bims-mimead 2026-01-11 papers

bims-mimead

Biomed News

on Adipose tissue and metabolic disease

Issue of 2026–01–11
eight papers selected by
Rachel M. Handy, University of Guelph

The effect of obesity and aging on NAD+/Sirtuin metabolism transcription and DNA methylation in subcutaneous adipose tissue of monozygotic twin pairs discordant for BMI.
The nature of sex differences in catecholamine-induced lipolysis in subcutaneous fat cells.
Human Skeletal Muscle Mitochondria Responses to Weight Loss Induced by Bariatric Surgery or Lifestyle Intervention.
Impact of time-restricted feeding on metabolic health and adipose tissue metabolism in aged female mice with high-fat diet-induced obesity.
TNF/TNFR1 is a Key Regulator of Prolonged Fasting-Induced Decrease in Adipose Tissue.
Greater early postprandial GLP-1 increase after Roux-en-Y than one-anastomosis gastric bypass, with unchanged secretin: a randomized controlled trial.
Dual inhibition of ACLY and ACSS2 by EVT0185 reduces steatosis, hepatic stellate cell activation, and fibrosis in mouse models of MASH.
A catecholamine-independent pathway controlling adaptive adipocyte lipolysis.

Int J Obes (Lond). 2026 Jan 05.

The effect of obesity and aging on NAD+/Sirtuin metabolism transcription and DNA methylation in subcutaneous adipose tissue of monozygotic twin pairs discordant for BMI.

Helena A K Lapatto, Birgitta W van der Kolk, Maheswary Muniandy, Sini Heinonen, Aino Heikkinen, Marcus Alvarez, Seung Hyuk T Lee, Riikka Jokinen, Jesper Lundbom, Juho Kuula, Antti Hakkarainen, Per-Henrik Groop, Jaakko Kaprio, Taru Tukiainen, Miina Ollikainen, Päivi Pajukanta, Eija Pirinen, Kirsi H Pietiläinen.

INTRODUCTION: The expression and/or activity of sirtuins (SIRTs), nicotinamide adenine dinucleotide (NAD+)-dependent enzymes that regulate cellular energy metabolism, is decreased in obesity and in aging in animal models. However, the impact of obesity compared to aging on NAD+/SIRT expression in human white adipose tissue (AT) remains unexplored. Here, we unravel the effects of obesity and aging on the expression of NAD+/SIRT pathway and their associated genes in subcutaneous AT of identical twin pairs discordant for weight, in two age groups.
METHODS: We examined 49 monozygotic twin pairs discordant for BMI (within-pair difference in BMI ≥ 2.5 kg/m2, with mean BMIs 25.6 kg/m2 (leaner) and 30.8 kg/m2 (heavier), aged 22-38 and 56-69 years. Detailed phenotyping included body composition, insulin resistance (oral glucose tolerance test) and plasma lipids and inflammation markers. RNA sequencing and DNA methylation analyses in AT identified differentially expressed and methylated NAD+/SIRT pathway genes in obesity and aging, with linear mixed models linking gene expression to metabolic features.
RESULTS: SIRT5 and NAD+ biosynthetic genes were downregulated in AT in both obesity and aging. Obesity was characterized by downregulation of AT NAD+/SIRT genes, and NAD+/SIRT regulated mitochondrial oxidative metabolism genes, and upregulation of stress markers. Aging showed a downregulation of AT PARPs, except upregulation for PARP1, a main consumer of NAD+. Mitochondrial metabolism and glycolysis genes were linked to corresponding DNA methylation. Downregulation of NAD+/SIRT genes correlated with increased adiposity, insulin resistance, inflammation, and dyslipidemia.
CONCLUSION: Impaired NAD+/SIRT metabolism in AT may play a key role in obesity- and aging-related diseases. Both conditions are characterized by downregulation of NAD+/SIRT pathway genes, correlating with increased adiposity, insulin resistance, inflammation, and dyslipidemia. Obesity uniquely disrupts expression of NAD+/SIRT regulated mitochondrial genes, while aging is characterized by altered PARP expression, particularly increased PARP1, likely exacerbating metabolic dysfunction in AT.

DOI: https://doi.org/10.1038/s41366-025-02007-w
iScience. 2025 Dec 19. 28(12): 113988

The nature of sex differences in catecholamine-induced lipolysis in subcutaneous fat cells.

Lucas Massier, Daniel P Andersson, Nathalie Viguerie, Jiawei Zhong, Danae Zareifi, Alastair G Kerr, Dominique Langin, Peter Arner.

  Women demonstrate a more efficient energy metabolism than men, which is important for sex differences in metabolic health. This dimorphism involves a greater capacity to mobilize lipids from adipose tissue through triglyceride lipolysis following catecholamine stimulation. Herein, we examined the cellular nature of this dimorphism of catecholamine action in human adipocytes from subcutaneous adipose tissue by combining extensive pharmacological experiments with descriptive proteome and transcriptome analyses in large cohorts. We observed two sex-dependent differences in catecholamine-stimulated adipocyte lipolysis: in women, the lipolytic sensitivity (half maximum effective hormone concentration) was 50% decreased, involving increased coupling of antilipolytic alpha-2A adrenoceptors to adenylyl cyclase. However, the maximum lipolytic hormone effect was 50% increased and linked to more efficient mono- and triacylglycerol lipases. Treatment targeting adipocyte lipolysis might be used in men to diminish sex differences in the regulation of lipid metabolism.

Keywords:  Human metabolism; Lipid; Omics

DOI:  https://doi.org/10.1016/j.isci.2025.113988
Acta Physiol (Oxf). 2026 Feb;242(2): e70150

Human Skeletal Muscle Mitochondria Responses to Weight Loss Induced by Bariatric Surgery or Lifestyle Intervention.

Birgitta W van der Kolk, Sini Heinonen, James W White, Anita Wagner, Jari E Karppinen, Sina Saari, Maheswary Muniandy, Simo Metsikkö, Eugène T Dillon, Per-Henrik Groop, Tuure Saarinen, Carel W Le Roux, Kirsi A Virtanen, Neil G Docherty, Eija Pirinen, Anne Juuti, Kirsi H Pietiläinen.

   AIM: We investigated how weight loss induced by bariatric surgery or lifestyle intervention affects skeletal muscle mitochondrial metabolism.
METHODS: We studied two weight-loss cohorts: RYSA (BMI ≥ 35 kg/m2; n = 39, including 18 with diabetes) undergoing bariatric surgery, and CRYO (BMI ≥ 30 kg/m2; n = 19) undergoing a lifestyle intervention with a low-calorie diet. Assessments were performed at 5-6 and 12 months and included muscle proteome (LC-MS/MS), mitochondrial biogenesis by mtDNA amount (qPCR), number and morphology (transmission electron microscopy) in both cohorts, and mitochondrial oxidative capacity (high-resolution respirometry) in the surgery cohort.
RESULTS: Both cohorts achieved clinically meaningful weight loss, greater following surgery (24.4% vs 9.0% at 12 months). Per 1% weight loss, bariatric surgery was associated with significant downregulation of glycolysis pathways at 12 months. OXPHOS complex subunit proteins were associated with upregulation in individuals without diabetes but downregulation in those with diabetes. Lifestyle intervention was associated with downregulated OXPHOS complex subunits at 5 months. Mitochondrial morphology remained unchanged, while mtDNA amount correlated negatively with weight loss percentage in both cohorts. In the surgery cohort, complex I and complex I + II-mediated respiration increased 3.2- and 2.9-fold at 12 months, reflecting improved oxidative capacity.
CONCLUSION: Bariatric surgery was associated with increased skeletal muscle mitochondrial respiration despite unchanged morphology and reduced mtDNA amount, whereas lifestyle-induced weight loss showed a transient downregulation of OXPHOS-related proteins with other mitochondrial markers remaining stable. Surgery-induced weight loss may reflect improved mitochondrial efficiency in skeletal muscle, potentially influenced by diabetes status. Long-term functional mitochondrial adaptations after weight loss require future studies.
TRIAL REGISTRATION: RYSA: ClinicalTrials.gov ID NCT02882685; CRYO: ClinicalTrials.gov ID NCT01312090.

Keywords:  bariatric surgery; lifestyle intervention; mitochondria; skeletal muscle; type 2 diabetes; weight loss

DOI:  https://doi.org/10.1111/apha.70150
J Physiol. 2026 Jan 05.

Impact of time-restricted feeding on metabolic health and adipose tissue metabolism in aged female mice with high-fat diet-induced obesity.

Theresa Bushman, Hongming Su, Xiaoli Chen.

  Ageing increases the risk of obesity and related metabolic diseases, emphasizing the need to understand how dietary interventions influence metabolism and metabolic health in older populations. This study aimed to investigate the impact of time-restricted feeding (TRF) on energy balance, adipose tissue metabolism and overall metabolic health in aged female mice with high-fat diet (HFD)-induced obesity. A 10-week TRF regimen was implemented in aged female mice following 12 weeks of HFD exposure. Mice were either maintained on HFD ad libitum (HFD-AL) or subjected to TRF with HFD access restricted to a 10 h daily feeding window (HFD-TRF). Glucose and insulin tolerance tests, meal pattern and indirect calorimetry were measured during the regimen. We showed that TRF partially reversed HFD-induced weight gain and fat mass accumulation. In white adipose tissue TRF reduced average adipocyte size and increased the heterogeneity in adipocyte size distribution. TRF also led to increased VO2 and VCO2, along with a decreased respiratory efficiency ratio (RER) compared to the HFD-AL group, particularly during the light phase. Meal pattern analysis showed increased meal frequency during the feeding window in HFD-TRF mice relative to HFD-AL. Additionally TRF lowered fasting blood glucose and reduced liver lipid accumulation. At the molecular level TRF induced significant metabolic adaptations in adipose tissue, including upregulation of genes involved in adipogenesis and lipid cycling, as well as depot-specific alterations in mitochondrial oxidation and circadian rhythm gene expression. In conclusion TRF promotes beneficial metabolic adaptations and may serve as an effective dietary strategy to improve metabolic health in aged females. KEY POINTS: Time-restricted feeding (TRF) reduced body weight and fat mass, lowered blood glucose and decreased lipid accumulation in the liver. TRF also changed energy fuel utilization, increased metabolic activity of adipose tissue and altered the size and function of fat cells. Altered meal timing can trigger beneficial metabolic changes and suggests that TRF may help protect against obesity-related diseases during ageing.

Keywords:  adipose tissue; high‐fat diet; metabolism; nutrition; obesity; time‐restricted feeding

DOI:  https://doi.org/10.1113/JP289464
FASEB J. 2026 Jan 15. 40(1): e71404

TNF/TNFR1 is a Key Regulator of Prolonged Fasting-Induced Decrease in Adipose Tissue.

Amanda Carla Clemente de Oliveira, Adma Maciel Babêtto, Mariele Lino Silva, Larisse de Souza Barbosa Lacerda, Thiago de Souza Rodrigues, Marina Chaves de Oliveira, Christine Rouault, Emmanuel L Gautier, André Gustavo Oliveira, Karine Clément, Mauro Martins Teixeira, Geneviève Marcelin, Adaliene Versiani Matos Ferreira.

  Nutrient availability influences white adipose tissue (WAT) inflammation, leading to decreased or increased adiposity. Tumor necrosis factor (TNF) is elevated in WAT under both conditions, being involved in lipolysis and regulation of interleukin 18 (IL-18) secretion, which may regulate lipolytic processes. However, the role of these cytokines in adiposity reduction due to low energy availability remains unclear. Wild-type (WT) mice fasted for 24 h showed decreased adiposity, whereas TNFR1 knockout mice (TNFR1-/-) were unresponsive to fat pad loss, even after 48-h fasting. TNFR1-/- mice were also resistant to β3-adrenergic receptor agonist CL316,243-induced fat mobilization, which was linked with reduced expression of lipases, β3-adrenergic receptors, and cytokines in WAT. Also, mice treated with the TNF-α inhibitor infliximab and fasted for 48 h showed resistance to adiposity loss, suggesting that prolonged fasting-induced TNF signaling may modulate adipose tissue reduction. Conversely, IL-18 does not seem to influence fat pad loss induced by 24-h fasting as IL-18 knockout mice (IL-18-/-) express TNF in WAT and respond to prolonged fasting similarly to WT animals. To assess the potential translational relevance of our findings to human obesity, we analyzed 53 samples from patients with obesity who underwent bariatric surgery. Interestingly, TNFR1 and IL-18 expressions in sWAT correlate with the expression of lipases and adipokines in the subcutaneous site despite no correlation with body weight or fat mass 1 year after surgery. In summary, this study suggests that the TNF/TNFR1 axis is crucial for metabolic adaptation and is a prerequisite for prolonged fasting-induced lipolysis in male mice.

Keywords:  Interleukin‐18; adipose tissue; bariatric surgery; prolonged fasting; tumor necrosis factor

DOI:  https://doi.org/10.1096/fj.202501928RR
Int J Obes (Lond). 2026 Jan 06.

Greater early postprandial GLP-1 increase after Roux-en-Y than one-anastomosis gastric bypass, with unchanged secretin: a randomized controlled trial.

S Heinonen, J E Karppinen, T Saarinen, P-H Groop, A Juuti, J J Holst, K H Pietiläinen.

BACKGROUND: Few studies have compared gut hormone responses between bariatric procedures. This study compared Roux-en-Y and one-anastomosis gastric bypass (RYGB and OAGB) regarding glucagon-like peptide-1 (GLP-1), secretin, and glucose-insulin dynamics.
METHODS: This study included 41 participants (RYGB: n = 21, OAGB: n = 20) from the randomized RYSA trial with similar amounts of bypassed intestine between the procedures. Plasma GLP-1, secretin, glucose, insulin, and C-peptide were measured during a 360-min mixed-meal test before, and at 6- and 12-months after surgery. Outcomes included total and early-phase (0-60 min) areas under the curve (AUCs) and peak concentrations. Visual analogue scales were used to measure hunger and satiety.
RESULTS: Both procedures resulted in ~25% weight loss and marked metabolic improvements over 12 months. While fasting GLP-1 remained largely unchanged, postprandial concentrations rose markedly at 6 months (total AUC increase in RYGB: ~330%, OAGB: ~259%; p < 0.001) and remained elevated at 12 months. The increases in early-phase GLP-1 AUC were 31% higher in RYGB than OAGB at 6 months (95% CI: 3 to 68; p = 0.030) and 25% higher at 12 months (95% CI: -2 to 59; p = 0.072). Peak GLP-1 increases were significantly higher ( ~ 32%) after RYGB at both follow-ups (p < 0.05). Postprandial reduction in hunger was greater after RYGB than OAGB from baseline to 12 months. Fasting or postprandial secretin concentrations showed no significant changes. Both operations were associated with decreased fasting glucose, insulin, and C-peptide; increased early glucose but decreased glucose total AUCs; and increased insulin early AUC and C-peptide total and early AUCs. Glucose early-phase AUC and peak concentration increases were greater after RYGB than OAGB.
CONCLUSIONS: Both RYGB and OAGB lead to markedly enhanced postprandial GLP-1 responses, with no corresponding change in secretin levels. RYGB produces higher early postprandial increases in GLP-1 and glucose than OAGB, demonstrating that procedural differences can influence gut hormone and glucose responses.

DOI: https://doi.org/10.1038/s41366-025-02000-3
Cell Metab. 2026 Jan 06. pii: S1550-4131(25)00529-7. [Epub ahead of print]38(1): 33-49.e10

Dual inhibition of ACLY and ACSS2 by EVT0185 reduces steatosis, hepatic stellate cell activation, and fibrosis in mouse models of MASH.

Fiorella Di Pastena, Jaya Gautam, James S V Lally, Russta Fayyazi, Estelle Grasset, Dipankar Bhattacharya, Gio Fidelito, Elham Ahmadi, Logan K Townsend, Battsetseg Batchuluun, Daniela Carmen Oniciu, Spencer Heaton, Roger S Newton, Theodoros Tsakiridis, Evangelia E Tsakiridis, Suhrid Banskota, Parneet Deo, François Briand, Kat Hall, Eunice Lee, Vijayaragavan Muralidharan, Matthew J Watt, Scott L Friedman, Dongdong Wang, Gregory R Steinberg.

  Metabolic dysfunction-associated steatohepatitis (MASH) is characterized by steatosis, inflammation, and fibrosis driven by hepatic stellate cell (HSC) activation. Acetyl-CoA is central to de novo lipogenesis (DNL) and cholesterol synthesis and is generated from citrate via ATP citrate lyase (ACLY) or from acetate via acetyl-CoA synthetase (ACSS2). Here, we demonstrate that a dual inhibitor of ACLY and ACSS2, EVT0185, reduces serum and liver triglycerides, insulin resistance, and fibrosis. EVT0185 directly suppresses HSC activation in vivo and in vitro, with spatial transcriptomics and single-cell RNA sequencing revealing inhibition of acetate metabolism via ACSS2 and cholesterol synthesis as key drivers of the phenotype. EVT0185 also inhibits de novo lipogenesis in human liver slices and blocks TGFβ1-induced activation of primary human HSCs. These findings suggest that targeting cholesterol and acetate metabolism through dual ACLY and ACSS2 inhibition represents a promising therapeutic approach for MASH and liver fibrosis.

Keywords:  EVT0185; HSCs; MASH; acetate; acetyl-CoA metabolism; cholesterol; fibrosis; hepatic stellate cells; metabolic dysfunction-associated steatohepatitis

DOI:  https://doi.org/10.1016/j.cmet.2025.11.015
Nat Metab. 2026 Jan 08.

A catecholamine-independent pathway controlling adaptive adipocyte lipolysis.

Xiao Zhang, Sreejith S Panicker, Jordan M Bollinger, Anurag Majumdar, Rami Kheireddine, Lila F Dabill, Clara Kim, Brian Kleiboeker, Fengrui Zhang, Yongbin Chen, Kristann L Magee, Brian S Learman, Adam Kepecs, Gretchen A Meyer, Jun Liu, Steven A Thomas, Irfan J Lodhi, Ormond A MacDougald, Erica L Scheller.

Several adipose depots, including constitutive bone marrow adipose tissue, resist conventional lipolytic cues. However, under starvation, wasting or cachexia, the body eventually catabolizes stable adipocytes through unknown mechanisms. Here we developed a mouse model of brain-evoked depletion of all fat, including stable constitutive bone marrow adipose tissue, independent of food intake, to study this phenomenon. Genetic, surgical and chemical approaches demonstrated that catabolism of stable adipocytes required adipose triglyceride lipase-dependent lipolysis but was independent of local nerves, the sympathetic nervous system and catecholamines. Instead, concurrent hypoglycaemia and hypoinsulinaemia activated a potent catabolic state by suppressing lipid storage and increasing catecholamine-independent lipolysis via downregulation of cell-autonomous lipolytic inhibitors including G0s2. This was also sufficient to delipidate classical adipose depots and was recapitulated in tumour-associated cachexic mice. Overall, this defines unique adaptations of stable adipocytes to resist lipolysis in healthy states while isolating a potent catecholamine-independent neurosystemic pathway by which the body can rapidly catabolize all adipose tissues.

DOI: https://doi.org/10.1038/s42255-025-01424-5