American journal of physiology. Endocrinology and metabolism最新文献

{"title":"Immunometabolism of IRF4 in adipose, muscle, and immune cells influences obesity and MASLD.","authors":"Daniel M Marko, Jonathan D Schertzer","doi":"10.1152/ajpendo.00554.2025","DOIUrl":"10.1152/ajpendo.00554.2025","url":null,"abstract":"<p><p>Interferon regulatory factor 4 (IRF4) connects immunity and metabolism in immune cells and parenchymal cells of metabolic tissues. In immune cells, IRF4 is a metabolic rheostat that promotes glycolysis to support macrophage polarization and increase oxidative phosphorylation to enable T cell proliferation and memory, while limiting transcription of pro-inflammatory programs. IRF4 also dictates cell-autonomous responses in adipocytes and muscle cells, including transcriptional regulation of lipolysis in white adipocytes, thermogenesis in brown adipocytes, and glucose and amino acid metabolism in muscle cells. IRF4 responds to nutritional status and hormonal signals involved in obesity pathogenesis and mediates interorgan communication involved in liver steatosis during metabolic dysfunction-associated steatotic liver disease (MASLD). This review summarizes how IRF4 participates in metabolic and immune responses in adipose tissue, skeletal muscle, liver, and tissue-resident immune cells during obesity. IRF4 immunometabolism is relevant to obesity and MASLD because of its bidirectional role in immune cells and metabolic cells. Obesity alters inflammatory and nutritional activators of IRF4, which modify immune and parenchymal cell metabolism to produce local and systemic metabolic inflammation, which can alter endocrine control of metabolism. Therefore, the cell-specific functions of IRF4 in immune cells and metabolic cells position IRF4 as a transcriptional node connecting changes in immunity and metabolism during metabolic disease.</p>","PeriodicalId":7594,"journal":{"name":"American journal of physiology. Endocrinology and metabolism","volume":" ","pages":"E520-E528"},"PeriodicalIF":4.2,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147375782","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":"Cardiometabolic and metabolic profiles in irritable bowel syndrome associated with type 2 diabetes.","authors":"Franziska Schmelter, Lotta Nowak, Paul Beier, Vivian Valeska Tetzlaff-Lelleck, Anna Kordowski, Bandik Föh, Oliver Witt, Torsten Schröder, Ulrich L Günther, Yves Laumonnier, Benjamin A H Jensen, Stephan C Bischoff, Stefanie Derer, Christian Sina","doi":"10.1152/ajpendo.00489.2025","DOIUrl":"10.1152/ajpendo.00489.2025","url":null,"abstract":"<p><p>Irritable bowel syndrome (IBS), a common disorder of gut-brain interaction, has been increasingly associated with metabolic dysfunction and cardiometabolic risk. This study aimed to comprehensively assess cardiometabolic risk factors in individuals with IBS and to characterize their metabolic profiles in comparison with those of healthy and diabetic cohorts. First, in a retrospective database analysis, cardiometabolic risk factors of patients with IBS (<i>n</i> = 582,377) were compared with healthy controls (HCs) (<i>n</i> = 1,492,376). Following propensity score matching (<i>n</i> = 492,468), cardiometabolic parameters were analyzed during a follow-up period of 1-24 mo postindex. Second, a total of 234 individuals underwent comprehensive metabolic phenotyping using state-of-the-art nuclear magnetic resonance spectroscopy, comparing blood profiles of patients diagnosed with type 2 diabetes (T2D), IBS, and HC. We observed an increased cardiometabolic risk profile in patients with IBS compared with HC, characterized by higher mean body mass index, higher triglyceride levels, lower high-density lipoprotein cholesterol, and higher hemoglobin A1c levels. Odds ratios (ORs) were significantly increased in IBS, particularly for chronic hyperglycemia (OR = 16.32; <i>P</i> < 0.001). Results were confirmed by deep metabolic phenotyping, revealing a metabolic tendency in patients with IBS toward profiles characteristic of T2D by alterations in amino acid (glycine, histidine, and phenylalanine), glucose (glucose, lactate, and pyruvate), and lipid metabolism (parameters related to very low-density lipoproteins). Our findings confirm that IBS is linked to a distinct cardiometabolic risk profile and reveal metabolic associations relevant to T2D.<b>NEW & NOTEWORTHY</b> We identified a distinct cardiometabolic risk profile in patients with IBS, characterized by elevated BMI, triglycerides, HbA1c, and reduced HDL-C levels. Metabolic phenotyping reveals a pattern in patients with IBS comparable with T2D profiles, including altered amino acid, glucose, and lipid metabolism.</p>","PeriodicalId":7594,"journal":{"name":"American journal of physiology. Endocrinology and metabolism","volume":" ","pages":"E422-E430"},"PeriodicalIF":4.2,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146218290","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":"LXR activation in skeletal muscle cells enhances differentiation and promotes protein synthesis.","authors":"Hayataka Takase, Miho Chikazawa, Makoto Noguchi, Ikuyo Ichi, Yu Takahashi, Yoshio Yamauchi, Makoto Shimizu, Ryuichiro Sato, Takashi Sasaki","doi":"10.1152/ajpendo.00261.2025","DOIUrl":"10.1152/ajpendo.00261.2025","url":null,"abstract":"<p><p>Skeletal muscle possesses a remarkable capacity for regeneration, which is largely orchestrated by muscle satellite cells (MuSCs), a population of tissue-resident stem cells. Upon injury, these cells sense cues from their niche, transition from quiescence to activation, and subsequently undergo proliferation and differentiation to restore damaged myofibers. Although cholesterol, an essential component of the plasma membrane, is critical for cell growth and membrane dynamics, the regulatory landscape governing cholesterol metabolism during muscle regeneration remains poorly defined. In this study, we investigated the temporal expression patterns of lipid-associated genes during regeneration and identified a pronounced upregulation of liver X receptor (LXR) target genes 3 days postinjury, implicating oxysterol-mediated signaling as a potential modulator of the regenerative process. Furthermore, gas chromatography-mass spectrometry (GC-MS) analyses revealed elevated levels of oxysterols, specifically 4β-hydroxycholesterol and 25-hydroxycholesterol, in response to muscle injury induced by cardiotoxin (CTX) or barium chloride (BaCl₂). Complementary in vitro experiments demonstrated that the administration of LXR agonists promoted myogenic differentiation in cultured skeletal muscle cells, whereas pharmacological inhibition of LXR signaling impaired this process. Importantly, LXR activation attenuates lipopolysaccharide (LPS)-induced inflammatory responses in myocytes and concurrently enhances anabolic signaling through the Akt-mTOR axis, leading to increased protein synthesis. Collectively, these findings highlight the previously underappreciated role of cholesterol-derived metabolites in coordinating muscle regeneration, suggesting that LXR-mediated transcriptional programs simultaneously govern differentiation, inflammation, and biosynthetic capacity in regenerating skeletal muscle.<b>NEW & NOTEWORTHY</b> This study aimed to investigate the role of cholesterol-derived metabolites in skeletal muscle regeneration. We found a marked upregulation of liver X receptor (LXR) target genes during muscle regeneration, with increased oxysterol levels (4β-hydroxycholesterol and 25-hydroxycholesterol) after injury. LXR activation promotes myogenic differentiation, inhibits LPS-induced inflammation, and enhances protein synthesis through the Akt-mTOR pathway. These results revealed that LXR is a key regulator of muscle regeneration, influencing differentiation, inflammation, and anabolic processes via cholesterol metabolism.</p>","PeriodicalId":7594,"journal":{"name":"American journal of physiology. Endocrinology and metabolism","volume":" ","pages":"E442-E460"},"PeriodicalIF":4.2,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146218320","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":"Acute interleukin-1β antagonism decreases systemic inflammation, increases GLP-1 release, and modulates insulin secretion in individuals with prediabetes.","authors":"Justus S Fischer, Matthias Hepprich, Marco Cattaneo, Lucia Seeger, Stefanie Dobler, Marc Y Donath","doi":"10.1152/ajpendo.00527.2025","DOIUrl":"10.1152/ajpendo.00527.2025","url":null,"abstract":"<p><p>Metabolic stress in obesity and diabetes activates innate immunity. Chronic IL-1β antagonism improves insulin secretion in type 2 diabetes. However, it is unclear how rapidly this effect occurs, whether it is also present in individuals with prediabetes, and if IL-1β influences GLP-1 secretion. Therefore, we acutely antagonized IL-1β in patients with prediabetes overnight. Two injections of anakinra significantly reduced total leucocyte count (<i>P</i> < 0.001), neutrophils (<i>P</i> < 0.001), monocytes (<i>P</i> = 0.006), and CRP (<i>P</i> = 0.030) compared with placebo. Lymphocytes were slightly elevated (<i>P</i> = 0.045). A mixed meal tolerance tests showed a trend toward increased early insulin (<i>P</i> = 0.11) and GLP-1 responses (<i>P</i> = 0.055), with GLP-1 (<i>P</i> = 0.020) and glucagon (<i>P</i> = 0.003) levels being significantly higher at 120 min under anakinra. Cytokine analysis showed elevated baseline concentrations of IL-1β, IL-6, and IL-1Ra under anakinra (all <i>P</i> < 0.001), with IL-1β (<i>P</i> < 0.001) and IL-18BP (<i>P</i> = 0.048) decreased, and IL-6 increased (<i>P</i> = 0.059) after 60 min. Therefore, an acute injection of anakinra significantly reduces CRP and leucocyte counts in individuals with prediabetes, indicating effective innate immune modulation even after immediate treatment. Despite seeing no significant improvements in insulin secretion or glucose metabolism, we observed a trend toward earlier insulin secretion, along with increased release of IL-6 and GLP-1. We conclude that acute IL-1 antagonism dampens systemic inflammation in prediabetes, with the potential to improve insulin secretion via IL-6-induced GLP-1.<b>NEW & NOTEWORTHY</b> Acute IL-1 blockade with anakinra markedly reduced CRP and leukocyte counts within 12 h, demonstrating rapid anti-inflammatory efficacy. Anakinra induced a trend toward earlier insulin secretion and significantly increased postprandial IL-6 and GLP-1 levels. The study demonstrates that even short-term IL-1 blockade can modulate both immune and incretin responses in prediabetes. Early IL-1β antagonism may represent a preventive, anti-inflammatory approach to preserve GLP-1 secretion and β-cell function in individuals with prediabetes.</p>","PeriodicalId":7594,"journal":{"name":"American journal of physiology. Endocrinology and metabolism","volume":" ","pages":"E500-E509"},"PeriodicalIF":4.2,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7618929/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147353416","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Synergistic potential of TREM2 agonists and exercise training in Alzheimer's disease.","authors":"Jinmin Zhang, Barbara St Pierre Schneider, Elias Muguerza, Eunhee Chung, Chia George Hsu","doi":"10.1152/ajpendo.00124.2025","DOIUrl":"10.1152/ajpendo.00124.2025","url":null,"abstract":"<p><p>Triggering receptor expressed on myeloid cells 2 (TREM2) is a microglia-enriched receptor that regulates phagocytosis, lipid metabolism, and inflammation resolution in the brain. Loss or mutation of TREM2, including the R47H variant, impairs amyloid-β clearance and lipid handling, thereby increasing the risk and accelerating the progression of Alzheimer's disease (AD). TREM2 signaling couples debris recognition with mitochondrial activation and fatty acid oxidation, maintaining microglial energy balance and promoting a reparative phenotype. Pharmacologic TREM2 agonists, such as AL002, DNL919, and VG-3927, enhance microglial survival, plaque compaction, and mitochondrial respiration in AD models, although clinical efficacy may depend on disease stage and metabolic fitness. Exercise training represents a complementary strategy that similarly enhances TREM2 expression, restores microglial homeostasis, and improves mitochondrial metabolism. Both aerobic and resistance exercise activate TREM2-dependent signaling pathways to reduce neuroinflammation and support synaptic integrity. Collectively, these findings highlight TREM2 as a central immunometabolic regulator and suggest that combining TREM2-targeted therapeutics with exercise may offer a synergistic strategy to slow neurodegeneration in AD.</p>","PeriodicalId":7594,"journal":{"name":"American journal of physiology. Endocrinology and metabolism","volume":" ","pages":"E298-E308"},"PeriodicalIF":3.1,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145909728","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":"Postbiotic gut bacteria site-specific immunomodulators improve liver steatosis, inflammation, and fibrosis in obese mice with MASLD.","authors":"Rodrigo Rodrigues E-Lacerda, Nicole G Barra, Meghan O Conn, Dana Kukje Zada, Nazli Robin, Han Fang, Daniel M Marko, Neeraja Punde, Shirin Kalyan, Hal Gunn, Jonathan D Schertzer","doi":"10.1152/ajpendo.00488.2025","DOIUrl":"10.1152/ajpendo.00488.2025","url":null,"abstract":"<p><p>Obesity promotes metabolic dysfunction-associated steatotic liver disease (MASLD). Gut microbiota can influence MASLD through local communication between the gut and liver. Bacterial components are often conceptualized only as contributors to chronic inflammation. However, certain postbiotics can protect against chronic inflammation and dysmetabolism by activating specific immune responses during obesity. Site-specific innate immune training can direct compartmentalized immune responses. We hypothesized that site-specific immunomodulation by gut-derived inactivated bacterial-based stimuli (i.e., postbiotics) would improve features of MASLD. We found that biweekly subcutaneous injections of an inactivated bacterial preparation of a gut bacterium (QBECO from <i>Escherichia coli</i>) improved markers of steatosis, inflammation, and fibrosis indicative of MASLD in obese mice. QBECO lowered liver mass, triglycerides, F4/80 macrophages, eosinophil peroxidase activity, and collagen content in the liver without altering food intake or body mass in obese mice. QBECO increased whole body lipid oxidation without altering total energy expenditure in obese mice. QBECO had an immunomodulatory effect that lowered liver eosinophil peroxidase activity, lowered liver nitrite/arginase ratio, and increased CD163 positive cells, a marker of M2 macrophages in the liver of obese mice. We confirmed that multiple gut bacteria-derived postbiotics improved MASLD as injections of an inactivated bacterial preparation of <i>Proteus mirabilis</i> (QBPMI) also lowered markers of steatosis, inflammation, and fibrosis in obese mice. A postbiotic from <i>Klebsiella variicola</i> (QBKPN), a bacterium typically pathogenic outside the gut, did not alter MASLD in obese mice. Therefore, site-specific immunomodulators derived from gut bacteria can improve the hallmarks of MASLD without causing weight loss.<b>NEW & NOTEWORTHY</b> This study demonstrates that site-specific immunomodulators (SSIs), prepared from inactivated bacteria, can attenuate liver steatosis, inflammation, and fibrosis in a mouse model of obesity and metabolic dysfunction-associated steatotic liver disease (MASLD). Gut bacteria-derived SSIs improved hallmarks of MASLD without altering body weight or food intake, but an SSI derived from a bacterium typically pathogenic outside the gut did not alter MASLD. Therefore, gut-derived SSI postbiotics can improve MASLD.</p>","PeriodicalId":7594,"journal":{"name":"American journal of physiology. Endocrinology and metabolism","volume":" ","pages":"E267-E275"},"PeriodicalIF":4.2,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145997004","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":"Substrate utilization during short-term fasting in older men and women.","authors":"San Y Wang, Rita H Tsay, Danya Zhang, Naomi K Fukagawa","doi":"10.1152/ajpendo.00530.2025","DOIUrl":"10.1152/ajpendo.00530.2025","url":null,"abstract":"<p><p>Older people are prone to involuntary fasting, but systematic assessment of their mobilization and oxidation of the three macronutrients during fasting has not been previously reported. Because of changes in body composition and metabolic regulatory pathways with aging, older people might have different kinetics of utilization of macronutrient stores during fasting than younger people. We measured body composition by dual-energy X-ray absorptiometry and studied the effects of a 36-h fast on protein mobilization, lipolysis, glucose output, and protein, fat, and carbohydrate oxidation in 10 older (60-81 yr) and 10 younger (18-35 yr) healthy adults. A 36-h fast induced a pronounced shift toward fat oxidation: in the postabsorptive state, fat oxidation averaged 52%-55% of resting energy expenditure (REE) and increased to 63%-68% after fasting, with corresponding decreases in carbohydrate oxidation. Protein oxidation decreased with fasting but still contributed 16%-18% of REE in older participants. For several metabolic variables (respiratory exchange ratio, glucose <i>R</i>_a, glycerol <i>R</i>_a, urea <i>R</i>_a, urea excretion, and percent of REE from carbohydrate and fat), we observed significant age × fasting interactions (<i>P</i> < 0.01). Younger adults exhibited larger decreases in glucose <i>R</i>_a and greater increases in markers of protein turnover (leucine <i>R</i>_a, urea production) and lipolysis, whereas older adults showed blunted glucose and leucine responses but maintained substantial protein oxidation. These age-related differences suggest that older adults rely relatively more on ongoing protein catabolism during short-term fasting, which may contribute to vulnerability to muscle loss during illness or prolonged inadequate intake.<b>NEW & NOTEWORTHY</b> A 36-h fast had a profound effect on substrate utilization in older women and men. In the postabsorptive state, fat oxidation averaged 52%-55% of REE. After a 36-h fast, fat oxidation increased to 63%-68%, with corresponding decreases in carbohydrate oxidation. The continued reliance on protein oxidation (16%-18% of REE) with fasting may be an important factor in the muscle loss seen in older adults with chronically inadequate food intake and impaired physical activity.</p>","PeriodicalId":7594,"journal":{"name":"American journal of physiology. Endocrinology and metabolism","volume":" ","pages":"E356-E368"},"PeriodicalIF":3.1,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146117570","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":"Impact of obesity on aromatic amino acids and brain glucose during acute hyperglycemia.","authors":"Brooke C Matson, Felona Gunawan, Douglas L Rothman, Graeme F Mason, Olga Ilkayeva, Christopher B Newgard, Janice J Hwang","doi":"10.1152/ajpendo.00463.2025","DOIUrl":"10.1152/ajpendo.00463.2025","url":null,"abstract":"<p><p>Hyperaminoacidemia is an early hallmark of insulin resistance, with aromatic and branched chain amino acids particularly associated with insulin resistance and type 2 diabetes. We previously showed that healthy adults with obesity exposed to acute hyperglycemia have lower brain glucose levels measured by magnetic resonance spectroscopy than lean controls, suggesting that a blunted brain response to hyperglycemia may be an early marker of insulin resistance. Here, in a secondary analysis of our prior study, we used targeted mass spectrometry-based metabolomics to measure plasma amino acids in participants with and without obesity to determine whether changes in peripheral metabolites associated with early insulin resistance such as amino acids were associated with changes in brain glucose levels during hyperglycemia. There were few differences in baseline amino acids between groups, but acute hyperglycemia unveiled higher plasma concentrations of amino acids including cysteine, cystine, glutamic acid, glutamine, methionine, and aromatic amino acids in obesity. Plasma glucagon levels were also higher in obesity during acute hyperglycemia. Higher plasma concentrations of aromatic amino acids and glucagon were significantly correlated with lower brain glucose levels, illustrating parallel development of central and peripheral metabolic changes in obesity.<b>NEW & NOTEWORTHY</b> We related early insulin resistance-associated peripheral factors with brain glucose measured by ¹³C magnetic resonance spectroscopy during acute hyperglycemia in young, healthy adults with and without obesity. Plasma amino acids including aromatic amino acids and glucagon were higher in obesity during acute hyperglycemia. There were negative correlations between aromatic amino acids and glucagon with the change in brain glucose. These findings may be related to brain oxidative stress and neurotransmitter synthesis in obesity.</p>","PeriodicalId":7594,"journal":{"name":"American journal of physiology. Endocrinology and metabolism","volume":" ","pages":"E346-E355"},"PeriodicalIF":4.2,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13036701/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146117546","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Colocalization and functional analyses identify <i>GBE1</i> as a gene linking muscle strength and cardiometabolic fitness.","authors":"Theresia M Schnurr, Miranda L Johnson, Christopher Jin, Kimmie V Sørensen, Lindsey Kim, James W Jahng, Amanda Ramste, Ewa Bielczyk-Maczynska, Michael J Gloudemans, Peter Saliba-Gustafsson, Elena Vinton, Patrick L Jurney, Ivan Carcamo-Orive, Euan A Ashley, Torben Hansen, Joshua W Knowles, Brian T Palmisano","doi":"10.1152/ajpendo.00470.2025","DOIUrl":"10.1152/ajpendo.00470.2025","url":null,"abstract":"<p><p>Handgrip strength is a proxy for muscular fitness, an indicator for general health status, and is associated with cardiometabolic health. The mechanisms connecting handgrip strength to skeletal muscle function are incompletely understood. We applied integrated linkage-disequilibrium-adjusted colocalization analysis of genome-wide association study summary statistics for handgrip strength, combined with expression and splicing quantitative trait loci from skeletal muscle, and identified glycogen branching enzyme 1 (<i>GBE1</i>) as a candidate gene for handgrip strength. CRISPR-interference knockdown of <i>GBE1</i> in immortalized human skeletal muscle cells (HMCL-7304) demonstrated decreased glycogen content and accumulation of polyglucosan bodies. Knockdown of <i>GBE1</i> led to increased oxygen consumption rate, oxidative stress, and changes in mitochondrial morphology. Transcriptomic profiling of <i>GBE1</i> knockdown cells identified upregulation of the human superoxide dismutase 2 and enrichment of pathways related to muscle contraction and oxidative stress responses. These functional genomic analyses prioritize <i>GBE1</i> as a muscle-relevant candidate gene for handgrip strength and provide mechanistic insights to muscle fitness.<b>NEW & NOTEWORTHY</b> Colocalization of genome-wide association study (GWAS) loci with quantitative trait loci (QTL) in skeletal muscle tissue identified <i>GBE1</i> as a candidate for handgrip strength. Cellular phenotypes with <i>GBE1</i> knockdown in immortalized human skeletal muscle cells include decreased glycogen content, accumulation of polyglucosan bodies, changes in mitochondrial function and morphology, and increased expression of reactive oxygen species (ROS) scavengers. Transcriptomic changes suggest a role for <i>GBE1</i> in muscle contraction and oxidative stress-mediated responses.</p>","PeriodicalId":7594,"journal":{"name":"American journal of physiology. Endocrinology and metabolism","volume":" ","pages":"E380-E389"},"PeriodicalIF":4.2,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13008485/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146206376","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Changes in body composition and resting energy expenditure during the first year after Roux-en-Y or one-anastomosis gastric bypass.","authors":"Jari E Karppinen, Sini Heinonen, Tuure Saarinen, Birgitta W van der Kolk, Ulla Säiläkivi, Henna Sammalkorpi, Anne K Penttilä, Per-Henrik Groop, Anne Juuti, Kirsi H Pietiläinen","doi":"10.1152/ajpendo.00185.2025","DOIUrl":"10.1152/ajpendo.00185.2025","url":null,"abstract":"<p><p>Resting energy expenditure (REE) declines during weight loss because of both organ-tissue mass loss and adaptive thermogenesis, but their relative contributions after bariatric surgery remain unclear. Our primary aim was to quantify these components during the first postoperative year and secondarily to compare Roux-en-Y gastric bypass (RYGB) with one-anastomosis gastric bypass (OAGB). Forty-two adults with obesity (RYGB, <i>n</i> = 21; OAGB, <i>n</i> = 21) underwent dual-energy X-ray absorptiometry (DXA) before surgery and at 6 and 12 mo, and organ-tissue masses were estimated using MRI-derived prediction equations. A smaller subset of 29 participants (RYGB, <i>n</i> = 15; OAGB, <i>n</i> = 14) had valid indirect calorimetry measurements for REE analysis. Participants lost 27.3 kg (21%) of baseline body weight at 6 mo and 32.3 kg (25%) at 12 mo, with no significant differences between procedures in the DXA-measured body composition outcomes or calculated organ-tissue masses. Measured REE decreased by 383 kcal/day at 6 mo (<i>P</i> < 0.001), of which 168 kcal/day [95% confidence interval (CI): 59-276, <i>P</i> = 0.004] was attributed to adaptive thermogenesis. At 12 mo, REE remained 315 kcal/day below baseline (<i>P</i> < 0.001), but adaptive thermogenesis was not statistically detectable (89 kcal/day; 95% CI: -19 to 198, <i>P</i> = 0.11). Adaptive thermogenesis did not significantly differ between procedures. In conclusion, ∼44% of the early 6-mo postoperative decline in REE was associated with adaptive thermogenesis, with the remaining ∼56% associated with organ-tissue mass loss. Adaptive thermogenesis was no longer clearly evident at 12 mo. RYGB and OAGB resulted in similar changes in body composition and REE.<b>NEW & NOTEWORTHY</b> Resting energy expenditure declines after bariatric surgery, but the relative roles of tissue loss and adaptive thermogenesis are unclear. Using DXA-based organ-tissue estimates with indirect calorimetry, we show that adaptive thermogenesis accounted for ∼44% of the 6-mo postoperative REE decline, with the remainder due to tissue loss. Adaptive thermogenesis was not robustly detectable at 12 mo. Roux-en-Y and one-anastomosis gastric bypass show similar body composition and REE changes.</p>","PeriodicalId":7594,"journal":{"name":"American journal of physiology. Endocrinology and metabolism","volume":" ","pages":"E287-E297"},"PeriodicalIF":4.2,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146008538","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}