , Valarie Yu Yan Tham , Jung-Hwa Choi , Marnie E. Halpern , Wei Leong Chew , Anand Kumar Andiappan , Sarah Xinwei Luo , Caroline Lei Wee
Objectives
The lateral hypothalamus (LH) plays a central role in appetite control, however the functional and evolutionary conservation of its subcircuits remain unclear. This study aimed to define the molecular and cellular identities of zebrafish LH neurons, identify conserved LH cell types across vertebrates, and investigate their roles in appetite regulation.
Methods
We performed the Act-seq method of single-cell RNA sequencing in the larval zebrafish LH under food-deprived and voracious feeding states to capture activity-dependent transcriptional signatures. Using integrative comparative transcriptomics, we aligned zebrafish neuronal clusters with a published mouse LH dataset to identify conserved neuronal sub-populations, and performed functional and molecular characterisation of a highly-conserved cell type in both zebrafish and mice.
Results
We identified several LH neuronal subtypes in zebrafish that are differentially activated during voracious feeding. Cross-species mapping revealed overlapping cellular clusters, especially for GABAergic neurons. We report a conserved GABAergic cluster co-expressing growth hormone (GH) receptors and tachykinin. In both species, feeding activates these neurons and elevates GH receptor and tachykinin expression. In zebrafish, upstream GH signaling is similarly regulated by feeding state, and acute GH administration both activates this cluster and enhances food intake.
Conclusions
These findings uncover a conserved GH receptor-tachykinin LH population which may link metabolic hormone signaling to appetite control. Beyond its established long-term roles in growth and metabolism, we propose that GH exerts acute appetite-enhancing effects through activation of this neuronal pathway. Our comparative LH atlas highlights the evolutionary biology of hypothalamic appetite circuits.
{"title":"Comparative transcriptomics of lateral hypothalamic cell types reveals conserved growth hormone-tachykinin dynamics in feeding","authors":"Vindhya Chaganty , Ruey-Kuang Cheng , Kimberle Shen , Na Zhang , Gaynah Javier Doblado , Sarah Ong , Sandra Tan , Valarie Yu Yan Tham , Jung-Hwa Choi , Marnie E. Halpern , Wei Leong Chew , Anand Kumar Andiappan , Sarah Xinwei Luo , Caroline Lei Wee","doi":"10.1016/j.molmet.2025.102251","DOIUrl":"10.1016/j.molmet.2025.102251","url":null,"abstract":"<div><h3>Objectives</h3><div>The lateral hypothalamus (LH) plays a central role in appetite control, however the functional and evolutionary conservation of its subcircuits remain unclear. This study aimed to define the molecular and cellular identities of zebrafish LH neurons, identify conserved LH cell types across vertebrates, and investigate their roles in appetite regulation.</div></div><div><h3>Methods</h3><div>We performed the Act-seq method of single-cell RNA sequencing in the larval zebrafish LH under food-deprived and voracious feeding states to capture activity-dependent transcriptional signatures. Using integrative comparative transcriptomics, we aligned zebrafish neuronal clusters with a published mouse LH dataset to identify conserved neuronal sub-populations, and performed functional and molecular characterisation of a highly-conserved cell type in both zebrafish and mice.</div></div><div><h3>Results</h3><div>We identified several LH neuronal subtypes in zebrafish that are differentially activated during voracious feeding. Cross-species mapping revealed overlapping cellular clusters, especially for GABAergic neurons. We report a conserved GABAergic cluster co-expressing growth hormone (GH) receptors and tachykinin. In both species, feeding activates these neurons and elevates GH receptor and tachykinin expression. In zebrafish, upstream GH signaling is similarly regulated by feeding state, and acute GH administration both activates this cluster and enhances food intake.</div></div><div><h3>Conclusions</h3><div>These findings uncover a conserved GH receptor-tachykinin LH population which may link metabolic hormone signaling to appetite control. Beyond its established long-term roles in growth and metabolism, we propose that GH exerts acute appetite-enhancing effects through activation of this neuronal pathway. Our comparative LH atlas highlights the evolutionary biology of hypothalamic appetite circuits.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"102 ","pages":"Article 102251"},"PeriodicalIF":6.6,"publicationDate":"2025-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145065109","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}
Pub Date : 2025-09-12DOI: 10.1016/j.molmet.2025.102249
Ivan Vlassakev , Christina Savva , Gianluca Renzi , Hema S. Ilamathi , Doste R. Mamand , Jacob G. Smith , Carolina M. Greco , Christopher Litwin , Qing Zhang , Leandro Velez , Angela Ma , Martin O. Bergo , Oscar P.B. Wiklander , Pura Muñoz-Cánovez , Niklas Mejhert , Marcus Seldin , Johan L.M. Björkegren , Paolo Sassone-Corsi , Kevin B. Koronowski , Salvador Aznar Benitah , Paul Petrus
Circadian rhythms are integral to maintaining metabolic health by temporally coordinating physiology across tissues. However, the mechanisms underlying circadian cross-tissue coordination remain poorly understood. In this study, we uncover a central role for the liver clock in regulating circadian rhythms in white adipose tissue (WAT). Using a hepatocyte-specific Bmal1 knockout mouse model, we show that hepatic circadian control modulates lipid metabolism in WAT. In addition, by utilizing a model where functional clocks are restricted to the hepatocytes, we demonstrate that the liver clock alone integrates feeding cues to modulate circadian gene expression in WAT, including Cebpa, a key regulator of adipogenesis. We show that the hepatocyte clock regulates adipocyte Cebpa rhythmicity through secreted proteins. Further investigation identified one of the contributing mediators to be the adaptor protein 14-3-3η (Ywhah). The clinical relevance of the liver clock for systemic metabolic function is supported by human cohort data, which revealed a gene regulatory network, consisting of several clock-controlled liver genes, linked to cardiometabolic risk. These findings provide evidence for how the hepatocyte clock coordinates WAT physiology and highlights the core clock system as a potential therapeutic target to improve cardiometabolic health.
{"title":"The liver clock modulates circadian rhythms in white adipose tissue","authors":"Ivan Vlassakev , Christina Savva , Gianluca Renzi , Hema S. Ilamathi , Doste R. Mamand , Jacob G. Smith , Carolina M. Greco , Christopher Litwin , Qing Zhang , Leandro Velez , Angela Ma , Martin O. Bergo , Oscar P.B. Wiklander , Pura Muñoz-Cánovez , Niklas Mejhert , Marcus Seldin , Johan L.M. Björkegren , Paolo Sassone-Corsi , Kevin B. Koronowski , Salvador Aznar Benitah , Paul Petrus","doi":"10.1016/j.molmet.2025.102249","DOIUrl":"10.1016/j.molmet.2025.102249","url":null,"abstract":"<div><div>Circadian rhythms are integral to maintaining metabolic health by temporally coordinating physiology across tissues. However, the mechanisms underlying circadian cross-tissue coordination remain poorly understood. In this study, we uncover a central role for the liver clock in regulating circadian rhythms in white adipose tissue (WAT). Using a hepatocyte-specific <em>Bmal1</em> knockout mouse model, we show that hepatic circadian control modulates lipid metabolism in WAT. In addition, by utilizing a model where functional clocks are restricted to the hepatocytes, we demonstrate that the liver clock alone integrates feeding cues to modulate circadian gene expression in WAT, including <em>Cebpa</em>, a key regulator of adipogenesis. We show that the hepatocyte clock regulates adipocyte <em>Cebpa</em> rhythmicity through secreted proteins. Further investigation identified one of the contributing mediators to be the adaptor protein 14-3-3η (<em>Ywhah</em>). The clinical relevance of the liver clock for systemic metabolic function is supported by human cohort data, which revealed a gene regulatory network, consisting of several clock-controlled liver genes, linked to cardiometabolic risk. These findings provide evidence for how the hepatocyte clock coordinates WAT physiology and highlights the core clock system as a potential therapeutic target to improve cardiometabolic health.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"101 ","pages":"Article 102249"},"PeriodicalIF":6.6,"publicationDate":"2025-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145065133","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}
Pub Date : 2025-09-11DOI: 10.1016/j.molmet.2025.102250
Andrea R. Ortiz , Kevin Nay , Brittany A. Stork , Adam M. Dean , Sean M. Hartig , Cristian Coarfa , Surafel Tegegne , Christopher RM. Asquith , Daniel E. Frigo , Brian York , Anthony R. Means , Mark A. Febbraio , John W. Scott
Objective
Obesity is associated with chronic, low-grade inflammation in metabolic tissues such as liver, adipose tissue and skeletal muscle implicating insulin resistance and type 2 diabetes as inflammatory diseases. This inflammatory response involves the accumulation of pro-inflammatory macrophages in these metabolically relevant organs. The Ca2+-calmodulin-dependent protein kinase kinase-2 (CAMKK2) is a key regulator of cellular and systemic energy metabolism, and a coordinator of macrophage-mediated inflammatory responses. However, its role in obesity-associated metabolic dysfunction is not fully defined. The aim of this study was to determine the contribution of CAMKK2 to the regulation of inflammation and systemic metabolism during diet-induced obesity.
Methods
Mice with myeloid-specific deletion of Camkk2 were generated and challenged with a high-fat diet. Metabolic phenotyping, histological analyses, and transcriptomic profiling were used to assess whole-body metabolism, liver lipid accumulation, and gene expression in macrophages and adipose tissue.
Results
Myeloid-specific Camkk2 deficiency protected mice from high fat diet-induced obesity, insulin resistance and liver steatosis. These protective effects were associated with rewiring of metabolic and inflammatory gene expression in both macrophages and adipose tissue, along with enhanced whole-body energy expenditure.
Conclusions
Our data establish CAMKK2 as an important regulator of macrophage function and putative therapeutic target for treating obesity and related metabolic disorders.
{"title":"Myeloid-specific CAMKK2 deficiency protects against diet-induced obesity and insulin resistance by rewiring metabolic gene expression and enhancing energy expenditure","authors":"Andrea R. Ortiz , Kevin Nay , Brittany A. Stork , Adam M. Dean , Sean M. Hartig , Cristian Coarfa , Surafel Tegegne , Christopher RM. Asquith , Daniel E. Frigo , Brian York , Anthony R. Means , Mark A. Febbraio , John W. Scott","doi":"10.1016/j.molmet.2025.102250","DOIUrl":"10.1016/j.molmet.2025.102250","url":null,"abstract":"<div><h3>Objective</h3><div>Obesity is associated with chronic, low-grade inflammation in metabolic tissues such as liver, adipose tissue and skeletal muscle implicating insulin resistance and type 2 diabetes as inflammatory diseases. This inflammatory response involves the accumulation of pro-inflammatory macrophages in these metabolically relevant organs. The Ca<sup>2+</sup>-calmodulin-dependent protein kinase kinase-2 (CAMKK2) is a key regulator of cellular and systemic energy metabolism, and a coordinator of macrophage-mediated inflammatory responses. However, its role in obesity-associated metabolic dysfunction is not fully defined. The aim of this study was to determine the contribution of CAMKK2 to the regulation of inflammation and systemic metabolism during diet-induced obesity.</div></div><div><h3>Methods</h3><div>Mice with myeloid-specific deletion of <em>Camkk2</em> were generated and challenged with a high-fat diet. Metabolic phenotyping, histological analyses, and transcriptomic profiling were used to assess whole-body metabolism, liver lipid accumulation, and gene expression in macrophages and adipose tissue.</div></div><div><h3>Results</h3><div>Myeloid-specific <em>Camkk2</em> deficiency protected mice from high fat diet-induced obesity, insulin resistance and liver steatosis. These protective effects were associated with rewiring of metabolic and inflammatory gene expression in both macrophages and adipose tissue, along with enhanced whole-body energy expenditure.</div></div><div><h3>Conclusions</h3><div>Our data establish CAMKK2 as an important regulator of macrophage function and putative therapeutic target for treating obesity and related metabolic disorders.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"101 ","pages":"Article 102250"},"PeriodicalIF":6.6,"publicationDate":"2025-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145058505","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}
Pub Date : 2025-09-11DOI: 10.1016/j.molmet.2025.102252
Janina Behrens , Tongtong Wang , Christoph Kilian , Anna Worthmann , Mark A. Herman , Joerg Heeren , Lorenz Adlung , Ludger Scheja
Objective and methods
Brown adipose tissue (BAT) comprises a heterogeneous population of adipocytes and non-adipocyte cell types. To characterize these cellular subpopulations and their adaptation to cold, we performed single-nucleus mRNA-sequencing (snRNA-seq) on interscapular BAT from mice maintained at room temperature or exposed to acute (24h) or chronic (10 days) cold (6 °C). To investigate the role of the de novo lipogenesis (DNL)-regulating transcription factor carbohydrate response element-binding protein (ChREBP), we analyzed control and brown adipocyte-specific ChREBP knockout mice.
Results
We identified different cell populations, including seven brown adipocyte subtypes with distinct metabolic profiles. One of them highly expressed ChREBP and DNL enzymes. Notably, these lipogenic adipocytes were highly sensitive to acute cold exposure, showing a marked depletion in BAT of control mice that was compensated by other brown adipocyte subtypes maintaining DNL. Chronic cold exposure resulted in an expansion of basal brown adipocytes and adipocytes putatively derived from stromal and endothelial precursors. In ChREBP-deficient mice, lipogenic adipocytes were almost absent under all conditions, identifying the transcription factor as a key determinant of this adipocyte subtype. Detailed expression analyses revealed Ttc25 as a specific marker of lipogenic brown adipocytes and as a downstream target of ChREBP. Furthermore, pathway and cell–cell interaction analyses implicated a Wnt–ChREBP axis in the maintenance of lipogenic adipocytes, with Wnt ligands from stromal and muscle cells providing instructive cues.
Conclusions
Our findings provide a comprehensive atlas of BAT cellular heterogeneity and reveal a critical role for ChREBP in lipogenic adipocyte identity, with implications for BAT plasticity and metabolic function.
{"title":"Single-nucleus mRNA-sequencing reveals dynamics of lipogenic and thermogenic adipocyte populations in murine brown adipose tissue in response to cold exposure","authors":"Janina Behrens , Tongtong Wang , Christoph Kilian , Anna Worthmann , Mark A. Herman , Joerg Heeren , Lorenz Adlung , Ludger Scheja","doi":"10.1016/j.molmet.2025.102252","DOIUrl":"10.1016/j.molmet.2025.102252","url":null,"abstract":"<div><h3>Objective and methods</h3><div>Brown adipose tissue (BAT) comprises a heterogeneous population of adipocytes and non-adipocyte cell types. To characterize these cellular subpopulations and their adaptation to cold, we performed single-nucleus mRNA-sequencing (snRNA-seq) on interscapular BAT from mice maintained at room temperature or exposed to acute (24h) or chronic (10 days) cold (6 °C). To investigate the role of the <em>de novo</em> lipogenesis (DNL)-regulating transcription factor carbohydrate response element-binding protein (ChREBP), we analyzed control and brown adipocyte-specific ChREBP knockout mice.</div></div><div><h3>Results</h3><div>We identified different cell populations, including seven brown adipocyte subtypes with distinct metabolic profiles. One of them highly expressed ChREBP and DNL enzymes. Notably, these lipogenic adipocytes were highly sensitive to acute cold exposure, showing a marked depletion in BAT of control mice that was compensated by other brown adipocyte subtypes maintaining DNL. Chronic cold exposure resulted in an expansion of basal brown adipocytes and adipocytes putatively derived from stromal and endothelial precursors. In ChREBP-deficient mice, lipogenic adipocytes were almost absent under all conditions, identifying the transcription factor as a key determinant of this adipocyte subtype. Detailed expression analyses revealed <em>Ttc25</em> as a specific marker of lipogenic brown adipocytes and as a downstream target of ChREBP. Furthermore, pathway and cell–cell interaction analyses implicated a Wnt–ChREBP axis in the maintenance of lipogenic adipocytes, with Wnt ligands from stromal and muscle cells providing instructive cues.</div></div><div><h3>Conclusions</h3><div>Our findings provide a comprehensive atlas of BAT cellular heterogeneity and reveal a critical role for ChREBP in lipogenic adipocyte identity, with implications for BAT plasticity and metabolic function.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"101 ","pages":"Article 102252"},"PeriodicalIF":6.6,"publicationDate":"2025-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145058568","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}
Pub Date : 2025-09-10DOI: 10.1016/j.molmet.2025.102248
Michaela E. Trautman , Cara L. Green , Michael R. MacArthur , Krittisak Chaiyakul , Yasmine H. Alam , Chung-Yang Yeh , Reji Babygirija , Isabella James , Michael Gilpin , Esther Zelenovskiy , Madelyn Green , Ryan N. Marshall , Alexander Raskin , Michelle M. Sonsalla , Victoria Flores , Judith A. Simcox , Irene M. Ong , Kristen C. Malecki , Cholsoon Jang , Dudley W. Lamming
The amino acid composition of the diet has recently emerged as a critical regulator of metabolic health. Consumption of the branched-chain amino acid isoleucine is positively correlated with body mass index in humans, and reducing dietary levels of isoleucine rapidly improves the metabolic health of diet-induced obese male C57BL/6J mice. However, there are some reports that dietary supplementation with extra BCAAs has health benefits. Further, the interactions between sex, genetic background, and dietary isoleucine levels in response to a Western Diet (WD) remain incompletely understood. Here, we find that although the magnitude of the effect varies by sex and strain, reducing dietary levels of isoleucine protects C57BL/6J and DBA/2J mice of both sexes from the deleterious metabolic effects of a WD, while increasing dietary levels of isoleucine impairs aspects of metabolic health. Despite broadly positive responses across all sexes and strains to reduced isoleucine, the molecular response of each sex and strain is highly distinctive. Using a multi-omics approach, we identify a core sex- and strain-independent molecular response to dietary isoleucine, and identify mega-clusters of differentially expressed hepatic genes, metabolites, and lipids associated with each phenotype. Intriguingly, the metabolic effects of reduced isoleucine in mice are not associated with FGF21 – and we find that in humans, plasma FGF21 levels are likewise not associated with dietary levels of isoleucine. Finally, an analysis of human NHANES data shows that isoleucine content varies widely across foods, and that individuals with higher Healthy Eating Index scores tend to consume lower amounts of isoleucine. Our results suggest that the dietary level of isoleucine is a potential mediator of the metabolic and molecular response to a WD, and imply that reducing dietary isoleucine may represent a theoretically translatable strategy to protect from the negative metabolic consequences of a WD.
{"title":"Dietary isoleucine content modulates the metabolic and molecular response to a Western diet in mice","authors":"Michaela E. Trautman , Cara L. Green , Michael R. MacArthur , Krittisak Chaiyakul , Yasmine H. Alam , Chung-Yang Yeh , Reji Babygirija , Isabella James , Michael Gilpin , Esther Zelenovskiy , Madelyn Green , Ryan N. Marshall , Alexander Raskin , Michelle M. Sonsalla , Victoria Flores , Judith A. Simcox , Irene M. Ong , Kristen C. Malecki , Cholsoon Jang , Dudley W. Lamming","doi":"10.1016/j.molmet.2025.102248","DOIUrl":"10.1016/j.molmet.2025.102248","url":null,"abstract":"<div><div>The amino acid composition of the diet has recently emerged as a critical regulator of metabolic health. Consumption of the branched-chain amino acid isoleucine is positively correlated with body mass index in humans, and reducing dietary levels of isoleucine rapidly improves the metabolic health of diet-induced obese male C57BL/6J mice. However, there are some reports that dietary supplementation with extra BCAAs has health benefits. Further, the interactions between sex, genetic background, and dietary isoleucine levels in response to a Western Diet (WD) remain incompletely understood. Here, we find that although the magnitude of the effect varies by sex and strain, reducing dietary levels of isoleucine protects C57BL/6J and DBA/2J mice of both sexes from the deleterious metabolic effects of a WD, while increasing dietary levels of isoleucine impairs aspects of metabolic health. Despite broadly positive responses across all sexes and strains to reduced isoleucine, the molecular response of each sex and strain is highly distinctive. Using a multi-omics approach, we identify a core sex- and strain-independent molecular response to dietary isoleucine, and identify mega-clusters of differentially expressed hepatic genes, metabolites, and lipids associated with each phenotype. Intriguingly, the metabolic effects of reduced isoleucine in mice are not associated with FGF21 – and we find that in humans, plasma FGF21 levels are likewise not associated with dietary levels of isoleucine. Finally, an analysis of human NHANES data shows that isoleucine content varies widely across foods, and that individuals with higher Healthy Eating Index scores tend to consume lower amounts of isoleucine. Our results suggest that the dietary level of isoleucine is a potential mediator of the metabolic and molecular response to a WD, and imply that reducing dietary isoleucine may represent a theoretically translatable strategy to protect from the negative metabolic consequences of a WD.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"101 ","pages":"Article 102248"},"PeriodicalIF":6.6,"publicationDate":"2025-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145054381","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}
Pub Date : 2025-09-05DOI: 10.1016/j.molmet.2025.102247
Xi Chen , Xing Fang , Hong Zhou , Jieyi Meng , Yang He , Leon G. Straub , Andrew Lemoff , Clair Crewe , Shangang Zhao , Yong Xu , Yi Zhu
Background and objective
Connexin43 (Cx43), encoded by Gja1, forms gap junctions between adjacent cells. In adipose tissue, it is upregulated during adipose beiging while downregulated by high-fat-diet (HFD) feeding. Adipocyte-specific Gja1 overexpression enhances adipose tissue beiging in response to mild cold stress of room temperature. Moreover, those mice display a surprising decrease in food intake, but the mechanism remains unclear. This study investigates how adipocyte Cx43 influences feeding behavior.
Methods
Mice with adipose tissue-specific Gja1 overexpression (Adipoq-Cx43) were fed with HFD. Food intake, weight gain, substrate utilization, and serum lipolysis were assessed. RNA-seq, proteomics, and cytokine measurements were employed to identify candidate signals. Sensory neurons were manipulated via subcutaneous capsaicin injection or iWAT-targeted optogenetics. Co-culture of adipocytes and sensory neurons in vitro was used to test gap junction communication between these two types of cells.
Results
Adipoq-Cx43 mice showed reduced food intake, fat mass, and weight gain on HFD, and shifted substrate utilization toward fatty acids. Although GDF15 was elevated, its neutralization did not reverse the reduced food intake. Instead, systemic ablation of sensory neurons using capsaicin abolished the suppressed food intake. Ooptogenetic activation of sensory neurons in iWAT acutely reduced food intake and improved glucose tolerance after two weeks. In the co-culture of adipocytes and in vitro differentiated sensory neurons, optogenetic stimulation of adipocytes enhanced firing of the adjacent sensory neurons via gap junctions, an effect blocked by the gap junction inhibitor carbenoxolone.
Conclusions
Gap junction–mediated electrical communication between adipocytes and sensory neurons may regulate feeding.
{"title":"Regulation of food intake by Connexin43 via adipocyte-sensory neuron electrical synapses","authors":"Xi Chen , Xing Fang , Hong Zhou , Jieyi Meng , Yang He , Leon G. Straub , Andrew Lemoff , Clair Crewe , Shangang Zhao , Yong Xu , Yi Zhu","doi":"10.1016/j.molmet.2025.102247","DOIUrl":"10.1016/j.molmet.2025.102247","url":null,"abstract":"<div><h3>Background and objective</h3><div>Connexin43 (Cx43), encoded by <em>Gja1</em>, forms gap junctions between adjacent cells. In adipose tissue, it is upregulated during adipose beiging while downregulated by high-fat-diet (HFD) feeding. Adipocyte-specific <em>Gja1</em> overexpression enhances adipose tissue beiging in response to mild cold stress of room temperature. Moreover, those mice display a surprising decrease in food intake, but the mechanism remains unclear. This study investigates how adipocyte Cx43 influences feeding behavior.</div></div><div><h3>Methods</h3><div>Mice with adipose tissue-specific <em>Gja1</em> overexpression (Adipoq-Cx43) were fed with HFD. Food intake, weight gain, substrate utilization, and serum lipolysis were assessed. RNA-seq, proteomics, and cytokine measurements were employed to identify candidate signals. Sensory neurons were manipulated via subcutaneous capsaicin injection or iWAT-targeted optogenetics. Co-culture of adipocytes and sensory neurons in vitro was used to test gap junction communication between these two types of cells.</div></div><div><h3>Results</h3><div>Adipoq-Cx43 mice showed reduced food intake, fat mass, and weight gain on HFD, and shifted substrate utilization toward fatty acids. Although GDF15 was elevated, its neutralization did not reverse the reduced food intake. Instead, systemic ablation of sensory neurons using capsaicin abolished the suppressed food intake. Ooptogenetic activation of sensory neurons in iWAT acutely reduced food intake and improved glucose tolerance after two weeks. In the co-culture of adipocytes and in vitro differentiated sensory neurons, optogenetic stimulation of adipocytes enhanced firing of the adjacent sensory neurons via gap junctions, an effect blocked by the gap junction inhibitor carbenoxolone.</div></div><div><h3>Conclusions</h3><div>Gap junction–mediated electrical communication between adipocytes and sensory neurons may regulate feeding.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"101 ","pages":"Article 102247"},"PeriodicalIF":6.6,"publicationDate":"2025-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145015882","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}
Pub Date : 2025-09-03DOI: 10.1016/j.molmet.2025.102243
Federica Campolo , Ottavia Giampaoli , Federica Barbagallo , Biagio Palmisano , Anna Di Maio , Francesca Sciarra , Flavio Rizzo , Serena Monti , Sandra Albanese , Silvia Cardarelli , Maria Rita Assenza , Eleonora Poggiogalle , Adriano Patriarca , Fabio Sciubba , Antonio Filippini , Andrea Lenzi , Daniele Gianfrilli , Mauro Giorgi , Susanna Dolci , Fabio Naro , Andrea M. Isidori
Objective
Cyclic nucleotides are central regulators of adipogenesis and adaptive thermogenesis, with their intracellular concentrations tightly controlled by phosphodiesterases (PDEs). Among them, phosphodiesterase type 5 (PDE5A) regulates cyclic guanosine monophosphate (cGMP) turnover in adipocytes. Although PDE5A inhibition has been explored in diabetes, its role in systemic metabolism remains poorly defined.
Methods
We employed different Pde5a knockout mouse models to investigate the impact of PDE5A deficiency on adipose tissue biology and whole-body energy homeostasis. Phenotypic, histological, and metabolic assessments were performed under chow and high-fat diet conditions, with a focus on thermogenic activation, hepatic lipid accumulation, and glucose metabolism.
Results
Loss of Pde5a resulted in robust activation of brown adipose tissue and moderate browning of white adipose depots, accompanied by a reduction in hepatic lipid content. Upon high-fat diet challenge, Pde5a-deficient mice exhibited resistance to obesity, improved glucose handling, and enhanced thermogenic capacity. Mechanistically, these protective effects originated from early developmental knockdown of Pde5a, which induced metabolic reprogramming via activation of the cAMP–protein kinase A (PKA) signaling pathway. The convergence of cGMP and cAMP signaling cascades orchestrated systemic metabolic adaptations.
Conclusions
Our study identifies PDE5A as a previously unrecognized regulator of thermogenesis and energy balance. Targeting PDE5A may therefore represent a promising adjuvant therapeutic approach for the treatment of metabolic disorders.
{"title":"Pde5a deficiency prevents diet-induced obesity via adipose cAMP-PKA activation enhancing fat browning","authors":"Federica Campolo , Ottavia Giampaoli , Federica Barbagallo , Biagio Palmisano , Anna Di Maio , Francesca Sciarra , Flavio Rizzo , Serena Monti , Sandra Albanese , Silvia Cardarelli , Maria Rita Assenza , Eleonora Poggiogalle , Adriano Patriarca , Fabio Sciubba , Antonio Filippini , Andrea Lenzi , Daniele Gianfrilli , Mauro Giorgi , Susanna Dolci , Fabio Naro , Andrea M. Isidori","doi":"10.1016/j.molmet.2025.102243","DOIUrl":"10.1016/j.molmet.2025.102243","url":null,"abstract":"<div><h3>Objective</h3><div>Cyclic nucleotides are central regulators of adipogenesis and adaptive thermogenesis, with their intracellular concentrations tightly controlled by phosphodiesterases (PDEs). Among them, phosphodiesterase type 5 (PDE5A) regulates cyclic guanosine monophosphate (cGMP) turnover in adipocytes. Although PDE5A inhibition has been explored in diabetes, its role in systemic metabolism remains poorly defined.</div></div><div><h3>Methods</h3><div>We employed different <em>Pde5a</em> knockout mouse models to investigate the impact of PDE5A deficiency on adipose tissue biology and whole-body energy homeostasis. Phenotypic, histological, and metabolic assessments were performed under chow and high-fat diet conditions, with a focus on thermogenic activation, hepatic lipid accumulation, and glucose metabolism.</div></div><div><h3>Results</h3><div>Loss of <em>Pde5a</em> resulted in robust activation of brown adipose tissue and moderate browning of white adipose depots, accompanied by a reduction in hepatic lipid content. Upon high-fat diet challenge, <em>Pde5a</em>-deficient mice exhibited resistance to obesity, improved glucose handling, and enhanced thermogenic capacity. Mechanistically, these protective effects originated from early developmental knockdown of <em>Pde5a</em>, which induced metabolic reprogramming via activation of the cAMP–protein kinase A (PKA) signaling pathway. The convergence of cGMP and cAMP signaling cascades orchestrated systemic metabolic adaptations.</div></div><div><h3>Conclusions</h3><div>Our study identifies PDE5A as a previously unrecognized regulator of thermogenesis and energy balance. Targeting PDE5A may therefore represent a promising adjuvant therapeutic approach for the treatment of metabolic disorders.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"101 ","pages":"Article 102243"},"PeriodicalIF":6.6,"publicationDate":"2025-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145006372","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}
Pub Date : 2025-09-03DOI: 10.1016/j.molmet.2025.102246
Karina Cunha e Rocha , Breanna Tan , Julia Kempf , Cristina Medina , Varsha Beldona , Chengjia Qian , Ying Duan , Qian Xiang , Ahjin Yoo , Xiaomi Du , Amit R. Majithia , Wei Ying
Obesity is intricately linked to various metabolic diseases; however, some individuals maintain metabolic health despite being classified as obese. A critical factor underlying this paradox is the expansion of white adipose tissue (WAT), which can occur through two mechanisms: hypertrophy (the enlargement of existing fat cells) and hyperplasia (the formation of new fat cells from adipocyte precursor cells, or APCs). Hyperplasia is regarded as a healthier mode of WAT expansion, as it tends to reduce inflammation and protect against insulin resistance. Thus, interventions that promote hyperplasia over hypertrophy could improve metabolic health in obese individuals. In this study, we investigate the role of microRNA-690 (miR-690), an anti-inflammatory and insulin-sensitizing molecule, in maintaining the APC population and facilitating the healthy expansion of epididymal WAT (eWAT). Our findings indicate that in lean mice, macrophages support the APC population by transferring miR-690 to APCs. However, during obesity, the recruitment of pro-inflammatory lipid-associated macrophages (LAMs) to eWAT diminishes miR-690 delivery to APCs, impairing adipogenesis and leading to unhealthy WAT expansion. We demonstrate that strategies aimed at increasing the availability of miR-690 to APCs or mimicking its effects can restore APC functionality. Additionally, mutations in Nadk, the target of miR-690, were shown to mitigate the adverse effects of obesity on APC maintenance in eWAT. These findings suggest that targeting the miR-690-Nadk axis in APCs may provide novel therapeutic strategies to promote healthy adipose tissue expansion and protect against obesity-related metabolic diseases.
{"title":"Adipose tissue macrophage-derived miR-690 modulates adipocyte precursor cell maintenance and adipogenesis","authors":"Karina Cunha e Rocha , Breanna Tan , Julia Kempf , Cristina Medina , Varsha Beldona , Chengjia Qian , Ying Duan , Qian Xiang , Ahjin Yoo , Xiaomi Du , Amit R. Majithia , Wei Ying","doi":"10.1016/j.molmet.2025.102246","DOIUrl":"10.1016/j.molmet.2025.102246","url":null,"abstract":"<div><div>Obesity is intricately linked to various metabolic diseases; however, some individuals maintain metabolic health despite being classified as obese. A critical factor underlying this paradox is the expansion of white adipose tissue (WAT), which can occur through two mechanisms: hypertrophy (the enlargement of existing fat cells) and hyperplasia (the formation of new fat cells from adipocyte precursor cells, or APCs). Hyperplasia is regarded as a healthier mode of WAT expansion, as it tends to reduce inflammation and protect against insulin resistance. Thus, interventions that promote hyperplasia over hypertrophy could improve metabolic health in obese individuals. In this study, we investigate the role of microRNA-690 (miR-690), an anti-inflammatory and insulin-sensitizing molecule, in maintaining the APC population and facilitating the healthy expansion of epididymal WAT (eWAT). Our findings indicate that in lean mice, macrophages support the APC population by transferring miR-690 to APCs. However, during obesity, the recruitment of pro-inflammatory lipid-associated macrophages (LAMs) to eWAT diminishes miR-690 delivery to APCs, impairing adipogenesis and leading to unhealthy WAT expansion. We demonstrate that strategies aimed at increasing the availability of miR-690 to APCs or mimicking its effects can restore APC functionality. Additionally, mutations in Nadk, the target of miR-690, were shown to mitigate the adverse effects of obesity on APC maintenance in eWAT. These findings suggest that targeting the miR-690-Nadk axis in APCs may provide novel therapeutic strategies to promote healthy adipose tissue expansion and protect against obesity-related metabolic diseases.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"101 ","pages":"Article 102246"},"PeriodicalIF":6.6,"publicationDate":"2025-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145006335","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}
Pub Date : 2025-09-02DOI: 10.1016/j.molmet.2025.102238
Anastasia Sacharidou , Ken L. Chambliss , Jun Peng , Keiji Tanigaki , Md Nurul Islam , Shashank Sirsi , Andrew Lemoff , Kenneth Hoyt , Chieko Mineo , Philip W. Shaul
Objective
The delivery of circulating insulin to skeletal muscle myocytes is a rate-limiting step in peripheral insulin action, and there is minimal understanding of the underlying mechanisms in endothelial cells. Recognizing that the LDL receptor family member apolipoprotein E receptor 2 (ApoER2, also known as LRP8) mediates apolipoprotein E (ApoE)-induced signaling in endothelial cells, the present project determined if endothelial ApoER2 influences glucose homeostasis in mice.
Methods
Mice were generated deficient in ApoER2 selectively in endothelial cells, and glucose homeostasis was studied. Insulin-stimulated recruitment of the skeletal muscle microvasculature was assessed using contrast-enhanced ultrasound imaging. Endothelial cell insulin uptake and transcytosis were evaluated in culture. The ApoER2 interactome in endothelial cells was interrogated using immunoprecipitation and liquid chromatography/tandem mass spectrometry. ApoER2 structure–function was studied by mutagenesis.
Results
Mice deficient in endothelial cell ApoER2 are glucose intolerant and insulin resistant due to a blunting of skeletal muscle glucose disposal that is related to a decrease in muscle insulin delivery. Endothelial ApoER2 manipulation does not alter direct insulin action on skeletal muscle or insulin-stimulated recruitment of the skeletal muscle microvasculature. Instead, ApoER2 stimulation by apolipoprotein E3 (ApoE3) increases endothelial cell insulin uptake and transcytosis. ApoE3 and ApoER2 stimulation of endothelial insulin transport require the ApoER2 adaptor protein Dab2 and the scaffolding protein IQGAP1, which is known to mediate insulin secretion by pancreatic β cells. IQGAP1 is not required for ApoE3/ApoER2-induced insulin uptake by endothelial cells; alternatively it is necessary for insulin transcytosis. ApoE3 prompts IQGAP1 recruitment to the exocyst complex, and ApoER2 interaction with IQGAP1 is necessary for the recruitment.
Conclusions
In endothelial cells the ApoE3 and ApoER2 tandem co-opts the role of IQGAP1 in pancreatic β cell insulin secretion to enhance endothelial insulin transport. In this manner endothelial ApoER2 promotes glucose disposal in skeletal muscle and supports normal glucose homeostasis.
{"title":"Apolipoprotein E receptor 2 in endothelium promote glucose tolerance by mediating insulin delivery to skeletal muscle","authors":"Anastasia Sacharidou , Ken L. Chambliss , Jun Peng , Keiji Tanigaki , Md Nurul Islam , Shashank Sirsi , Andrew Lemoff , Kenneth Hoyt , Chieko Mineo , Philip W. Shaul","doi":"10.1016/j.molmet.2025.102238","DOIUrl":"10.1016/j.molmet.2025.102238","url":null,"abstract":"<div><h3>Objective</h3><div>The delivery of circulating insulin to skeletal muscle myocytes is a rate-limiting step in peripheral insulin action, and there is minimal understanding of the underlying mechanisms in endothelial cells. Recognizing that the LDL receptor family member apolipoprotein E receptor 2 (ApoER2, also known as LRP8) mediates apolipoprotein E (ApoE)-induced signaling in endothelial cells, the present project determined if endothelial ApoER2 influences glucose homeostasis in mice.</div></div><div><h3>Methods</h3><div>Mice were generated deficient in ApoER2 selectively in endothelial cells, and glucose homeostasis was studied. Insulin-stimulated recruitment of the skeletal muscle microvasculature was assessed using contrast-enhanced ultrasound imaging. Endothelial cell insulin uptake and transcytosis were evaluated in culture. The ApoER2 interactome in endothelial cells was interrogated using immunoprecipitation and liquid chromatography/tandem mass spectrometry. ApoER2 structure–function was studied by mutagenesis.</div></div><div><h3>Results</h3><div>Mice deficient in endothelial cell ApoER2 are glucose intolerant and insulin resistant due to a blunting of skeletal muscle glucose disposal that is related to a decrease in muscle insulin delivery. Endothelial ApoER2 manipulation does not alter direct insulin action on skeletal muscle or insulin-stimulated recruitment of the skeletal muscle microvasculature. Instead, ApoER2 stimulation by apolipoprotein E3 (ApoE3) increases endothelial cell insulin uptake and transcytosis. ApoE3 and ApoER2 stimulation of endothelial insulin transport require the ApoER2 adaptor protein Dab2 and the scaffolding protein IQGAP1, which is known to mediate insulin secretion by pancreatic β cells. IQGAP1 is not required for ApoE3/ApoER2-induced insulin uptake by endothelial cells; alternatively it is necessary for insulin transcytosis. ApoE3 prompts IQGAP1 recruitment to the exocyst complex, and ApoER2 interaction with IQGAP1 is necessary for the recruitment.</div></div><div><h3>Conclusions</h3><div>In endothelial cells the ApoE3 and ApoER2 tandem co-opts the role of IQGAP1 in pancreatic β cell insulin secretion to enhance endothelial insulin transport. In this manner endothelial ApoER2 promotes glucose disposal in skeletal muscle and supports normal glucose homeostasis.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"101 ","pages":"Article 102238"},"PeriodicalIF":6.6,"publicationDate":"2025-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145000984","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}
扫码关注我们
求助内容：
应助结果提醒方式：
京公网安备 11010802042870号