bims-mimead 2026-11-01 papers

bims-mimead

Biomed News

on Adipose tissue and metabolic disease

Issue of 2026–11–01
nine papers selected by
Rachel M. Handy, University of Guelph and Universiteit Mastricht

Combined time-restricted feeding and resistance training enhance tirzepatide-induced improvements in adiposity and whole-body insulin sensitivity in female mice.
Adipocyte lipolysis is a determinant of skeletal muscle size during fasting and feeding.
Collagen VI-derived endotrophin impairs adipocyte function and insulin action in human obesity.
Longitudinal Analysis of Skeletal Muscle and Cardiometabolic Risk During the Menopause Transition.
Differential expression of endoplasmic reticulum stress and oxidative stress markers in visceral versus subcutaneous adipose tissue: insights from women with obesity.
Late Sleep Timing is Associated with Metabolic Risk in Postmenopausal Women.
Lipocalin-2 deficiency attenuates early fibrotic remodeling and later adipocyte death in diet-induced obesity.
Genomic profiling of estrogen-related receptor identifies adult adipocyte-specific targets in Drosophila.
Human Subcutaneous Adipose Transcriptomes Link Mitochondrial Transcription to Metabolic Heterogeneity in Obesity.

J Physiol. 2026 Oct 30.

Combined time-restricted feeding and resistance training enhance tirzepatide-induced improvements in adiposity and whole-body insulin sensitivity in female mice.

Ana Paula Azevêdo Macêdo, Luciana Renata da Conceição de Mattis, Robson Damasceno de Lima, Louise Ailey Barbosa, Camila Barboza Pinotti, Guilherme Domingos Brisque, Larissa Moreira Dias, Beatriz de Souza Pitoli, Amanda Abreu Avelino, Guilherme Correia Ferri Antonio, Vitor Rosetto Muñoz, Gabriel Calheiros Antunes, Letícia de Souza Figueiredo, Dennys Esper Cintra, Adelino Sanchez Ramos da Silva, Eduardo Rochete Ropelle, José Rodrigo Pauli.

  Tirzepatide is a dual agonist of glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptors with potent effects on body weight regulation, glucose homeostasis and metabolic health. However, its interaction with dietary and exercise interventions as well as its impact on obesity and hepatic metabolic pathways, particularly in females, remain unclear. Here, we tested whether tirzepatide, alone or combined with time-restricted feeding (TRF) or resistance training, modulates energy balance, strength performance, adipose tissue remodelling, insulin sensitivity and hepatic lipid accumulation in female mice. Female Swiss mice after 10 weeks of obesity induction were treated with tirzepatide, TRF or resistance training for 8 weeks. Tirzepatide was administered subcutaneously using a dose-escalation protocol. TRF consisted of a 12 h feeding window, and resistance training was performed as stair climbing on alternating days. Body weight, caloric intake and feed efficiency were monitored longitudinally. Glucose homeostasis was assessed by intraperitoneal glucose and insulin tolerance tests. Adipose depots, skeletal muscle and liver mass were quantified, and hepatic lipid accumulation was evaluated by histology and RT-qPCR of lipogenic metabolism genes. Tirzepatide reduced body weight gain and feed efficiency, consistent with a negative energy balance. When combined with TRF and resistance training, tirzepatide accelerated weight loss, and the addition of resistance training further enhanced this effect, bringing body weight close to control levels. These effects were associated with reduced adipose mass and adipocyte hypertrophy, indicating improved adipose tissue remodelling. Resistance training improved strength performance and increased skeletal muscle mass. Tirzepatide combined with TRF, with or without resistance training, improved glucose tolerance in female mice. All interventions reduced hepatic lipid accumulation. Collectively, tirzepatide, particularly in combination with TRF and resistance training, exerts enhanced metabolic benefits on obesity, insulin sensitivity and metabolic regulation in female mice. KEY POINTS: Tirzepatide combined with time-restricted feeding and resistance training produced greater reductions in body weight and adiposity in obese female mice. Combined interventions improved whole-body insulin sensitivity more effectively than isolated strategies. Resistance training preserved skeletal muscle mass during tirzepatide-induced weight loss. All interventions similarly reduced hepatic lipid accumulation and lipogenic gene expression. Tirzepatide-based therapies enhanced systemic metabolic health without additional hepatic benefits from combined interventions.

Keywords:  exercise training; fatty liver; glucose metabolism; incretin agonist; intermittent fasting; obesity

DOI:  https://doi.org/10.1113/JP291770
Am J Physiol Endocrinol Metab. 2026 Nov 01. 331(5): E562-E571

Adipocyte lipolysis is a determinant of skeletal muscle size during fasting and feeding.

Daniel M Marko, Rhea V Vemula, Meghan O Conn, Nazli Robin, Angela M Schmidt, Irena A Rebalka, Jonathan D Schertzer.

  Intermittent fasting (IF) can lower fat mass, but also muscle mass. The mechanisms governing tissue partitioning during fasting remain unclear. During fasting, adipose-derived fatty acids from lipolysis and lipolysis-fueled hepatic ketogenesis maintain blood glucose and systemic energy homeostasis. We hypothesized that impaired lipolysis during fasting would shift substrate provision from adipose to muscle, increasing muscle catabolism during IF. We tested male adipocyte-specific adipose triglyceride lipase knockout (aKO) and littermate floxed-control mice during ad libitum feeding on a 10-wk 5:2 IF protocol consisting of two nonconsecutive 24-h fasts and 5 ad libitum feeding days per week. After 10 wk of IF, aKO mice had lower blood lipids and ketones and lost more lean mass and less fat mass than floxed-control mice when mice were fed a standard control diet and also retained more inguinal white adipose tissue and had lower hindlimb muscle mass when IF was compared with ad libitum feeding. In addition, aKO mice had larger adipocytes, smaller muscle fibers, and increased expression of the atrogene, Atrogin1. We then provided exogenous lipids by feeding an obesogenic high-fat diet (HFD). HFD-fed aKO mice had higher whole body fat oxidation and lower blood lipids and ketones than floxed-controls. Obese HFD-fed aKO mice still had smaller skeletal muscle myofibers and increased muscle atrogene expression despite smaller adipocytes during ad libitum feeding or IF. Therefore, adipocyte ATGL-mediated lipolysis is a determinant of skeletal muscle size, and lower lipolysis influences the balance of fat vs. muscle loss during fasting.NEW & NOTEWORTHY This study demonstrates that adipocyte ATGL is a critical regulator of adipose-muscle metabolic crosstalk. Limiting adipocyte lipolysis through adipose ATGL deletion reduced blood lipid and ketone fuel availability, thereby increasing adipose retention, decreasing skeletal muscle mass and fiber size, and increasing muscle atrogene expression, particularly during intermittent fasting. These findings support a model in which impaired adipocyte lipid mobilization shifts whole body energy demands away from adipose and toward skeletal muscle, promoting muscle catabolism during fasting.

Keywords:  ATGL; intermittent fasting; lipolysis; obesity

DOI:  https://doi.org/10.1152/ajpendo.00262.2026
J Clin Endocrinol Metab. 2026 Oct 28. pii: dgag441. [Epub ahead of print]

Collagen VI-derived endotrophin impairs adipocyte function and insulin action in human obesity.

Dimitrios M Karadedos, Alaa Alhomsi, Isla Koiso-Kanttila, Maria K Svensson, Magnus Sundbom, Giovanni Fanni, Jan W Eriksson, Maria J Pereira.

   CONTEXT: Obesity-associated adipose tissue dysfunction is characterized by extracellular matrix (ECM) remodeling and fibrosis, where collagen VI and its bioactive cleavage peptide endotrophin have been implicated as key mediators.
OBJECTIVE: Characterize collagen VI alpha-3 (COL6A3) depot-specific expression in obesity and determine whether endotrophin impairs adipocyte metabolism and insulin responsiveness.
DESIGN, SETTING, AND PARTICIPANTS: COL6A3 expression was examined in paired subcutaneous (SAT) and omental adipose tissue (OAT) from 60 individuals spanning a broad Body-Mass-Index (BMI) range. Plasma endotrophin was measured in a subset of the cohort (n=42). Endotrophin effects were assessed in adipose explants, primary human and SGBS adipocytes.
MAIN OUTCOME ME: asures. Depot-specific COL6A3 expression relative to BMI and endotrophin's effects on adipose tissue gene expression, GLUT4 levels, and adipocyte glucose uptake rate.
RESULTS: COL6A3 expression was associated with adiposity only in SAT. BMI remained an independent predictor after adjustment for age, sex, and metabolic covariates. COL6A3 co-expression patterns were positively associated with ECM remodeling and inflammation genes in both depots, while inverse associations with lipid metabolism and insulin signaling genes were specific to SAT. Circulating endotrophin levels were associated with fat mass percentage and triglyceride-to-HDL-cholesterol ratio, but not with adipose tissue COL6A3 expression. Endotrophin treatment reduced expression of PPARγ, SLC2A4 (GLUT4), and NR3C1, decreased GLUT4 protein, and impaired adipocyte insulin-stimulated glucose uptake rate without affecting AKT phosphorylation. Endotrophin reduced PPARγ, DGAT2, and SLC2A4 expression in differentiating SGBS adipocytes. Glucocorticoids upregulated COL6A3 in both depots.
CONCLUSIONS: These findings implicate COL6A3-associated ECM remodelling and endotrophin in adipose dysfunction and impaired adipocyte insulin responsiveness in obesity.

Keywords:  Collagen VI; Endotrophin; adipocyte dysfunction; extracellular matrix; metabolic dysregulation

DOI:  https://doi.org/10.1210/clinem/dgag441
Am J Physiol Endocrinol Metab. 2026 Oct 23.

Longitudinal Analysis of Skeletal Muscle and Cardiometabolic Risk During the Menopause Transition.

Hannah E Cabre, Kaja Falkenhain, Steve R Smith, Catherine M Champagne, Fanchao Yi, Jennifer C Lovejoy, Leanne M Redman.

  We assessed longitudinal changes in body composition and cardiometabolic risk in those with normal-weight and overweight/obese women across the menopausal transition. We examined a 10-year longitudinal analysis of 81 healthy women in the prospective Healthy Transitions cohort. Body composition measures were obtained via dual-energy X-ray absorptiometry. Skeletal muscle was estimated using a validated prediction model: 1.12 × appendicular lean mass- 0.63. Serum sex steroid hormones and cardiometabolic factors were quantified in fasting blood. Participants were stratified by BMI into normal weight (n=41) and overweight/obesity (n=40) groups. Changes within and between BMI groups across the menopause transition were assessed with linear mixed models. At menopause onset, compared to those with normal weight, participants with overweight/obesity had lower sex hormone-binding globulin (-30.9±10.3 nmol/L; p=0.01), greater percent body fat (13.1±1.3%; p<0.001), greater skeletal muscle mass (2.5±0.6 kg; p<0.001), and worse cardiometabolic risk factors (p<0.001). In the 5 years before menopause, participants with overweight/obesity gained skeletal muscle (+1.2 kg) and fat mass (+3.5 kg), while participants with normal weight increased percent body fat (+1.5%) only. At menopause onset, women with overweight/obesity exhibit distinct alterations in body composition, hormonal profiles, and cardiometabolic risk that exist in the years preceding menopause, highlighting the importance of early, targeted interventions to mitigate adverse health trajectories during the menopause transition.

Keywords:  Estrogen; Healthy Transitions; fat-free mass; normal weight; obesity

DOI:  https://doi.org/10.1152/ajpendo.00173.2026
Mol Biol Rep. 2026 Oct 29. pii: 1846. [Epub ahead of print]53(1):

Differential expression of endoplasmic reticulum stress and oxidative stress markers in visceral versus subcutaneous adipose tissue: insights from women with obesity.

Fataneh Esmaeili, Leila Saeidi, Shadi Sadat Seyyed Ebrahimi, Mehrnoosh Shanaki, Hossein Zabihi-Mahmoudabadi, Marzieh Sadat Madani, Zhila Maghbooli, Solaleh Emamgholipour.

   BACKGROUND: Obesity is closely associated with metabolic dysfunction, inflammation, and reduced life expectancy. Emerging evidence highlights endoplasmic reticulum (ER) stress and oxidative stress as key contributors to obesity-related metabolic abnormalities. Notably, visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) exhibit distinct biological properties, yet comparative data on ER stress and antioxidant responses in these depots in humans remain limited. This study aimed to simultaneously compare the expression of selected ER stress and oxidative stress markers in VAT and SAT of women with normal weight and women with obesity.
METHODS: In this cross-sectional study, 23 women with obesity (BMI ≥ 30 kg/m²) undergoing bariatric surgery and 20 women with normal weight (BMI ≤ 25 kg/m²) undergoing elective surgery were enrolled. Anthropometric and biochemical parameters were assessed after overnight fasting. VAT and SAT biopsies were collected intraoperatively. Gene expression of ER stress markers (CHOP, GRP-78) and oxidative stress-related genes (Nrf2, TRX, HO-1, NQO) was quantified using real-time PCR. Antioxidant enzyme activities of manganese superoxide dismutase (MnSOD) and catalase were measured in adipose tissues.
RESULTS: CHOP mRNA expression showed a borderline increase in VAT of women with obesity, while GRP-78 expression did not differ significantly between groups. VAT from women with obesity demonstrated significantly higher expression of Nrf2, TRX, HO-1, and NQO compared with women with normal weight, whereas SAT showed less pronounced changes. MnSOD and catalase activities were markedly elevated in both VAT and SAT of women with obesity.
CONCLUSIONS: Data highlight oxidative stress and ER stress as key contributors to the etiology of obesity and its metabolic complications.

Keywords:  Endoplasmic reticulum (ER) stress; Obesity; Oxidative stress

DOI:  https://doi.org/10.1007/s11033-026-12956-8
medRxiv. 2026 Oct 06. pii: 2026.10.02.26364600. [Epub ahead of print]

Late Sleep Timing is Associated with Metabolic Risk in Postmenopausal Women.

J Matthew Thomas, Philip A Kern, Dorothy D Sears, Samuel E Armstrong, Cody Bumgardner, Catherine J Russell, Courtney F Murray, Jean L Fry, Yuriko Katsumata, Julie S Pendergast.

Postmenopausal women are vulnerable to metabolic dysfunction. Compelling evidence suggests this is because they lack the protective effects of estrogens. We have shown that circulating estrogens regulate daily eating and activity rhythms in female mice and protect them from obesity and metabolic dysfunction. However, few studies have investigated whether postmenopausal women have disrupted eating and sleep-activity rhythms that could contribute to metabolic dysfunction. The purpose of this cross-sectional study was to investigate the relationship between sleep and eating rhythms and metabolic risk in postmenopausal women with overweight or obesity. Seven days of sleep and food intake behavior data were collected from postmenopausal women with overweight or obesity. Sleep timing was assessed using wrist-worn actigraphy and sleep logs. First and last calorie intake times were collected daily using text messaging. Visceral adipose tissue (DXA), insulin resistance (Matsuda index), blood pressure, and triglycerides were analyzed as markers of metabolic risk. In 122 postmenopausal women (mean ± SD: 58.1 ± 3.6 yr, 33.2 ± 5.2 kg/m 2 BMI), we found that later sleep onset was associated with greater visceral adipose tissue ( p =0.0007), but not insulin resistance, blood pressure, or triglycerides. Next, we used a random-forest model to quantify the relative contributions of sleep and meal timing variables to predict visceral adipose tissue. The top predictors of visceral adipose tissue were time of sleep onset, sleep duration, and time of last caloric intake. These data suggest that interventions that advance sleep onset may reduce metabolic risk in postmenopausal women.

DOI: https://doi.org/10.64898/2026.10.02.26364600
Biochem Biophys Res Commun. 2026 Oct 26. pii: S0006-291X(26)01577-9. [Epub ahead of print]841 154811

Lipocalin-2 deficiency attenuates early fibrotic remodeling and later adipocyte death in diet-induced obesity.

Yundong Sun, Wan-Seog Shim, Kyung Eun Kim, Hyun Joo Shin, Jaewoong Lee.

  Adipose tissue fibrosis and adipocyte death are prominent features of obesity; however, their temporal relationship with diet-induced obesity remains unclear. Lipocalin-2 (LCN2) is a secreted glycoprotein associated with metabolic inflammation and fibrogenesis; however, its contribution to adipose tissue remodeling is not fully understood. Wild-type (WT) and Lcn2-deficient (LCN2KO) mice were fed normal or high-fat (HFD) diets for 10 or 20 weeks, and epididymal white adipose tissue (eWAT) was analyzed. In WT mice, crown-like structure (CLS) formation, perilipin-1 loss, and NLRP3 induction became more pronounced after 20 weeks of HFD feeding, whereas phosphorylated SMAD3, α-SMA, and Tgfb1 mRNA expression increased after 10 weeks but declined by 20 weeks. LCN2 expression and collagen accumulation, assessed using Sirius Red staining and Col1a1 and Col6a1 mRNA expression, increased progressively throughout HFD feeding, indicating that LCN2 abundance did not parallel the temporal pattern of canonical TGF-β/SMAD3 signaling. Lcn2 deletion attenuated p-SMAD3 induction at 10 weeks, reduced α-SMA and collagen accumulation throughout HFD feeding, lowered Ccl2 and Il1b expression at both time points, and attenuated CLS formation, perilipin-1 loss, and NLRP3 induction at 20 weeks. These results indicate that early activation of TGF-β/SMAD3-driven fibrogenic signaling occurs before the more pronounced adipocyte death and NLRP3-associated inflammatory changes in eWAT during HFD-induced obesity, and that Lcn2 deletion attenuates both the early fibrogenic response and later adipocyte death-associated remodeling during HFD feeding.

Keywords:  Adipocyte death; Adipocyte dysfunction; Lipocalin-2; Obesity; TGF-β/SMAD3 signaling

DOI:  https://doi.org/10.1016/j.bbrc.2026.154811
G3 (Bethesda). 2026 Oct 27. pii: jkag293. [Epub ahead of print]

Genomic profiling of estrogen-related receptor identifies adult adipocyte-specific targets in Drosophila.

Jun Yin, Douglas B Rusch, Jitika S Bhatta, David M Merritt, Lesley N Weaver.

  Adipose tissue is a key metabolic organ for carbohydrate and lipid metabolism. Multiple nutrient sensing pathways and metabolic enzymes operate in adipocytes to control energy production and lipid mobilization in response to physiological conditions. Important regulators of glycolytic and lipid metabolism in many species are members of the estrogen-related receptor (ERR) family of nuclear receptors. We previously showed that ERR is required for transcriptional regulation of glycolytic and pentose phosphate pathway enzymes in adult Drosophila females, consistent with what is observed in ERR mutant males and larvae. However, the cell-type specific targets of ERR in adipose and other tissues have not been fully elucidated. Here, using a modified targeted DamID approach (NanoDam), we identified ERR occupancy specifically in adult adipocytes at the loci that encode genes involved in glycolysis, the pentose phosphate pathway, and fatty acid metabolism. Overall, our results predict that ERR centrally functions in adipose tissue to regulate multiple metabolic pathways.

Keywords:  beta-oxidation; glycolysis; metabolism; nuclear receptor; pentose phosphate pathway (PPP)

DOI:  https://doi.org/10.1093/g3journal/jkag293
Genes (Basel). 2026 Sep 28. pii: 1199. [Epub ahead of print]17(10):

Human Subcutaneous Adipose Transcriptomes Link Mitochondrial Transcription to Metabolic Heterogeneity in Obesity.

Shuang Bai, Meng Qi, Shuang Wu, Junzhu Wang, Qing Yang, Yajuan Cui, Siyuan Ma, Dongling Wang.

   BACKGROUND: Metabolically healthy obesity and metabolically unhealthy obesity may occupy different positions along a continuum of adipose-tissue dysfunction, but stable molecular distinctions remain uncertain.
METHODS: We integrated three public human subcutaneous-adipose-tissue transcriptomic datasets while preserving participant and platform independence. GSE244118 was used for discovery, GSE152991 was restricted to 14 participants not overlapping with the discovery cohort, and GSE55200 provided cross-platform supportive evidence. We performed differential-expression analysis, correlation-adjusted Reactome testing, direction-aware cross-dataset integration, discovery-defined module scoring, and adipose-tissue deconvolution.
RESULTS: Fifty genes met conventional thresholds for metabolically unhealthy versus metabolically healthy obesity in the discovery dataset, but none passed the prespecified fold-change-aware test or strict cross-dataset replication. Among 1570 shared Reactome pathways, 409 reached false-discovery rate < 0.05 in signed-Z integration and 387 had concordant directions across all datasets. Metabolically unhealthy obesity consistently showed lower mitochondrial translation, respiratory-chain, and energy-metabolism programs, accompanied by secondary increases in extracellular-matrix remodeling. A discovery-defined mitochondrial module was lower in metabolically unhealthy obesity in synthesis restricted to non-discovery datasets under both rank and z-mean scoring. The 14-person holdout alone did not establish a significant module difference, and the extracellular-matrix module synthesis was nonsignificant. Ordered cross-sectional patterns and composition sensitivity described tissue-level associations.
CONCLUSIONS: Metabolic obesity heterogeneity was therefore more reproducible at pathway and module levels than at the single-gene level. Unresolved clinical confounding and bulk tissue composition limit functional and causal interpretation.

Keywords:  cell deconvolution; extracellular matrix; metabolically healthy obesity; metabolically unhealthy obesity; mitochondrial transcription; subcutaneous adipose tissue; transcriptomics

DOI:  https://doi.org/10.3390/genes17101199