bims-mimead 2025-11-30 papers

bims-mimead

Biomed News

on Adipose tissue and metabolic disease

Issue of 2025–11–30
ten papers selected by
Rachel M. Handy, University of Guelph

Sex-Specific Subcutaneous Adipose Tissue Transcriptome in Obesity: Insights From Monozygotic Twin Pairs Discordant for BMI.
Integrative analysis of gene expression and histone modifications for DES, DSP, GJA1 and SMOC2 in adipose tissue reveals potential relationship to cardiometabolic health.
Effects of Marked Weight Loss Induced by Gastric Bypass Surgery or Low-Calorie Diet Alone on Postprandial Glucose Disposal in Type 2 Diabetes.
Type 2 Diabetes and Obesity Alter Exercise Training-Induced Transcriptional Adaptations to Subcutaneous White Adipose Tissue.
Coenzyme Q10 ameliorates obesity by promoting white adipose tissue browning and preserving mitochondrial dynamics in ovariectomized rats fed a high-fat diet.
MitoQ supplementation does not impact redox responses to acute exercise in skeletal muscle of older individuals.
Inhibiting peripheral serotonin activates liver AMPK and reduces monocyte-derived macrophages and fibrosis.
Exercise intensity modulates the human plasma secretome and interorgan communication.
Deletion of MMP12 improves energy metabolism and brown adipose tissue function in mice prone to cardiometabolic disease.
Perimenopausal state oestradiol to progesterone imbalance drives Alzheimer's risk via ERRα dysregulation and energy dyshomeostasis.

Obesity (Silver Spring). 2025 Nov 23.

Sex-Specific Subcutaneous Adipose Tissue Transcriptome in Obesity: Insights From Monozygotic Twin Pairs Discordant for BMI.

Hanna Haltia, Maheswary Muniandy, Sini Heinonen, Sina Saari, Marcus Alvarez, Antti Hakkarainen, Jesper Lundbom, Juho Kuula, Per-Henrik Groop, Jaakko Kaprio, Päivi Pajukanta, Kirsi H Pietiläinen, Birgitta W van der Kolk.

   OBJECTIVE: We investigated the impact of sex on the subcutaneous adipose tissue (AT) transcriptome and its obesity-related adaptations.
METHODS: We studied rare BMI-discordant monozygotic twin pairs (ΔBMI > 2.5 kg/m2; 21 female, 16 male pairs) to assess how sex affects AT and whole-body metabolism. AT RNA sequencing was analyzed using linear mixed modeling and pathway enrichment for: (1) sex differences in individual twins, adjusted for BMI, (2) sex-stratified effects of acquired obesity (ΔBMI between co-twins separately in females and males), (3) sex-specific effects of obesity (differences in the ΔBMI effect between sexes).
RESULTS: (1) AT transcriptional profiles differed between sexes, associating with insulin sensitivity. (2) Sex-stratified obesity effects within pairs were stronger in females, with upregulated inflammation and downregulated mitochondrial oxidative phosphorylation; males showed increased inflammation and decreased histone modification. (3) The response to obesity was sex-specific: lower expression of genes in unsaturated fatty acid metabolism in obesity was seen in females only. Sex-specific obesity AT gene expression was associated with metabolic health, with a negative association between unsaturated fatty acid metabolism and insulin sensitivity in males only.
CONCLUSIONS: Biological sex influences the AT transcriptome and its response to obesity, highlighting distinct molecular mechanisms that may contribute to sex-specific metabolic health.

Keywords:  adipose tissue; monozygotic twins; obesity; sex differences; transcriptome

DOI:  https://doi.org/10.1002/oby.70078
Mol Med. 2025 Nov 22.

Integrative analysis of gene expression and histone modifications for DES, DSP, GJA1 and SMOC2 in adipose tissue reveals potential relationship to cardiometabolic health.

Sadia Saeed, Anne Hoffmann, Stina Ingrid Alice Svensson, Tina Visnovska, Tobias Hagemann, Adhideb Ghosh, Christian Wolfrum, Akin Cayir, Tom Mala, Jon A Kristinsson, Matthias Blüher, Tone Gretland Valderhaug, Yvonne Böttcher.

   BACKGROUND: Adipose tissue influences cardiometabolic health through its endocrine activity and its role in regulating inflammation, lipid metabolism, and cardiovascular function. The expression of cardiac-associated genes within adipose tissue may reflect or contribute to cardiometabolic risk, yet this relationship remains poorly understood. This study investigates the expression profiles of the cardiac function associated genes GJA1, DES, DSP and SMOC2 in human adipose tissue, and analyses their associations with cardiometabolic traits. Additionally, we explore epigenomic mechanisms that may underlie their differential gene expression.
METHODS: Expression profiling and functional enrichment analyses were conducted to identify depot-specific cardiac gene expression patterns. Quantitative PCR validated gene expression in paired subcutaneous (SAT) and omental visceral adipose tissue (OVAT) samples from 78 individuals with obesity. Gene expression was further validated in three independent cohorts (N = 1,548 total). Associations with clinical traits were assessed using Spearman correlations and multivariate linear regression, adjusted for age, sex, and BMI. Integration with transcriptomic and proteomic datasets publicly available from the Adipose Tissue Knowledge Portal was performed to strengthen clinical relevance. Epigenomic profiling using genome-wide ChIP-seq for histone marks (H3K4me3, H3K4me1, H3K27ac, H3K27me3) was conducted in paired SAT and OVAT samples from five individuals.
RESULTS: DES, DSP, GJA1, and SMOC2 were significantly upregulated in OVAT compared to SAT. DES, DSP, and SMOC2 showed consistent expression patterns across all cohorts, while GJA1 exhibited context-dependent regulation. Gene expression in SAT was negatively correlated with cardiometabolic traits, including blood pressure, insulin resistance, and liver function markers. These associations were confirmed by regression analysis and supported by publicly available multi-omics data. Epigenetic analyses revealed OVAT-specific enrichment of active histone marks and reduced repressive marks, supporting higher differential transcriptional activity in OVAT.
CONCLUSIONS: Depot-specific gene expression of DES, DSP, and SMOC2 in adipose tissue is robustly linked to cardiometabolic traits and supported by distinct epigenetic landscapes in OVAT vs SAT, highlighting their potential as novel biomarkers for cardiometabolic health.

Keywords:  Adipose tissue; Cardiometabolic health; Epigenetics; Gene expression; Obesity

DOI:  https://doi.org/10.1186/s10020-025-01391-3
Diabetes. 2025 Nov 26. pii: db250737. [Epub ahead of print]

Effects of Marked Weight Loss Induced by Gastric Bypass Surgery or Low-Calorie Diet Alone on Postprandial Glucose Disposal in Type 2 Diabetes.

Bettina Mittendorfer, Bruce W Patterson, J Christopher Eagon, Mihoko Yoshino, Samuel Klein.

We used a dual (intravenous and oral) glucose tracer protocol to evaluate rates of glucose appearance in the circulation, insulin-mediated glucose disposal (IMGD), and noninsulin-mediated glucose disposal (NIMGD) for 4 h after consumption of a mixed meal in people with obesity and type 2 diabetes before and after marked (∼20%) weight loss, induced by behavioral diet therapy (BDT, n = 11) or Roux-en-Y gastric bypass (RYGB) surgery (n = 9). Total postprandial glucose appearance rate was lower after compared with before weight loss in both the BDT and RYGB groups because of a decrease in endogenous glucose production, without a difference between groups. However, the decreases in total and incremental postprandial plasma glucose concentration areas under the curve were greater in the BDT group than the RYGB group because IMGD doubled in the BDT group but did not change in the RYGB group. These results demonstrate that the improvement in postprandial glycemia is greater after marked, matched weight loss induced by BDT compared with RYGB in people with obesity and type 2 diabetes, because of increased IMGD after BDT but not RYGB. Nonetheless, these findings do not diminish the potent therapeutic effect of RYGB surgery on glycemic control and even achieving remission of type 2 diabetes.
ARTICLE HIGHLIGHTS: In people with obesity and diabetes, marked (∼20%) weight loss induced by behavioral diet therapy (BDT) causes a greater decrease in postprandial plasma glucose area under the curve than matched weight loss after Roux-en-Y gastric bypass (RYGB), even though insulin sensitivity and postprandial plasma insulin area under the curve are the same in both groups. We studied the effects of marked weight loss after BDT or RYGB on insulin-mediated glucose disposal (IMGD) and non-insulin-mediated glucose disposal. Weight loss induced by BDT, but not RYGB, increased IMGD. Postprandial glycemia improves more after marked weight loss induced by BDT than by RYGB because of increased IMGD after BDT but not RYGB.

DOI: https://doi.org/10.2337/db25-0737
bioRxiv. 2025 Oct 12. pii: 2025.10.11.681273. [Epub ahead of print]

Type 2 Diabetes and Obesity Alter Exercise Training-Induced Transcriptional Adaptations to Subcutaneous White Adipose Tissue.

Roeland J W Middelbeek, Jiekun Yang, Pasquale Nigro, Benjamin James, Danaé Papadopoulos, Laura K Simpson, Jeu Park, Maria Vamvini, Li-Lun Ho, Hui Zhang, Nicholas P Carbone, Michael F Hirshman, Manolis Kellis, Laurie J Goodyear.

White adipose tissue (WAT) dysfunction contributes to obesity-associated metabolic disease and type 2 diabetes (T2D). Rodent studies have demonstrated that exercise training improves WAT function, but molecular studies investigating exercise training effects on WAT in humans have been limited, particularly in the context of metabolic disease. Here, we defined the subcutaneous WAT (scWAT) transcriptome in middle-aged adults (10 male, 19 female) that were classified by lower BMI (<27 kg/m 2 ), higher BMI (≥27 kg/m 2 ), and T2D status before and after a 10-week endurance exercise regimen. At baseline, 624 genes were significantly upregulated and 112 genes downregulated in the scWAT from higher BMI participants compared to lower BMI. There was a spectrum of pathway dysregulation in scWAT in higher BMI individuals, ranging from increased markers of extracellular matrix (ECM) deposition and inflammation to decreased circadian rhythm gene expression. In people with T2D, there were additional transcriptomic differences such as translation-related pathways, selenoamino acid metabolism, and proteoglycans. Exercise training had robust effects on the transcriptome regardless of metabolic status, and notably, for the high BMI and T2D groups, training reversed several of the detrimental gene expression patterns in a cell-type-specific manner. These beneficial exercise-induced transcriptomic adaptations significantly correlated with lower levels of free fatty acids and blood pressure, particularly in participants with higher BMI and T2D. By integrating our exercise training-modulated genes with GWAS meta-analysis of physical activity, genes influenced by exercise training in the higher BMI group showed a significant enrichment in genetic associations of exercise traits in the population. A circadian rhythm-related transcription factor NR1D1 was enriched in enhancers linked with both the exercise differentially expressed genes (DEGs) and GWAS signals, suggesting a link between the circadian rhythm and training-induced adaptations. These findings demonstrate that obesity and T2D result in marked, progressive alterations in cell-type specific gene transcription in scWAT, while endurance exercise training reverses many of the metabolic disease-associated adaptations. Identification of novel molecular pathways regulated by exercise training can lead to therapeutic targets for obesity and metabolic disease.

DOI: https://doi.org/10.1101/2025.10.11.681273
J Nutr Biochem. 2025 Nov 21. pii: S0955-2863(25)00349-3. [Epub ahead of print] 110187

Coenzyme Q10 ameliorates obesity by promoting white adipose tissue browning and preserving mitochondrial dynamics in ovariectomized rats fed a high-fat diet.

Tong Pan, Shu-Ying Chen, Ching-Wen Kung, Hsuan- Yu Chen, Pao-Yun Cheng, Hsin-Hsueh Shen, Ing-Luen Shyu, Yen-Mei Lee.

  Estrogen deficiency caused by menopause leads to obesity in women. In obesity, excessive visceral fat accumulation induces a chronic, low-grade inflammatory response, thereby increasing the risk of cardiovascular disease, insulin resistance, and type 2 diabetes mellitus. Browning of white adipose tissue (WAT) has emerged as a promising strategy to counteract obesity and related metabolic disorders. Coenzyme Q10 (CoQ10) has been reported to reduce oxidative stress, enhance mitochondria function and improve metabolic syndrome in obese and diabetic animals and patients. In this study, we evaluated whether long-term CoQ10 supplementation could induce WAT browning to ameliorate obesity in ovariectomized (OVX) rats fed a high-fat diet (HFD), and explored the underlying mechanisms. Supplementation with CoQ10 (20 and 40 mg/kg, once daily by gavage) for 12 weeks in OVX rats significantly reduced weight gain, excessive visceral fat accumulation, white adipocyte hypertrophy, plasma triglyceride levels, and glucose intolerance, while increasing energy expenditure compared to OVX rats treated with vehicle (p < 0.05). High dose CoQ10 (40 mg/kg) significantly lowered plasma insulin levels, reduced HIF-1α, MCP-1 and IL-6 protein expression, and increased phosphorylated AKT in retroperitoneal WAT (p < 0.05). In inguinal WAT (iWAT), CoQ10 enhanced the expression of browning-related proteins including UCP-1, CIDEA, PRDM16, PGC-1α, and phosphorylated AMPK, and elevated plasma irisin levels (p < 0.05). CoQ10 also regulated mitochondria dynamics of iWAT, as evidenced by increased MFN1, MFN2, and OPA1, and decreased FIS1 protein expression compared with the OVX group (p < 0.05). In 3T3-L1 adipocytes, CoQ10-induced expression of browning markers (UCP-1, TBX1 and PRDM16) was significantly suppressed by dorsomorphin, an AMPK inhibitor, and by AMPK knockdown (p < 0.05). In conclusion, long-term CoQ10 supplementation ameliorates weight gain, white adipocyte hypertrophy and inflammation in WAT, and metabolic disorders caused by combined estrogen deficiency and HFD, likely through its WAT browning effect. AMPK activation is suggested to contribute to the browning effect and enhance the expression of proteins involved in mitochondrial dynamics. Therefore, CoQ10 supplementation could be an effective intervention for preventing postmenopausal obesity.

Keywords:  AMP-activated protein kinase; WAT browning; WAT inflammation; coenzyme Q10; estrogen deficiency; mitochondrial dynamics; ovariectomy; white adipocyte hypertrophy

DOI:  https://doi.org/10.1016/j.jnutbio.2025.110187
Redox Biol. 2025 Nov 14. pii: S2213-2317(25)00440-9. [Epub ahead of print]88 103927

MitoQ supplementation does not impact redox responses to acute exercise in skeletal muscle of older individuals.

Sophie C Broome, Jamie Whitfield, Kristel Janssens, John A Hawley.

  Ageing is associated with attenuated exercise responses in skeletal muscle, which may be related to a failure of muscle redox signalling. The attenuation of redox responses to exercise in aged muscle has been linked to perturbations in redox homeostasis induced by age-related increases in mitochondrial oxidative stress. Accordingly, we investigated the effects of supplementation with the mitochondria-targeted antioxidant MitoQ on mitochondrial bioenergetics and H2O2 emission as well as acute exercise-induced redox responses in skeletal muscle of older individuals. In a randomised, double-blind, placebo-controlled, parallel design, 10 males and 12 females aged 65-80 years were randomised to receive either MitoQ (20 mg/day) or a placebo for 12 weeks before completing a single bout of exercise. Vastus lateralis muscle biopsies were collected before supplementation and before, immediately post- and 4 h post-exercise. MitoQ supplementation reduced mitochondrial H2O2 emission capacity in skeletal muscle but did not impact mitochondrial respiration, H2O2 emission in the presence of ADP, or the sensitivity for ADP to stimulate respiration (apparent Km) and attenuate H2O2 emission (apparent IC50). Acute exercise-induced peroxiredoxin oxidation in skeletal muscle was not altered by MitoQ supplementation. Similarly, MitoQ had no effect on the phosphorylation of several redox-sensitive protein kinases (AMPK, p38 MAPK, and ERK1/2) or the upregulation of mitochondrial and antioxidant genes following exercise. Collectively, these findings indicate that MitoQ supplementation did not influence the basal myocellular redox state or redox responses to exercise in skeletal muscle of older individuals.

Keywords:  Ageing; Antioxidant; Mitochondria; Reactive oxygen species

DOI:  https://doi.org/10.1016/j.redox.2025.103927
Cell Rep. 2025 Nov 26. pii: S2211-1247(25)01379-8. [Epub ahead of print]44(12): 116607

Inhibiting peripheral serotonin activates liver AMPK and reduces monocyte-derived macrophages and fibrosis.

Battsetseg Batchuluun, Tinne Thoné, Andre Djalalvandi, Russta Fayyazi, Parneet Deo, Julian M Yabut, Sara Maggiore, Bavo Vanneste, Jaya Gautam, Logan K Townsend, Elham Ahmadi, Maria Joy Therese Jabile, Marisa Morrow, Eric M Desjardins, Evangelia E Tsakiridis, Sonia Rehal, Waliul I Khan, Dongdong Wang, Charlotte L Scott, Gregory R Steinberg.

  Monocyte-derived liver macrophages are critical in the pathogenesis of metabolic dysfunction-associated steatohepatitis (MASH) and liver fibrosis, but their recruitment mechanisms remain unclear. Serotonin (5-hydroxytryptamine [5HT]) is a conserved monoamine synthesized by tryptophan hydroxylase 1 (Tph1) in peripheral tissues and Tph2 in the brain. We show that, in mice housed at thermoneutrality and fed a high-fat, high-fructose diet, inhibition of peripheral serotonin (pe5HT) through genetic deletion of Tph1 prevents MASH independent of reduction in body weight. Liver flow cytometry and single-nucleus sequencing showed reduced pro-inflammatory Ly6Chigh monocytes, monocyte-derived Kupffer cells (moKCs), and lipid-associated macrophages (LAMs) in Tph1 knockout (KO) mice. Tph1 deletion also decreased circulating monocytes, specifically Ly6Chigh monocytes. A single 5HT injection increased Ly6Chigh monocytes, while Tph1 KO mice had reduced monocytes without affecting bone marrow monocytes. Mechanistically, serotonin inhibition increases liver AMP-activated protein kinase (AMPK) activity, and this is important for reducing CCL2 and monocyte recruitment. These findings link two ancient energy sensors, 5HT and AMPK, with obesity-associated liver fibrosis.

Keywords:  AMPK; CP: Immunology; CP: Metabolism; MASH; immunometabolism; liver fibrosis; macrophage; metabolic syndrome; monocyte; obesity; serotonin

DOI:  https://doi.org/10.1016/j.celrep.2025.116607
bioRxiv. 2025 Oct 23. pii: 2025.10.22.683699. [Epub ahead of print]

Exercise intensity modulates the human plasma secretome and interorgan communication.

Luke Olsen, Javier Botella, Douglas Barrows, Ethan Romero, Kaitlyn Baird, Mutsumi Katayama, Ece Kilic, Christopher Peralta, Henry Sanford, Laurie Farrell, Christopher L Axelrod, Kaja Plucińska, Jeanne Walker, Lu Yan, Katie Fredrickson, Olivier Pourquie, Jeremy M Robbins, Ekaterina V Vinogradova, John P Kirwan, Juleen R Zierath, Anna Krook, Robert E Gerszten, David J Bishop, Paul Cohen.

Exercise is recognized as first-line therapy for many cardiometabolic diseases, including obesity, type 2 diabetes, and hypertension. Despite the abundant health-promoting effects of exercise, in-depth characterization of circulatory factors that mediate these benefits in humans remains incomplete. Moreover, how different modes and intensities of exercise uniquely regulate these processes is unclear. Here, we address these questions by conducting a multi-cohort human exercise intervention, incorporating sprint-interval exercise (SIE) and moderate-intensity exercise (MIE) to analyze intensity-dependent regulation of interorgan crosstalk. We find that exercise intensity distinctly influences the plasma proteome and metabolome in both untrained and trained participants. SIE led to immediate and robust changes to the plasma proteome, whereas MIE resulted in delayed secretory kinetics. By leveraging large, multi-organ gene and protein expression datasets, in combination with in vitro and in vivo tissue sampling, we map the differentially regulated proteins to their predicted tissue of origin and destination. We find that adipocytes are particularly sensitive to exercise intensity, undergoing broad transcriptomic remodeling following in vitro incubation with SIE as compared to MIE plasma. These findings underscore the integrated whole-body response following acute exercise and highlight exercise intensity as a key factor influencing interorgan communication.

DOI: https://doi.org/10.1101/2025.10.22.683699
J Lipid Res. 2025 Nov 25. pii: S0022-2275(25)00214-7. [Epub ahead of print] 100951

Deletion of MMP12 improves energy metabolism and brown adipose tissue function in mice prone to cardiometabolic disease.

Melina Amor, Malena Diaz, Alexander Fuerlinger, Monika Svecla, Valentina Bianco, Laszlo Schooltink, Anja Dobrijević, Birgit Schwarz, Alena Akhmetshina, Nemanja Vujić, Melanie Korbelius, Martin Hirtl, Martin Buerger, Anita Pirchheim, Silvia Rainer, Silvia Schauer, Giangiacomo Beretta, Walter Goessler, Dagmar Kolb, Gerald Hoefler, Hubert Hackl, Corina Madreiter-Sokolowski, Mahmoud Abdellatif, Giuseppe Danilo Norata, Dagmar Kratky.

  Matrix metalloproteinase-12 (MMP12) is a proinflammatory macrophage-secreted protein with immunomodulatory functions that affects neutrophil infiltration, cytokine release, macrophage recruitment, and proliferation. We have previously demonstrated that the genetic deletion of MMP12 in a cardiometabolic mouse model ameliorates obesity-induced low-grade inflammation, white adipose tissue dysfunction, and atherosclerosis. Based on the various beneficial metabolic effects of MMP-12 deletion, we hypothesized that loss of MMP-12 also positively affects whole-body energy metabolism and/or brown adipose tissue (BAT) function in a cardiometabolic mouse model. To investigate the effects of MMP12 deletion on whole-body energy metabolism and/or BAT function, we used low-density lipoprotein receptor (Ldlr)/Mmp12 double knockout (DKO) fed a high-fat, sucrose- and cholesterol-enriched diet. DKO mice housed at 22°C showed increased energy expenditure and decreased BAT size and triglyceride (TG) content. Untargeted proteomic analyses revealed the upregulation of proteins and pathways related to mitochondrial function, glucose metabolism, and fatty acid oxidation in the BAT of DKO mice, whereas abundance of proteins and pathways associated with inflammation were reduced. In addition, DKO mice exhibited reduced macrophage infiltration in BAT with the infiltrating macrophages showing lower expression of lipid-associated marker genes. Loss of MMP12 was associated with reduced compactness and sphericity of the mitochondria in the BAT. Following an acute cold exposure, DKO mice had decreased circulating lipid concentrations, especially very low-density lipoprotein-TG and LDL-cholesterol, and increased expression of thermogenic genes. We conclude that MMP12 may play a detrimental role in whole-body energy homeostasis and thermogenesis, as it triggers macrophage infiltration, inflammation, and mitochondria dysfunction in BAT.

Keywords:  Adipose tissue; Extracellular matrix; Inflammation; Mitochondria; Proteomics; brown

DOI:  https://doi.org/10.1016/j.jlr.2025.100951
Nat Commun. 2025 Nov 22.

Perimenopausal state oestradiol to progesterone imbalance drives Alzheimer's risk via ERRα dysregulation and energy dyshomeostasis.

Jacquelyne Ka-Li Sun, Amy Zexuan Peng, Ronald P Hart, Karl Herrup, Deng Wu, Genper Chi-Ngai Wong, Kim Hei-Man Chow.

Sex-biased differences in Alzheimer's disease (AD) are well documented, but the mechanisms underlying increased vulnerability in postmenopausal women remain unclear. This study aimed to model the effects of perimenopausal hormonal fluctuations on AD pathophysiology. Using a VCD-induced accelerated ovarian failure model in young female C57BL/6 J and 3xTg mice, we simulated a perimenopausal state with hormonal changes characterised by elevated oestradiol levels and reduced progesterone levels. Supporting human brain transcriptomic and metabolomic data from the ROSMAP study revealed that impaired oestrogen-related receptor alpha (ERRα) function was a key driver of female sex-biased vulnerability. In female mice, progesterone-guided oestrogen receptor signalling maintained ERRα activity by regulating neuronal cholesterol homoeostasis and the TCA cycle. Hormonal imbalances disrupted this mechanism, triggering an aspartate-driven "minicycle," which increased glutamate release, neuronal excitability, ATP depletion, and energy crisis susceptibility. This study demonstrates how perimenopausal hormonal imbalances exacerbate AD risk via ERRα dysfunction, linking neuronal cholesterol and energy homeostasis to disease vulnerability.

DOI: https://doi.org/10.1038/s41467-025-66726-4