Pub Date : 2026-03-01Epub Date: 2026-02-05DOI: 10.1016/j.molmet.2026.102330
Yingying Su , Xiaoya Li , Yikai Wang , Xuhong Lu , Yafen Ye , Jingjing Sun , Tianwen Liu , Jinghao Cai , Xiaojing Ma , Ying Yang , Jian Zhou
Aims
Human adipose tissue is central to obesity-associated metabolic dysfunction. ANKRD53 is a human-specific, adipocyte-enriched ankyrin repeat scaffold protein with largely unknown function. We investigated its role in human adipocyte metabolism and the underlying mechanism.
Methods
RNA-seq analysis of subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) from 236 individuals quantified ANKRD53 expression and its association with metabolic traits. In human primary adipocytes, we assessed lipolysis (free fatty acid and glycerol release) and mitochondrial respiration (oxygen consumption rate) after ANKRD53 overexpression or knockdown. An AAV was used to overexpress ANKRD53 in mouse inguinal white adipose tissue (iWAT). Protein interactors were identified by immunoprecipitation–mass spectrometry, and knockdown experiments confirmed a functional role of ACSL1.
Results
ANKRD53 expression in both adipose depots was markedly reduced in obesity and inversely correlated with BMI, adiposity measures, insulin resistance indices, and circulating triglycerides, while positively associated with adiponectin and HDLc. In human adipocytes, ANKRD53 overexpression enhanced forskolin-stimulated lipolysis and mitochondrial respiration, whereas silencing impaired these processes. Adipose-targeted ANKRD53 overexpression in mice increased lipolysis in vivo. Mechanistically, ANKRD53 interacted with ACSL1 and promoted its mitochondrial localization, channeling lipolysis-derived FFAs into β-oxidation; silencing ACSL1 abrogated ANKRD53's effects.
Conclusions
ANKRD53 is reduced in obesity and coordinates lipolysis with mitochondrial oxidative metabolism in human adipocytes, promoting efficient use of lipolysis-derived FFAs via ACSL1. These findings establish ANKRD53 as a key regulator of adipocyte energy metabolism and a potential therapeutic target for improving metabolic health in obesity.
{"title":"ANKRD53 is downregulated in human obesity and coordinates lipolysis with mitochondrial oxidative metabolism in adipocytes","authors":"Yingying Su , Xiaoya Li , Yikai Wang , Xuhong Lu , Yafen Ye , Jingjing Sun , Tianwen Liu , Jinghao Cai , Xiaojing Ma , Ying Yang , Jian Zhou","doi":"10.1016/j.molmet.2026.102330","DOIUrl":"10.1016/j.molmet.2026.102330","url":null,"abstract":"<div><h3>Aims</h3><div>Human adipose tissue is central to obesity-associated metabolic dysfunction. ANKRD53 is a human-specific, adipocyte-enriched ankyrin repeat scaffold protein with largely unknown function. We investigated its role in human adipocyte metabolism and the underlying mechanism.</div></div><div><h3>Methods</h3><div>RNA-seq analysis of subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) from 236 individuals quantified <em>ANKRD53</em> expression and its association with metabolic traits. In human primary adipocytes, we assessed lipolysis (free fatty acid and glycerol release) and mitochondrial respiration (oxygen consumption rate) after ANKRD53 overexpression or knockdown. An AAV was used to overexpress ANKRD53 in mouse inguinal white adipose tissue (iWAT). Protein interactors were identified by immunoprecipitation–mass spectrometry, and knockdown experiments confirmed a functional role of ACSL1.</div></div><div><h3>Results</h3><div><em>ANKRD53</em> expression in both adipose depots was markedly reduced in obesity and inversely correlated with BMI, adiposity measures, insulin resistance indices, and circulating triglycerides, while positively associated with adiponectin and HDLc. In human adipocytes, ANKRD53 overexpression enhanced forskolin-stimulated lipolysis and mitochondrial respiration, whereas silencing impaired these processes. Adipose-targeted ANKRD53 overexpression in mice increased lipolysis in vivo. Mechanistically, ANKRD53 interacted with ACSL1 and promoted its mitochondrial localization, channeling lipolysis-derived FFAs into β-oxidation; silencing ACSL1 abrogated ANKRD53's effects.</div></div><div><h3>Conclusions</h3><div>ANKRD53 is reduced in obesity and coordinates lipolysis with mitochondrial oxidative metabolism in human adipocytes, promoting efficient use of lipolysis-derived FFAs via ACSL1. These findings establish ANKRD53 as a key regulator of adipocyte energy metabolism and a potential therapeutic target for improving metabolic health in obesity.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"105 ","pages":"Article 102330"},"PeriodicalIF":6.6,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146137764","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}
While glucagon raises blood glucose levels, it also promotes lipolysis and energy expenditure, and suppresses food intake and gastrointestinal motility, thereby resulting in weight loss. We previously reported that sodium-glucose cotransporter 1 (SGLT1) is highly expressed in pancreatic α cells. The present study aimed to investigate the effects of α-methyl d-glucopyranoside (αMG), an SGLT-specific substrate, on endogenous glucagon secretion and metabolic parameters in obese diabetic mice.
Methods
We injected αMG intraperitoneally daily into high fat, high sucrose diet (HFHSD)-fed mice and db/db mice, and measured metabolic parameters including plasma glucagon concentration. During the treatment with αMG, we evaluated various metabolic conditions, such as body weight, glucose tolerance and hepatic steatosis, in these mice. We also used SGLT1-specific inhibitor and liver-specific glucagon receptor knockout mice to elucidate the underlying mechanism.
Results
We showed that αMG stimulates endogenous glucagon secretion, and that chronic injection of αMG led to dramatic weight loss, improved glucose intolerance, and ameliorated hepatic steatosis, by reducing food intake and increasing energy expenditure and fat utilization, among obese diabetic mice. Interestingly amelioration of hepatic steatosis was abolished in liver-specific glucagon receptor knockout mice, but body weight reduction was not abolished. In addition, αMG, although to a modest extent, distinctly enhanced urinary glucose excretion.
Conclusions
These results in this study suggest that αMG stimulates endogenous glucagon secretion and may lead to a therapeutic strategy for obesity-associated metabolic diseases.
{"title":"Sodium-glucose cotransporter-specific substrate αMG stimulates endogenous glucagon secretion and ameliorates obesity-associated metabolic disorders in mice","authors":"Takayoshi Suga , Yoko Tabei , Osamu Kikuchi , Daisuke Kohno , Yuichi Ikeuchi , Masaki Kobayashi , Yuko Nakagawa , Hiroki Tojima , Yuichi Yamazaki , Ken Sato , Satoru Kakizaki , Takashi Nishimura , Yoshio Fujitani , Takumi Takizawa , Toshio Uraoka , Tadahiro Kitamura","doi":"10.1016/j.molmet.2026.102324","DOIUrl":"10.1016/j.molmet.2026.102324","url":null,"abstract":"<div><h3>Objectives</h3><div>While glucagon raises blood glucose levels, it also promotes lipolysis and energy expenditure, and suppresses food intake and gastrointestinal motility, thereby resulting in weight loss. We previously reported that sodium-glucose cotransporter 1 (SGLT1) is highly expressed in pancreatic α cells. The present study aimed to investigate the effects of α-methyl <span>d</span>-glucopyranoside (αMG), an SGLT-specific substrate, on endogenous glucagon secretion and metabolic parameters in obese diabetic mice.</div></div><div><h3>Methods</h3><div>We injected αMG intraperitoneally daily into high fat, high sucrose diet (HFHSD)-fed mice and <em>db/db</em> mice, and measured metabolic parameters including plasma glucagon concentration. During the treatment with αMG, we evaluated various metabolic conditions, such as body weight, glucose tolerance and hepatic steatosis, in these mice. We also used SGLT1-specific inhibitor and liver-specific glucagon receptor knockout mice to elucidate the underlying mechanism.</div></div><div><h3>Results</h3><div>We showed that αMG stimulates endogenous glucagon secretion, and that chronic injection of αMG led to dramatic weight loss, improved glucose intolerance, and ameliorated hepatic steatosis, by reducing food intake and increasing energy expenditure and fat utilization, among obese diabetic mice. Interestingly amelioration of hepatic steatosis was abolished in liver-specific glucagon receptor knockout mice, but body weight reduction was not abolished. In addition, αMG, although to a modest extent, distinctly enhanced urinary glucose excretion.</div></div><div><h3>Conclusions</h3><div>These results in this study suggest that αMG stimulates endogenous glucagon secretion and may lead to a therapeutic strategy for obesity-associated metabolic diseases.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"105 ","pages":"Article 102324"},"PeriodicalIF":6.6,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146097293","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 : 2026-03-01Epub Date: 2026-01-23DOI: 10.1016/j.molmet.2026.102323
Tanya Pattnaik , Benjamin Wang , Patrick Sweeney
The pregnancy period is accompanied by increased feeding behavior to accommodate the elevated energy demands associated with fetal growth and development. However, the underlying neural circuitry and molecular mechanisms mediating increased feeding during pregnancy are largely unknown. Here, we utilized a combination of fiber photometry, chemogenetics, and mouse behavioral assays to characterize altered feeding behavior during pregnancy in mice. We uncover that pregnancy increases the average activity of the mesolimbic dopamine system during feeding behavior in mice. VTA dopamine neurons promote increased high fat diet feeding during pregnancy as inhibition of these cells selectively reduces acute high fat diet intake in pregnant mice. Further, pregnant mice exhibit increased sensitivity to food deprivation, an effect which requires activity of the mesolimbic dopamine system. Together, these findings provide a circuit basis mediating altered palatable food intake and sensitivity to negative energy balance during pregnancy in mice.
{"title":"Elevated activity of the mesolimbic dopamine system promotes feeding during pregnancy in mice","authors":"Tanya Pattnaik , Benjamin Wang , Patrick Sweeney","doi":"10.1016/j.molmet.2026.102323","DOIUrl":"10.1016/j.molmet.2026.102323","url":null,"abstract":"<div><div>The pregnancy period is accompanied by increased feeding behavior to accommodate the elevated energy demands associated with fetal growth and development. However, the underlying neural circuitry and molecular mechanisms mediating increased feeding during pregnancy are largely unknown. Here, we utilized a combination of fiber photometry, chemogenetics, and mouse behavioral assays to characterize altered feeding behavior during pregnancy in mice. We uncover that pregnancy increases the average activity of the mesolimbic dopamine system during feeding behavior in mice. VTA dopamine neurons promote increased high fat diet feeding during pregnancy as inhibition of these cells selectively reduces acute high fat diet intake in pregnant mice. Further, pregnant mice exhibit increased sensitivity to food deprivation, an effect which requires activity of the mesolimbic dopamine system. Together, these findings provide a circuit basis mediating altered palatable food intake and sensitivity to negative energy balance during pregnancy in mice.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"105 ","pages":"Article 102323"},"PeriodicalIF":6.6,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146046826","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 : 2026-03-01Epub Date: 2026-02-03DOI: 10.1016/j.molmet.2026.102325
Andres F. Ortega , Cha Mee Vang , Ferrol I. Rome , Kaitlyn M. Andreoni , Aiden M. Phoebe , Alisa B. Nelson , Peter A. Crawford , James J. Galligan , Stanley Ching-Cheng Huang , Curtis C. Hughey
Dietary sulfur amino acid restriction (SAAR) improves whole-body glucose homeostasis, elevates liver insulin action, and lowers liver triglycerides. These adaptations are associated with an increased expression of hepatic de novo serine synthesis enzymes, phosphoglycerate dehydrogenase (PHGDH) and phosphoserine aminotransferase 1 (PSAT1). This study tested the hypothesis that enhanced hepatic serine synthesis is necessary for glucose and lipid adaptations to SAAR. Hepatocyte-specific PSAT1 knockout (KO) mice and wild type (WT) littermates were fed a high-fat control or SAAR diet. In WT mice, SAAR increased liver PSAT1 protein (∼70-fold), serine concentration (∼2-fold), and 13C-serine (∼20-fold) following an intravenous infusion of [U–13C]glucose. The elevated liver serine and partitioning of circulating glucose to liver serine by SAAR were attenuated in KO mice. This was accompanied by a blunted improvement in glucose tolerance in KO mice fed a SAAR diet. Interestingly, SAAR decreased liver lysine lactoylation, a SAA-supported post-translational modification known to inhibit PHGDH enzymatic activity. This suggests dietary SAAR may increase serine synthesis, in part, by lowering lysine lactoylation. Beyond glucose metabolism, dietary SAAR reduced body weight, adiposity, and liver triglycerides similarly in WT and KO mice. Collectively, these results demonstrate that hepatic PSAT1 is necessary for glucose, but not lipid, adaptations to SAAR.
{"title":"Dietary sulfur amino acid restriction improves glucose homeostasis through hepatic de novo serine synthesis","authors":"Andres F. Ortega , Cha Mee Vang , Ferrol I. Rome , Kaitlyn M. Andreoni , Aiden M. Phoebe , Alisa B. Nelson , Peter A. Crawford , James J. Galligan , Stanley Ching-Cheng Huang , Curtis C. Hughey","doi":"10.1016/j.molmet.2026.102325","DOIUrl":"10.1016/j.molmet.2026.102325","url":null,"abstract":"<div><div>Dietary sulfur amino acid restriction (SAAR) improves whole-body glucose homeostasis, elevates liver insulin action, and lowers liver triglycerides. These adaptations are associated with an increased expression of hepatic <em>de novo</em> serine synthesis enzymes, phosphoglycerate dehydrogenase (PHGDH) and phosphoserine aminotransferase 1 (PSAT1). This study tested the hypothesis that enhanced hepatic serine synthesis is necessary for glucose and lipid adaptations to SAAR. Hepatocyte-specific PSAT1 knockout (KO) mice and wild type (WT) littermates were fed a high-fat control or SAAR diet. In WT mice, SAAR increased liver PSAT1 protein (∼70-fold), serine concentration (∼2-fold), and <sup>13</sup>C-serine (∼20-fold) following an intravenous infusion of [U–<sup>13</sup>C]glucose. The elevated liver serine and partitioning of circulating glucose to liver serine by SAAR were attenuated in KO mice. This was accompanied by a blunted improvement in glucose tolerance in KO mice fed a SAAR diet. Interestingly, SAAR decreased liver lysine lactoylation, a SAA-supported post-translational modification known to inhibit PHGDH enzymatic activity. This suggests dietary SAAR may increase serine synthesis, in part, by lowering lysine lactoylation. Beyond glucose metabolism, dietary SAAR reduced body weight, adiposity, and liver triglycerides similarly in WT and KO mice. Collectively, these results demonstrate that hepatic PSAT1 is necessary for glucose, but not lipid, adaptations to SAAR.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"105 ","pages":"Article 102325"},"PeriodicalIF":6.6,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146125854","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 : 2026-03-01Epub Date: 2026-02-05DOI: 10.1016/j.molmet.2026.102329
Jake W. Willows , Lindsey M. Lazor , Gabriela Wandling , William Butke , Fatma Fenesha , Kara N. Corps , Sarah B. Peters , Kristy L. Townsend
Purpose
Adipose tissue innervation is critical for regulating lipolysis, adipogenesis, and thermogenesis, yet the mechanisms that establish and maintain these neural networks remain poorly understood. Semaphorin 7A (Sema7A) is a well-characterized axon guidance and neuroimmune signaling molecule that is highly expressed in adipose tissue. Sema7A regulates adipocyte metabolic processes, including lipid accumulation and thermogenic gene expression, via Integrin β1 signaling. However, its potential role in shaping adipose tissue innervation and coordinating neural–metabolic communication has not been explored.
Methods
In this study, we investigated a knockout of Sema7A in mice, and its influences on adipose tissue innervation and metabolic regulation during postnatal development and in adulthood, both under baseline conditions and following cold exposure, a potent activator of sympathetic nerve activity and axonal remodeling in scWAT.
Results
Deletion of Sema7A increased adiposity at postnatal day 21, marked by enlarged subcutaneous and brown adipose depots and reduced lipolytic enzyme expression. Tyrosine hydroxylase-expressing (TH+), and calcitonin gene-related peptide-expressing (CGRP+) innervation was markedly reduced, indicating dysregulated neuro-adipose communication. Plexin C1, a receptor for Sema7A, was strongly expressed on subcutaneous adipose axons, suggesting direct signaling to support neuronal growth. In adulthood, Sema7A-deficient mice displayed normal metabolic responses to cold exposure but failed to mount the typical increase in sympathetic axon outgrowth within beige regions of scWAT.
Conclusions
Together, these findings identify Sema7A as a critical mediator of adipose neural development and remodeling, required for establishing and maintaining proper innervation and metabolic function.
{"title":"Semaphorin 7A regulates axon outgrowth in subcutaneous white adipose tissue","authors":"Jake W. Willows , Lindsey M. Lazor , Gabriela Wandling , William Butke , Fatma Fenesha , Kara N. Corps , Sarah B. Peters , Kristy L. Townsend","doi":"10.1016/j.molmet.2026.102329","DOIUrl":"10.1016/j.molmet.2026.102329","url":null,"abstract":"<div><h3>Purpose</h3><div>Adipose tissue innervation is critical for regulating lipolysis, adipogenesis, and thermogenesis, yet the mechanisms that establish and maintain these neural networks remain poorly understood. Semaphorin 7A (Sema7A) is a well-characterized axon guidance and neuroimmune signaling molecule that is highly expressed in adipose tissue. Sema7A regulates adipocyte metabolic processes, including lipid accumulation and thermogenic gene expression, via Integrin β1 signaling. However, its potential role in shaping adipose tissue innervation and coordinating neural–metabolic communication has not been explored.</div></div><div><h3>Methods</h3><div>In this study, we investigated a knockout of Sema7A in mice, and its influences on adipose tissue innervation and metabolic regulation during postnatal development and in adulthood, both under baseline conditions and following cold exposure, a potent activator of sympathetic nerve activity and axonal remodeling in scWAT.</div></div><div><h3>Results</h3><div>Deletion of Sema7A increased adiposity at postnatal day 21, marked by enlarged subcutaneous and brown adipose depots and reduced lipolytic enzyme expression. Tyrosine hydroxylase-expressing (TH<sup>+</sup>), and calcitonin gene-related peptide-expressing (CGRP<sup>+</sup>) innervation was markedly reduced, indicating dysregulated neuro-adipose communication. Plexin C1, a receptor for Sema7A, was strongly expressed on subcutaneous adipose axons, suggesting direct signaling to support neuronal growth. In adulthood, Sema7A-deficient mice displayed normal metabolic responses to cold exposure but failed to mount the typical increase in sympathetic axon outgrowth within beige regions of scWAT.</div></div><div><h3>Conclusions</h3><div>Together, these findings identify Sema7A as a critical mediator of adipose neural development and remodeling, required for establishing and maintaining proper innervation and metabolic function.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"105 ","pages":"Article 102329"},"PeriodicalIF":6.6,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146137814","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 : 2026-03-01Epub Date: 2025-12-16DOI: 10.1016/j.molmet.2025.102305
Julius E.R. Grothen , Jaime M. Martinez , Nikos Sidiropoulos , Lucas Massier , Danae Zareifi , Jiawei Zhong , Ida Davidsen , Jette W. Platou , Jette Mandelbaum , Pia Rothe , Henning Hvid , Mads Grønborg , Christian Toft Madsen , Jens M. Bruun , Mikael Rydén , Niklas Mejhert , Jørn W. Helge , Zachary Gerhart-Hines , Thomas Å. Pedersen
Background
Combination of increased physical exercise and hypocaloric diet has long been recognized to improve cardiometabolic health and adipose tissue function, including lipid turnover. How such lifestyle interventions mediate benefits at the cellular level remains unknown. Given the critical role of subcutaneous white adipose tissue (scWAT) to systemic metabolic homeostasis, we set out to interrogate how exercise and diet lifestyle intervention impacted scWAT in individuals living with obesity, with a particular focus on lipolytic capacity and cell-specific gene profiling.
Methods
Single nuclei RNA sequencing (snRNAseq) was performed on cryopreserved scWAT biopsies originally collected before and after lifestyle intervention, involving regular exercise and hypocaloric diet in obese individuals. Findings on regulation of lipolysis in adipocytes were followed up with meta-analysis of clinical studies and pharmacological experiments in mature human adipocytes.
Results
snRNAseq analysis revealed intervention-induced changes in all scWAT cell-types. In adipocytes genes linked to protein and organelle turnover, branch chain amino acid catabolism, and lipolytic control were most significantly regulated. We identified a cell autonomous brake on adipocyte lipolysis via the neuropeptide Y receptor 1 (NPY1R). Expression of adipocyte NPY1R was reduced after weight loss and correlated positively with body fat percentage and body mass index. Findings were confirmed in meta-analysis across 23 studies. Finally, we found a negative correlation between NPY1R and beta-adrenergic-induced lipolysis and that NPY dose-dependently attenuated lipolysis and cAMP-signaling in primary human subcutaneous adipocytes.
Conclusions
Our work suggests that decreases in adipocyte NPY1R during weight loss boost lipolytic capacity and contribute to improved systemic cardiometabolic health.
{"title":"Single cell transcriptomics of human weight loss links adipocyte NPY1R to control of lipolysis","authors":"Julius E.R. Grothen , Jaime M. Martinez , Nikos Sidiropoulos , Lucas Massier , Danae Zareifi , Jiawei Zhong , Ida Davidsen , Jette W. Platou , Jette Mandelbaum , Pia Rothe , Henning Hvid , Mads Grønborg , Christian Toft Madsen , Jens M. Bruun , Mikael Rydén , Niklas Mejhert , Jørn W. Helge , Zachary Gerhart-Hines , Thomas Å. Pedersen","doi":"10.1016/j.molmet.2025.102305","DOIUrl":"10.1016/j.molmet.2025.102305","url":null,"abstract":"<div><h3>Background</h3><div>Combination of increased physical exercise and hypocaloric diet has long been recognized to improve cardiometabolic health and adipose tissue function, including lipid turnover. How such lifestyle interventions mediate benefits at the cellular level remains unknown. Given the critical role of subcutaneous white adipose tissue (scWAT) to systemic metabolic homeostasis, we set out to interrogate how exercise and diet lifestyle intervention impacted scWAT in individuals living with obesity, with a particular focus on lipolytic capacity and cell-specific gene profiling.</div></div><div><h3>Methods</h3><div>Single nuclei RNA sequencing (snRNAseq) was performed on cryopreserved scWAT biopsies originally collected before and after lifestyle intervention, involving regular exercise and hypocaloric diet in obese individuals. Findings on regulation of lipolysis in adipocytes were followed up with meta-analysis of clinical studies and pharmacological experiments in mature human adipocytes.</div></div><div><h3>Results</h3><div>snRNAseq analysis revealed intervention-induced changes in all scWAT cell-types. In adipocytes genes linked to protein and organelle turnover, branch chain amino acid catabolism, and lipolytic control were most significantly regulated. We identified a cell autonomous brake on adipocyte lipolysis via the neuropeptide Y receptor 1 (NPY1R). Expression of adipocyte <em>NPY1R</em> was reduced after weight loss and correlated positively with body fat percentage and body mass index. Findings were confirmed in meta-analysis across 23 studies. Finally, we found a negative correlation between <em>NPY1R</em> and beta-adrenergic-induced lipolysis and that NPY dose-dependently attenuated lipolysis and cAMP-signaling in primary human subcutaneous adipocytes.</div></div><div><h3>Conclusions</h3><div>Our work suggests that decreases in adipocyte <em>NPY1R</em> during weight loss boost lipolytic capacity and contribute to improved systemic cardiometabolic health.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"105 ","pages":"Article 102305"},"PeriodicalIF":6.6,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145781569","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 : 2026-03-01Epub Date: 2026-02-02DOI: 10.1016/j.molmet.2026.102326
Tina Zimmermann , Katherin Bleymehl , Peter Haebel , Johanna Perens , Urmas Roostalu , Jacob Hecksher-Sørensen , Jonas Doerr , Sebastian Jarosch , Daniel Lam , Holger Klein , Anton Pekcec , Samar N. Chehimi , Richard C. Crist , Benjamin C. Reiner , Matthew R. Hayes , Robert Augustin
Survodutide is a novel GCG/GLP-1 receptor (GCGR/GLP-1R) dual agonist in clinical development for people with obesity and people with metabolic dysfunction-associated steatohepatitis (MASH). Preclinically, survodutide demonstrated body weight lowering efficacy through decreased energy intake and increased energy expenditure. Here, we investigated the central site of action of survodutide and provide further insights into its mechanism of action in reducing body weight. We assessed GCGR and GLP1R expression in human and mouse circumventricular organs (CVOS) and showed for the first time that GCGR is barely detectable in area postrema (AP) and arcuate nucleus of the hypothalamus (ARH) at the single cell level. In contrast, GLP1R is expressed in these tissues. Using a fluorophore labeled survodutide to visualize sites of action in the mouse brain, survodutide was observed to directly access the CVOs and adjacent hypothalamic and hindbrain nuclei, without evidence of uniformly crossing the blood–brain-barrier. In addition, c-Fos labeling showed that multiple nuclei associated with the control of food intake were activated by survodutide. Consistent with the hypothesis that the intake suppressive effects of survodutide are GLP-1R dependent, a long-acting GCGR agonist did not induce neuronal activation in satiety-mediating regions, nor reduced food intake but showed reduction in body weight. These data further support the dual mode of action of survodutide and its potential to provide clinical benefit for people with obesity and/or MASH.
{"title":"Survodutide acts through circumventricular organs in the brain and activates neuronal regions associated with appetite regulation","authors":"Tina Zimmermann , Katherin Bleymehl , Peter Haebel , Johanna Perens , Urmas Roostalu , Jacob Hecksher-Sørensen , Jonas Doerr , Sebastian Jarosch , Daniel Lam , Holger Klein , Anton Pekcec , Samar N. Chehimi , Richard C. Crist , Benjamin C. Reiner , Matthew R. Hayes , Robert Augustin","doi":"10.1016/j.molmet.2026.102326","DOIUrl":"10.1016/j.molmet.2026.102326","url":null,"abstract":"<div><div>Survodutide is a novel GCG/GLP-1 receptor (GCGR/GLP-1R) dual agonist in clinical development for people with obesity and people with metabolic dysfunction-associated steatohepatitis (MASH). Preclinically, survodutide demonstrated body weight lowering efficacy through decreased energy intake and increased energy expenditure. Here, we investigated the central site of action of survodutide and provide further insights into its mechanism of action in reducing body weight. We assessed <em>GCGR</em> and <em>GLP1R</em> expression in human and mouse circumventricular organs (CVOS) and showed for the first time that <em>GCGR</em> is barely detectable in area postrema (AP) and arcuate nucleus of the hypothalamus (ARH) at the single cell level. In contrast, <em>GLP1R</em> is expressed in these tissues. Using a fluorophore labeled survodutide to visualize sites of action in the mouse brain, survodutide was observed to directly access the CVOs and adjacent hypothalamic and hindbrain nuclei, without evidence of uniformly crossing the blood–brain-barrier. In addition, c-Fos labeling showed that multiple nuclei associated with the control of food intake were activated by survodutide. Consistent with the hypothesis that the intake suppressive effects of survodutide are GLP-1R dependent, a long-acting GCGR agonist did not induce neuronal activation in satiety-mediating regions, nor reduced food intake but showed reduction in body weight. These data further support the dual mode of action of survodutide and its potential to provide clinical benefit for people with obesity and/or MASH.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"105 ","pages":"Article 102326"},"PeriodicalIF":6.6,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146119417","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 : 2026-03-01Epub Date: 2026-01-21DOI: 10.1016/j.molmet.2026.102322
Fabian Bock , Xinyu Dong , Kakali Ghoshal , David A. Cappel , John W. Deaver , Dan S. Lark , Luciano Cozzani , Deanna P. Bracy , Louise Lantier , Allison Do , Richard L. Printz , Santosh Thapa , Owen P. McGuinness , David H. Wasserman , Ambra Pozzi , Roy Zent , Nathan C. Winn
Skeletal muscle and liver insulin resistance are early features in the sequelae of type 2 diabetes. Integrins are extracellular matrix receptors expressed on skeletal muscle cells and hepatocytes, which have been implicated in modulating obesity-associated insulin resistance. Integrins regulate cell function through intracellular proteins including the ILK-PINCH-Parvin (IPP) complex. ILK signaling amplifies skeletal muscle and liver insulin resistance in diet-induced obesity in mice but the role of α-Parvin is unexplored. The hyperinsulinemic-euglycemic clamp was used to assess hepatic and muscle insulin action. We demonstrate that deletion of hepatocyte-specific α-Parvin had only minimal influence on obesity-induced liver or whole-body insulin resistance. In contrast, deletion of α-Parvin in skeletal muscle caused a striking reduction in muscle glucose uptake during an insulin clamp in lean mice which was not exacerbated by diet-induced obesity. The decrease in muscle glucose uptake in lean mice was due to a decrease in insulin-mediated GLUT4 membrane recruitment, which was associated with significant morphological abnormalities including actin cytoskeleton dysfunction. In addition, severe muscular dysfunction, blunted mitochondrial oxidative capacity and reduced aerobic exercise capacity were manifest in muscle α-Parvin KO mice. Thus, α-Parvin has a minor role in liver insulin action but is required for insulin-stimulated glucose uptake in skeletal muscle in lean mice due to its role in actin cytoskeleton regulation. These data suggest that individual IPP complex proteins link cell structure to metabolism via distinct mechanisms in a tissue-specific fashion.
{"title":"α-Parvin promotes glucose uptake and metabolism in skeletal muscle with minimal influence on hepatic insulin sensitivity","authors":"Fabian Bock , Xinyu Dong , Kakali Ghoshal , David A. Cappel , John W. Deaver , Dan S. Lark , Luciano Cozzani , Deanna P. Bracy , Louise Lantier , Allison Do , Richard L. Printz , Santosh Thapa , Owen P. McGuinness , David H. Wasserman , Ambra Pozzi , Roy Zent , Nathan C. Winn","doi":"10.1016/j.molmet.2026.102322","DOIUrl":"10.1016/j.molmet.2026.102322","url":null,"abstract":"<div><div>Skeletal muscle and liver insulin resistance are early features in the sequelae of type 2 diabetes. Integrins are extracellular matrix receptors expressed on skeletal muscle cells and hepatocytes, which have been implicated in modulating obesity-associated insulin resistance. Integrins regulate cell function through intracellular proteins including the ILK-PINCH-Parvin (IPP) complex. ILK signaling amplifies skeletal muscle and liver insulin resistance in diet-induced obesity in mice but the role of α-Parvin is unexplored. The hyperinsulinemic-euglycemic clamp was used to assess hepatic and muscle insulin action. We demonstrate that deletion of hepatocyte-specific α-Parvin had only minimal influence on obesity-induced liver or whole-body insulin resistance. In contrast, deletion of α-Parvin in skeletal muscle caused a striking reduction in muscle glucose uptake during an insulin clamp in lean mice which was not exacerbated by diet-induced obesity. The decrease in muscle glucose uptake in lean mice was due to a decrease in insulin-mediated GLUT4 membrane recruitment, which was associated with significant morphological abnormalities including actin cytoskeleton dysfunction. In addition, severe muscular dysfunction, blunted mitochondrial oxidative capacity and reduced aerobic exercise capacity were manifest in muscle α-Parvin KO mice. Thus, α-Parvin has a minor role in liver insulin action but is required for insulin-stimulated glucose uptake in skeletal muscle in lean mice due to its role in actin cytoskeleton regulation. These data suggest that individual IPP complex proteins link cell structure to metabolism via distinct mechanisms in a tissue-specific fashion.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"105 ","pages":"Article 102322"},"PeriodicalIF":6.6,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146041281","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 : 2026-02-01Epub Date: 2026-01-13DOI: 10.1016/j.molmet.2026.102318
Sahika Cingir Koker , Amit Mhamane , Julia Geppert , George Shakir , Raquel Guillamat-Prats , Bingni Chen , Pernilla Katra , Martina Geiger , Foivos-Filippos Tsokanos , Gretchen Wolff , Julia Szendrödi , Maria Rohm , Carolin Daniel , Lars Maegdefessel , Sabine Steffens , Stephan Herzig
Atherosclerosis is a long-term complication of obesity and diabetes and as such a key driver of vascular dysfunction and eventually mortality in affected patients. Both aberrant lipid metabolism and inflammatory reactions promote atherosclerotic plaque development in the vessel wall by triggering a cascade of cellular events involving multiple cell types, including smooth muscle cells, monocytic macrophages, and lymphocytes. Despite its eminent impact on human health, molecular drivers of cellular dysfunction in atherosclerosis remain poorly defined and therapeutic options are scarce.
Here we show by single-cell RNA sequencing that the expression of the nuclear receptor co-factors, TBL1X and TBL1XR1, was particularly prominent in the CD4+ T cell population of human carotid artery plaques. Indeed, genetic double deletion of TBL1X/TBL1XR1 in CD4+ T cells led to a substantial shift from naïve CD44lowCD62Lhi cells to CD44hiCD62Llow effector and Foxp3+ Tregs. CD4+ TBL1X/TBL1XR1 KO cells exhibited enhanced cytokine production capacity upon ionomycin/PMA stimulation, correlating with the induction of pro-inflammatory and cytokine-producing transcriptional pathways in these cells. Consistently, transplantation of bone marrow from CD4+-specific TBL1X/TBL1XR1 knock out mice into LDLR KO recipients doubled the development of atherosclerotic plaques in the aortic arch compared with wild-type bone marrow transplanted littermates. As TBL1X/TBL1XR1 expression levels were diminished in carotid arteries from patients with advanced unstable plaques compared to stable plaques or healthy controls, these data suggest that aberrant inhibition of TBL1X/TBL1XR1 in CD4+ T cells may contribute to the development of atherosclerosis in humans. Restoration of TBL1X/TBL1XR1 functionality may thus serve as a novel, druggable strategy for preventing or limiting atherosclerosis progression.
{"title":"Nuclear receptor co-factor TBL1X/TBL1XR1 T cell activity protects against atherosclerosis","authors":"Sahika Cingir Koker , Amit Mhamane , Julia Geppert , George Shakir , Raquel Guillamat-Prats , Bingni Chen , Pernilla Katra , Martina Geiger , Foivos-Filippos Tsokanos , Gretchen Wolff , Julia Szendrödi , Maria Rohm , Carolin Daniel , Lars Maegdefessel , Sabine Steffens , Stephan Herzig","doi":"10.1016/j.molmet.2026.102318","DOIUrl":"10.1016/j.molmet.2026.102318","url":null,"abstract":"<div><div>Atherosclerosis is a long-term complication of obesity and diabetes and as such a key driver of vascular dysfunction and eventually mortality in affected patients. Both aberrant lipid metabolism and inflammatory reactions promote atherosclerotic plaque development in the vessel wall by triggering a cascade of cellular events involving multiple cell types, including smooth muscle cells, monocytic macrophages, and lymphocytes. Despite its eminent impact on human health, molecular drivers of cellular dysfunction in atherosclerosis remain poorly defined and therapeutic options are scarce.</div><div>Here we show by single-cell RNA sequencing that the expression of the nuclear receptor co-factors, TBL1X and TBL1XR1, was particularly prominent in the CD4<sup>+</sup> T cell population of human carotid artery plaques. Indeed, genetic double deletion of TBL1X/TBL1XR1 in CD4<sup>+</sup> T cells led to a substantial shift from naïve CD44<sup>low</sup>CD62L<sup>hi</sup> cells to CD44<sup>hi</sup>CD62L<sup>low</sup> effector and Foxp3<sup>+</sup> Tregs. CD4<sup>+</sup> TBL1X/TBL1XR1 KO cells exhibited enhanced cytokine production capacity upon ionomycin/PMA stimulation, correlating with the induction of pro-inflammatory and cytokine-producing transcriptional pathways in these cells. Consistently, transplantation of bone marrow from CD4<sup>+</sup>-specific TBL1X/TBL1XR1 knock out mice into LDLR KO recipients doubled the development of atherosclerotic plaques in the aortic arch compared with wild-type bone marrow transplanted littermates. As TBL1X/TBL1XR1 expression levels were diminished in carotid arteries from patients with advanced unstable plaques compared to stable plaques or healthy controls, these data suggest that aberrant inhibition of TBL1X/TBL1XR1 in CD4<sup>+</sup> T cells may contribute to the development of atherosclerosis in humans. Restoration of TBL1X/TBL1XR1 functionality may thus serve as a novel, druggable strategy for preventing or limiting atherosclerosis progression.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"104 ","pages":"Article 102318"},"PeriodicalIF":6.6,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145990100","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 : 2026-02-01Epub Date: 2025-12-15DOI: 10.1016/j.molmet.2025.102308
Nandini K. Doshi , Tristan Pesaresi , Trishya Pagadala , William Dion , Yang Zhang , Natalie L. David , Tânia Amorim , Wenjia Wang , G.V. Naveen Kumar , Bokai Zhu , Silvia Liu , Parth Patwari , Pouneh K. Fazeli , Matthew L. Steinhauser
Sterile inflammation is associated with a broad range of metabolic stressors including both dietary excess and prolonged fasting. In a 10-day human fasting study, we previously identified a surge in the circulating inflammatory biomarker, C-reactive protein (CRP), which we leveraged in the current study to identify novel metabolic inflammatory correlates. With a variety of longitudinal metabolic variables as input, including metabolomics, we identified branched chain amino acids (BCAA) as the top candidate inflammatory correlate. We then used in vitro myeloid/macrophage culture and in vivo murine models to test BCAA as a determinant of inflammatory signaling. Short-term exposure to BCAA alone had modest effects on a variety of immune readouts; however, when coupled with a second stimulus, such as exposure to endotoxin or when administered to diet-induced obese mice, members of the JAK/STAT/cytokine signaling pathways were augmented on the transcriptional level by concurrent BCAA administration in multiple tissues, including visceral adipose and liver. The modifying effect of BCAA on inflammatory stressors translated into increased levels of circulating inflammatory cytokines. Collectively, these data position BCAA as an immune priming factor, a potential mechanism underlying the well-established association between circulating BCAA and diverse diseases of aging.
{"title":"Branched chain amino acids prime metabolic inflammation","authors":"Nandini K. Doshi , Tristan Pesaresi , Trishya Pagadala , William Dion , Yang Zhang , Natalie L. David , Tânia Amorim , Wenjia Wang , G.V. Naveen Kumar , Bokai Zhu , Silvia Liu , Parth Patwari , Pouneh K. Fazeli , Matthew L. Steinhauser","doi":"10.1016/j.molmet.2025.102308","DOIUrl":"10.1016/j.molmet.2025.102308","url":null,"abstract":"<div><div>Sterile inflammation is associated with a broad range of metabolic stressors including both dietary excess and prolonged fasting. In a 10-day human fasting study, we previously identified a surge in the circulating inflammatory biomarker, C-reactive protein (CRP), which we leveraged in the current study to identify novel metabolic inflammatory correlates. With a variety of longitudinal metabolic variables as input, including metabolomics, we identified branched chain amino acids (BCAA) as the top candidate inflammatory correlate. We then used <em>in vitro</em> myeloid/macrophage culture and <em>in vivo</em> murine models to test BCAA as a determinant of inflammatory signaling. Short-term exposure to BCAA alone had modest effects on a variety of immune readouts; however, when coupled with a second stimulus, such as exposure to endotoxin or when administered to diet-induced obese mice, members of the JAK/STAT/cytokine signaling pathways were augmented on the transcriptional level by concurrent BCAA administration in multiple tissues, including visceral adipose and liver. The modifying effect of BCAA on inflammatory stressors translated into increased levels of circulating inflammatory cytokines. Collectively, these data position BCAA as an immune priming factor, a potential mechanism underlying the well-established association between circulating BCAA and diverse diseases of aging.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"104 ","pages":"Article 102308"},"PeriodicalIF":6.6,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145775023","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}
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