Molecular Metabolism最新文献

{"title":"Uncovering the role of Gpr45 in obesity regulation","authors":"Eva O. Karolczak , Chia Li , Ivan C. Alcantara , Isabel M. Cohen , Claire Gao , Cuiying Xiao , Abigail I. Goldschmidt , Cynthia A. Pinkus , Junjie Li , Monica M. Li , Ryan M. Esquejo , Jean-Philippe Fortin , Kendra K. Bence , Marc L. Reitman , Michael J. Krashes","doi":"10.1016/j.molmet.2025.102174","DOIUrl":"10.1016/j.molmet.2025.102174","url":null,"abstract":"<div><h3>Objectives</h3><div>G protein-coupled receptors (GPCRs) are the most druggable targets in biology due to their cell-type specificity, ligand binding, and cell surface accessibility. Underscoring this, agonists for GPCRs have recently revolutionized the treatment of diabetes and obesity. The rampant success of these compounds has invigorated interest in identifying additional GPCRs that modulate appetite and body weight homeostasis. One such potential therapeutic target is G-protein couped receptor 45 (Gpr45), an orphan GPCR expressed both centrally and peripherally. We aimed to explore the role of Gpr45 as well as neurons expressing Gpr45 in energy balance.</div></div><div><h3>Methods</h3><div>Three novel transgenic mouse models were engineered to investigate the functional contribution of Gpr45 to body weight and appetite regulation: 1) a global Gpr45 knockout, 2) a conditional floxed Gpr45 allele, and 3) a Gpr45-CreERT2 knock-in. Metabolic profiling was performed in global Gpr45 knockout animals including body weight, food intake, body mass, energy expenditure, and body temperature measurements. Animals harboring a conditional floxed Gpr45 allele were bred to mice expressing Cre-recombinase in excitatory neurons labeled via <em>Vesicular glutamate transporter 2</em> (<em>Vglut2</em>)<em>,</em> inhibitory cells expressing <em>Vesicular GABA transporter</em> (<em>Vgat</em>), or neurons marked by the transcription factor <em>Single-minded 1</em> (<em>Sim1</em>) and monitored for body weight and food consumption. Additionally, floxed Gpr45 mice were bilaterally injected with AAV-Cre targeting the paraventricular nucleus of the hypothalamus (PVH) and body weight and food intake were evaluated. The Gpr45-CreERT2 knock-in model was used to express chronic and acute actuators to the PVH to assess the role of PVH<sup>Gpr45</sup> neurons in energy homeostasis.</div></div><div><h3>Results</h3><div>Global Gpr45 disruption caused marked weight gain, increased food intake and fat mass, but no detectable alterations in core temperature or energy output. Selective deletion of Gpr45 from Sim1+ or excitatory Vglut2+ but not inhibitory Vgat+, neurons produced obesity and hyperphagia. Targeted deletion of Gpr45 from the PVH phenocopies these metabolic changes suggesting a major site of action of Gpr45 signaling is glutamatergic neurons residing in the PVH. Tetanus toxin light chain (TeNT) was used to permanently silence PVH<sup>Gpr45</sup> neuronal activity in Gpr45-CreER mice leading to rapid weight accumulation and escalated food intake. These experiments highlight the critical role of both Gpr45 signaling and neural network activity in the regulation of body weight and appetite. A mutated version of the bacterial sodium channel, NaChBac, was used to constitutively activate PVH<sup>Gpr45</sup> neuronal activity in Gpr45-CreER mice with limited to no effect on body weight and food consumption, implicating redundant circuitry acting in concert to bias wei","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"98 ","pages":"Article 102174"},"PeriodicalIF":7.0,"publicationDate":"2025-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144191972","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":"Genetic depletion of adipose-derived Isthmin-1 causes hepatic steatosis","authors":"Saranya C. Reghupaty ,&nbsp;Laetitia Coassolo ,&nbsp;Meng Zhao ,&nbsp;Ramya Lakshmi Narasimhan ,&nbsp;Aayan Patel ,&nbsp;Jameel Lone ,&nbsp;Ewa Bielczyk-Maczynska ,&nbsp;Niels B. Danneskiold-Samsoee ,&nbsp;Taylor Brown ,&nbsp;Zewen Jiang ,&nbsp;Veronica L. Li ,&nbsp;Katrin J. Svensson","doi":"10.1016/j.molmet.2025.102172","DOIUrl":"10.1016/j.molmet.2025.102172","url":null,"abstract":"<div><h3>Objectives</h3><div>Adipose tissue plays a critical role in obesity, as its dysfunction can impair lipid homeostasis and result in lipid overflow and ectopic lipid deposition in the liver. We previously demonstrated that Isthmin-1 (Ism1) regulates glucose uptake into the adipose tissue and suppresses hepatic steatosis, but the role of adipose-derived Ism1 is unknown. Here, we investigate the role of adipose-derived Ism1 in metabolic health and its impact on hepatic steatosis and lipid metabolism.</div></div><div><h3>Methods</h3><div>In this study, we employed both a genetic knockout approach, selectively deleting Ism1 in adipose tissue of mice (AdipoQ-Ism1-KO), and a pharmacological approach by administering recombinant Ism1 protein to mice. These mice were subjected to a high fat-high fructose diet to simulate conditions that promote Metabolic-dysfunction Associated Steatotic Liver Disease (MASLD).</div></div><div><h3>Results</h3><div>AdipoQ-Ism1-KO are of normal weight, but prone to severe hepatic steatosis in response to high fat-high fructose feeding. Lipidomic profiling through untargeted analyses in both gain-of-function and loss-of-function models was used to assess changes in hepatic lipid homeostasis. These results provide <em>in vivo</em> genetic support for the role of Ism1 as a regulator of the adipose–hepatic axis.</div></div><div><h3>Conclusions</h3><div>Collectively, these data demonstrate that loss of adipose-derived Ism1 disrupts lipid homeostasis and accelerates the development of hepatic steatosis. This study provides a genetic basis for Ism1's involvement in metabolic regulation, suggesting a potential therapeutic target for treating metabolic disorders.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"98 ","pages":"Article 102172"},"PeriodicalIF":7.0,"publicationDate":"2025-05-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144174198","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":"JNK1 in SF1 neurons regulates the central action of thyroid hormones on hepatic lipid metabolism","authors":"Iara Fernández-González ,&nbsp;Oscar Freire-Agulleiro ,&nbsp;Vitor Ferreira ,&nbsp;María Silveira-Loureiro ,&nbsp;Eva Rial-Pensado ,&nbsp;Pablo Garrido-Gil ,&nbsp;Gloria Martínez ,&nbsp;Patricia Rada ,&nbsp;José L. Labandeira-García ,&nbsp;Jens Mittag ,&nbsp;Ismael González-García ,&nbsp;Carlos Diéguez ,&nbsp;Rubén Nogueiras ,&nbsp;Ángela M. Valverde ,&nbsp;Roger J. Davis ,&nbsp;Guadalupe Sabio ,&nbsp;Olga Barca-Mayo ,&nbsp;Miguel López","doi":"10.1016/j.molmet.2025.102170","DOIUrl":"10.1016/j.molmet.2025.102170","url":null,"abstract":"<div><h3>Objective</h3><div>Hypothalamic energy sensors, such as AMP-activated protein kinase (AMPK), and stress sensors, such as c-Jun N-terminal kinase 1 (JNK1, also known as MAPK8) modulate whole body energy balance. While the role of AMPK in steroidogenic factor 1 (SF1) neurons of the VMH has been investigated, the relevance of JNK1 in this neuronal population has not been addressed. Here, we investigated the involvement of JNK1 SF1 on energy homeostasis.</div></div><div><h3>Methods</h3><div>We generated mice bearing conditional JNK1 disruption through <em>Mapk8</em> gene deletion in SF1 neurons (<em>Sf1</em>^<em>Cre</em><em>/Jnk1</em>^{<em>fl/fl</em>}). Complete metabolic phenotyping, fasting/refeeding and cold challenges, as well as the central response to triiodothyronine (T3) on brown adipose tissue (BAT) thermogenesis and hepatic lipid metabolism were carried out.</div></div><div><h3>Results</h3><div><em>Sf1</em>^<em>Cre</em><em>/Jnk1</em>^{<em>fl/fl</em>} mice displayed decreased body weight, improved glucose tolerance, and reduced hepatic lipid levels. However, <em>Sf1</em>^<em>Cre</em><em>/Jnk1</em>^{<em>fl/fl</em>} did not properly defend their temperature upon cold exposure. While central administration of T3 elicited feeding independent weight loss in both wildtype (<em>Jnk1</em>^{<em>fl/fl</em>}) and <em>SF1</em>^<em>Cre</em><em>/Jnk1</em>^{<em>fl/fl</em>} mice, it did not promote hepatic lipid accretion in null animals.</div></div><div><h3>Conclusions</h3><div>Our data demonstrated for the first time that JNK1 in SF1 neurons is necessary for the regulation of hepatic lipid metabolism, cold adaptation and central T3 actions.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"98 ","pages":"Article 102170"},"PeriodicalIF":7.0,"publicationDate":"2025-05-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144151262","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":"Training-induced plasma miR-29a-3p is secreted by skeletal muscle and contributes to metabolic adaptations to resistance exercise in mice","authors":"Paola Pinto-Hernandez ,&nbsp;Manuel Fernandez-Sanjurjo ,&nbsp;Daan Paget ,&nbsp;Xurde M. Caravia ,&nbsp;David Roiz-Valle ,&nbsp;Juan Castilla-Silgado ,&nbsp;Sergio Diez-Robles ,&nbsp;Almudena Coto-Vilcapoma ,&nbsp;David Fernandez-Vivero ,&nbsp;Pau Gama-Perez ,&nbsp;Pablo M. Garcia-Roves ,&nbsp;Carlos Lopez-Otin ,&nbsp;Juleen R. Zierath ,&nbsp;Anna Krook ,&nbsp;Benjamin Fernandez-Garcia ,&nbsp;Cristina Tomas-Zapico ,&nbsp;Eduardo Iglesias-Gutierrez","doi":"10.1016/j.molmet.2025.102173","DOIUrl":"10.1016/j.molmet.2025.102173","url":null,"abstract":"<div><h3>Objective</h3><div>The adaptive response to different models of regular exercise involves complex tissue crosstalk. Our aim was to explore the involvement of extracellular vesicle (EV) microRNAs (miRNAs) in this process, the secretory role of skeletal muscle and its functional metabolic interaction with the liver.</div></div><div><h3>Methods</h3><div>Plasma EV miRNAs obtained from mice after 4-weeks of endurance or resistance training were sequenced. Subsequent experiments using trained genetically modified mouse models and in vitro approaches involving knock-down and electrostimulated cells, were conducted.</div></div><div><h3>Results</h3><div>Resistance training increased the expression of a group of 11 miRNAs functionally divided into two clusters. Among them, miR-29a-3p emerges as a molecular mediator released in EVs by skeletal muscle, with a relevant role in adaptation to endurance training, by contributing to modulate the expression and secretion of other miRNAs associated with training and regulating processes related to substrate availability, transport, and metabolic use in skeletal muscle and liver.</div></div><div><h3>Conclusions</h3><div>Our study suggests that miR-29a-3p is a training-induced molecular mediator in the response and adaptation to resistance training, possibly due to its regulatory role in energy metabolism in skeletal muscle in response to exercise.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"98 ","pages":"Article 102173"},"PeriodicalIF":7.0,"publicationDate":"2025-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144143155","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":"IL-6 decodes sex and diet-dependent circadian and metabolic rhythms","authors":"Antía González-Vila ,&nbsp;Ali Mohammad Ibrahim-Alasoufi ,&nbsp;María Luengo-Mateos ,&nbsp;Víctor Pardo-García ,&nbsp;Alejandro Diaz-López ,&nbsp;Belén Fernández-Rodríguez ,&nbsp;Matti Poutanen ,&nbsp;Claes Ohlsson ,&nbsp;Manuel Tena-Sempere ,&nbsp;Carlos Diéguez-González ,&nbsp;María del Carmen García-García ,&nbsp;Olga Barca-Mayo","doi":"10.1016/j.molmet.2025.102171","DOIUrl":"10.1016/j.molmet.2025.102171","url":null,"abstract":"<div><h3>Objective</h3><div>Interleukin-6 (IL-6) is a pleiotropic cytokine involved in immune regulation and energy metabolism. Its diurnal secretion influences core circadian components, emphasizing its critical role in circadian biology. Despite known sex differences in immune, circadian, and metabolic processes, how IL-6 integrates these processes remains poorly understood.</div></div><div><h3>Methods</h3><div>IL6 knockout (KO) and control mice of both sexes were phenotyped for circadian and metabolic traits under standard (STD) and high-fat diet (HFD), fasting, and time-restricted feeding. Molecular analyses in muscle, liver, and hypothalamus assessed clock gene expression and IL-6 signaling pathway. Circulating sex steroid hormones were quantified to examine their contribution to the observed sex-specific phenotypes.</div></div><div><h3>Results</h3><div>IL-6 deficiency disrupts circadian locomotor and metabolic rhythms in a sex- and diet-dependent manner. Males exhibit impaired light-driven circadian rhythms under STD conditions and metabolic misalignment under HFD, whereas females display greater circadian resilience under STD conditions but increased vulnerability to circadian disruption during HFD. Additionally, IL-6 emerges as a novel regulator of the food-entrainable oscillator (FEO), linking food anticipatory activity and metabolic cycles under both STD and HFD in a sex-dependent manner.</div></div><div><h3>Conclusions</h3><div>These findings identify IL-6 as a critical mediator of circadian-metabolic plasticity, shaping sex- and diet-specific trade-offs between circadian stability and metabolic homeostasis. Our study highlights IL-6 as a potential therapeutic target for mitigating circadian misalignment-associated metabolic disorders, with implications for the timed modulation of IL-6 signaling.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"97 ","pages":"Article 102171"},"PeriodicalIF":7.0,"publicationDate":"2025-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144143154","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":"Whole body and hematopoietic cell-specific deletion of G-protein coupled receptor 65 (GPR65) improves insulin sensitivity in diet-induced obese mice","authors":"Yingjiang Zhou ,&nbsp;EunJu Bae ,&nbsp;Simon S. Hoffman ,&nbsp;Da Young Oh ,&nbsp;Gordon I. Smith ,&nbsp;Samuel Klein ,&nbsp;Saswata Talukdar","doi":"10.1016/j.molmet.2025.102169","DOIUrl":"10.1016/j.molmet.2025.102169","url":null,"abstract":"<div><h3>Objective</h3><div>Acidic extracellular microenvironments, resulting from enhanced glycolysis and lactic acid secretion by immune cells, along with metabolic acidosis may interfere with the insulin signaling pathway and contribute to the development of insulin resistance. In the present study, we investigated the role of G protein-coupled receptor GPR65, an extracellular pH sensing protein, in modulating insulin resistance.</div></div><div><h3>Methods</h3><div>We measured <em>GPR65</em> expression in the adipose tissue (AT) of subjects with varying metabolic health states. We utilized whole-body and hematopoietic cell-specific GPR65 knockout (KO) mice to investigate the mechanism underlying the associations between GPR65, inflammatory response, and insulin resistance.</div></div><div><h3>Results</h3><div>Elevated <em>GPR65</em> expression was observed in the AT of subjects with obesity, compared to their lean counterparts, and was inversely correlated with insulin resistance. In GPR65 KO mice, improved insulin sensitivity and decreased hepatic lipid content were observed, attributed to concomitant increases in mitochondrial activity and fatty acid β-oxidation in liver. GPR65 KO mice also exhibited increased Akt phosphorylation in skeletal muscle, suppressed proinflammatory gene expression in AT, and decreased serum cytokine levels, collectively suggesting the anti-inflammatory effects of GPR65 depletion. This was further confirmed by observations of decreased macrophage chemotaxis towards AT <em>in vitro</em>, and depressed inflammatory signaling pathway activation in bone marrow-derived dendritic cells from GPR65 KO mice. Additionally, hematopoietic lineage-specific GPR65 KO mice exhibited improved whole body insulin sensitivity in clamp studies, demonstrating GPR65 signaling in immune cells mediates this effect.</div></div><div><h3>Conclusions</h3><div>Our data suggests that macrophage-specific GPR65 signaling contributes to inflammation and the development of insulin resistance.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"97 ","pages":"Article 102169"},"PeriodicalIF":7.0,"publicationDate":"2025-05-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144102030","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":"Tetraspanin7 in adipose tissue remodeling and its impact on metabolic health","authors":"Shino Nemoto ,&nbsp;Kazuyo Uchida ,&nbsp;Tetsuya Kubota ,&nbsp;Manabu Nakayama ,&nbsp;Yong-Woon Han ,&nbsp;Shigeo Koyasu ,&nbsp;Hiroshi Ohno","doi":"10.1016/j.molmet.2025.102168","DOIUrl":"10.1016/j.molmet.2025.102168","url":null,"abstract":"<div><h3>Objective</h3><div>We previously identified tetraspanin 7 (<em>Tspan7</em>) as a candidate gene influencing body weight in an obesity-related gene screening study. However, the mechanisms underlying its involvement in body weight regulation remained unclear. This study aims to investigate the role of TSPAN7 from a metabolic perspective.</div></div><div><h3>Methods</h3><div>We utilized genetically modified mice, including adipose tissue-specific <em>Tspan7</em>-knockout and <em>Tspan7</em>-overexpressing models, as well as human adipose-derived stem cells with TSPAN7 knockdown and overexpression. Morphological, molecular, and omics analyses, including proteomics and transcriptomics, were performed to investigate TSPAN7 function. Physiological effects were assessed by measuring blood markers associated with lipid regulation under metabolic challenges, such as high-fat feeding and aging.</div></div><div><h3>Results</h3><div>We show that TSPAN7 is involved in regulating lipid droplet formation and stabilization. <em>Tspan7</em>-knockout mice exhibited an increased proportion of small-sized adipocytes and a reduced visceral-to-subcutaneous fat ratio. This shift in fat distribution was associated with improved insulin sensitivity and altered branched-chain amino acid metabolism, as evidenced by increased expression of the branched-chain α-keto acid dehydrogenase complex subunit B in <em>Tspan7</em>-modified mice. Mechanistically, TSPAN7 deficiency promoted subcutaneous fat expansion, alleviating metabolic stress on visceral fat, a major contributor to insulin resistance.</div></div><div><h3>Conclusions</h3><div>TSPAN7 influences lipid metabolism by modulating adipose tissue remodeling, particularly under metabolic challenges, such as high-fat diet exposure and aging. Its modulation enhances subcutaneous fat storage capacity while mitigating visceral fat accumulation, leading to improved insulin sensitivity. These findings position TSPAN7 as a potential target for therapeutic interventions aimed at improving metabolic health and preventing obesity-related diseases.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"97 ","pages":"Article 102168"},"PeriodicalIF":7.0,"publicationDate":"2025-05-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144079131","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":"Reduced liver mitochondrial energy metabolism impairs food intake regulation following gastric preloads and fasting","authors":"Michael E. Ponte ,&nbsp;John C. Prom ,&nbsp;Mallory A. Newcomb ,&nbsp;Annabelle B. Jordan ,&nbsp;Lucas L. Comfort ,&nbsp;Jiayin Hu ,&nbsp;Patrycja Puchalska ,&nbsp;Devin C. Koestler ,&nbsp;Caroline E. Geisler ,&nbsp;Matthew R. Hayes ,&nbsp;E. Matthew Morris","doi":"10.1016/j.molmet.2025.102167","DOIUrl":"10.1016/j.molmet.2025.102167","url":null,"abstract":"<div><h3>Objective</h3><div>The capacity of the liver to serve as a peripheral sensor in the regulation of food intake has been debated for over half a century. The anatomical position and physiological roles of the liver suggest it is a prime candidate to serve as an interoceptive sensor of peripheral tissue and systemic energy state. Importantly, maintenance of liver ATP levels and within-meal food intake inhibition is impaired in human subjects with obesity and obese pre-clinical models. Previously, we have shown decreased hepatic mitochondrial energy metabolism (i.e., oxidative metabolism &amp; ADP-dependent respiration) in male liver-specific, heterozygous PGC1a mice results in increased short-term diet-induced weight gain with increased within meal food intake. Herein, we tested the hypothesis that decreased liver mitochondrial energy metabolism impairs meal termination following nutrient oral pre-loads.</div></div><div><h3>Methods</h3><div>Liver mitochondrial respiratory response to changes in ΔG_ATP and adenine nucleotide concentration following fasting were examined in male liver-specific, heterozygous PGC1a mice. Further, food intake and feeding behavior during basal conditions, following nutrient oral pre-loads, and following fasting were investigated.</div></div><div><h3>Results</h3><div>We observed male liver-specific, heterozygous PGC1a mice have reduced mitochondrial response to changes in ΔG_ATP and tissue ATP following fasting. These impairments in liver energy state are associated with larger and longer meals during chow feeding, impaired dose-dependent food intake inhibition in response to mixed and individual nutrient oral pre-loads, and greater acute fasting-induced food intake.</div></div><div><h3>Conclusions</h3><div>These data support previous work proposing liver-mediated food intake regulation through modulation of peripheral satiation signals.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"97 ","pages":"Article 102167"},"PeriodicalIF":7.0,"publicationDate":"2025-05-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144079065","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":"Corrigendum to “Inactivation of Minar2 in mice hyperactivates mTOR signaling and results in obesity” [Mol Metabol 73 (July 2023) 101744]","authors":"Saran Lotfollahzadeh ,&nbsp;Chaoshuang Xia ,&nbsp;Razie Amraei ,&nbsp;Ning Hua ,&nbsp;Konstantin V. Kandror ,&nbsp;Stephen R. Farmer ,&nbsp;Wenyi Wei ,&nbsp;Catherine E. Costello ,&nbsp;Vipul Chitalia ,&nbsp;Nader Rahimi","doi":"10.1016/j.molmet.2025.102160","DOIUrl":"10.1016/j.molmet.2025.102160","url":null,"abstract":"","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"97 ","pages":"Article 102160"},"PeriodicalIF":7.0,"publicationDate":"2025-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143923262","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":"Functional regulation of macrophages by Ces1d-mediated lipid signaling in immunometabolism","authors":"Long J. Shao ,&nbsp;Fathima Elizondo ,&nbsp;Feng Gao ,&nbsp;Rabie Habib ,&nbsp;Xin Li ,&nbsp;Katherine Pham ,&nbsp;Jazmin Ysaguirre ,&nbsp;Maryam Elizondo ,&nbsp;Shirindokht Shirazi ,&nbsp;Kristin L. Eckel-Mahan ,&nbsp;Sean Hartig ,&nbsp;Huaizhu Wu ,&nbsp;Kai Sun","doi":"10.1016/j.molmet.2025.102166","DOIUrl":"10.1016/j.molmet.2025.102166","url":null,"abstract":"<div><h3>Objective</h3><div>Macrophage accumulation in metabolically active tissues during obesity is common in both animals and humans, but the lipid signaling mechanisms that trigger macrophage inflammation remain unclear. This study investigates the role of Ces1d, an unconventional lipase, in regulating macrophage inflammation under nutritional stress.</div></div><div><h3>Methods</h3><div>A myeloid-specific Ces1d knockout (LysM-Cre-Ces1d ^{floxed/floxed}, KO) mouse model was used for the studies. For in vitro tests, bone marrow-derived macrophages (BMDMs) from control (Ces1d ^{floxed/floxed}, WT) and KO mice were assessed for migration, polarization, and activation. For in vivo experiments, WT and KO mice were induced to obesity via a high-fat diet (HFD) and subjected to metabolic characterization. Adipose tissue, liver, and serum samples were analyzed histologically and biochemically. Endogenous macrophages and T cells from adipose tissue were isolated and analyzed for functional interactions by flow cytometry.</div></div><div><h3>Results</h3><div>Ces1d expression changes during the differentiation of monocytes into macrophages in both mice and humans. Loss of Ces1d causes larger lipid droplets, with increased accumulation of triacylglycerol (TAG) and diacylglycerol (DAG), and impaired lipid signaling in KO macrophages. Lipid dysregulation in macrophages triggers pro-inflammatory activation, enhancing migration, activation, and polarization toward an M1-like phenotype. The pro-inflammatory macrophages further promote CD3+CD8+ T cell accumulation in obese adipose tissue, which contributes to worsened metabolic disorders, including more severe fatty liver, increased local inflammation in adipose tissue, and impaired systemic glucose tolerance in KO mice on a high-fat diet.</div></div><div><h3>Conclusions</h3><div>This study demonstrates Ces1d is a crucial factor in maintaining lipid homeostasis in macrophages. Loss of Ces1d leads to metabolic dysregulation in macrophages and other immune cells during obesity.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"97 ","pages":"Article 102166"},"PeriodicalIF":7.0,"publicationDate":"2025-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144028119","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}