bims-mimead Biomed News
on Adipose tissue and metabolic disease
Issue of 2026–02–22
seven papers selected by
Rachel M. Handy, University of Guelph
  1. Adipose Tissue Resistance to the Antilipolytic Effect of Insulin and Niacin in Humans With Obesity.
  2. Insulin and adipocyte IRF4 promote fat retention over muscle preservation during intermittent fasting in obesity.
  3. Siah2 is a lipid-meditated metabolic sensor in adipose tissue macrophage.
  4. Deletion of Mfn2 in endothelial cells triggers a mitohormetic response that improves systemic metabolism and healthspan in mice.
  5. Adipocyte NADH dehydrogenase reverses circadian and diet-induced metabolic syndrome.
  6. Gpr75 Deletion in Adipocytes Protects From Diet-Induced Obesity: Changes in Glucose Homeostasis and Inflammatory Responses.
  7. Benefits of Oral Nitrite Supplementation on Mitochondrial Respiration and Physical Function In Older Adults.
  1. Diabetes. 2026 Feb 17. pii: db250979. [Epub ahead of print]
    Adipose Tissue Resistance to the Antilipolytic Effect of Insulin and Niacin in Humans With Obesity.
    Shuhao Lin, Kelli A Lytle, Nicola Fink, Michael D Jensen.
      Adipose tissue (AT) lipolysis insulin resistance results in excess free fatty acid (FFA) release. We tested the hypothesis that the ability of insulin to suppress AT lipolysis is unrelated to the ability of niacin to suppress lipolysis, because niacin acts through a different proximal signaling pathway. Ten volunteers (5 women/5 men) with upper body obesity and/or type 2 diabetes mellitus (T2DM) underwent two study visits with overnight intravenous infusions of niacin (1.4 mg/min) or saline, followed by a hyperinsulinemic-euglycemic clamp. FFA-palmitate Ra was measured using [U-13C] and [2H9]palmitate infusions; abdominal AT biopsies were performed before and during the insulin clamp. The suppression of FFA-palmitate Ra by insulin on the saline control day and by niacin after an overnight infusion were highly correlated (r = -0.93, P < 0.001). Fasting AT Akt (pAktS473/474-to-panAkt ratio, P = 0.01) and perilipin 1 (PLN 1) (pPLN1S552-to-panPLN1 ratio, P = 0.02) phosphorylation were less during niacin than the saline control study. Because the suppression of lipolysis by insulin and niacin are highly correlated within individuals and because niacin and insulin act through different proximal signaling pathways, we propose dysregulated AT lipolysis in obesity/T2DM is due to dysfunction(s) in distal lipolysis proteins rather than isolated "insulin resistance."
    ARTICLE HIGHLIGHTS: We undertook this study to compare adipose tissue lipolysis responses to insulin and niacin in humans. We tested the hypothesis that adipose tissue insulin resistance would be unrelated to adipose tissue niacin resistance. The suppression of lipolysis by insulin and niacin were highly correlated. Dysregulated adipose tissue lipolysis in obesity/type 2 diabetes is due to dysfunction(s) in distal lipolysis proteins rather than isolated "insulin resistance."
    DOI:  https://doi.org/10.2337/db25-0979
  2. Cell Rep. 2026 Feb 19. pii: S2211-1247(26)00101-4. [Epub ahead of print]45(3): 117023
    Insulin and adipocyte IRF4 promote fat retention over muscle preservation during intermittent fasting in obesity.
    Daniel M Marko, Meghan O Conn, Joseph F Cavallari, Helena Neudorf, Alexandra P Steele, Brittany M Duggan, Breanne T McAlpin, Nicole G Barra, Thomas J Hawke, Jonathan P Little, Jonathan D Schertzer.
      Intermittent fasting (IF) can lower body mass during obesity, but it is unknown why certain individuals lose less fat and more lean mass during IF. We hypothesized that hyperinsulinemia and an insulin-responsive adipocyte factor regulate the balance between fat and muscle loss. Chronic elevation of insulin led to higher adipose tissue mass, larger adipocytes, and lower muscle mass after 10 weeks of 5:2 IF in obese male mice. Chronic hyperinsulinemia lowered adipose tissue interferon regulatory factor 4 (IRF4). Whole-body or adipocyte-specific deletion of Irf4 resulted in higher adipose tissue mass and lower muscle mass after IF in obese male mice in two separate models of equal or reduced caloric intake during IF. Males living with obesity and higher blood insulin levels lost more lean mass after a 48-h fast. Therefore, hyperinsulinemia and lower adipocyte IRF4 alter nutrient partitioning to promote higher adipose retention and lower muscle preservation during IF during obesity.
    Keywords:  CP: metabolism; IRF4; adipose; insulin; intermittent fasting; muscle; obesity
    DOI:  https://doi.org/10.1016/j.celrep.2026.117023
  3. J Lipid Res. 2026 Feb 12. pii: S0022-2275(26)00025-8. [Epub ahead of print] 100999
    Siah2 is a lipid-meditated metabolic sensor in adipose tissue macrophage.
    Thanh N Dang, Bhaswati Ghosh, Pradip R Panta, Jessica M Taylor, Gail Kilroy, Robbie Beyl, Krisztian Stadler, Z Elizabeth Floyd.
      Adipose tissue macrophage lipid accumulation is associated with developing obesity-related insulin resistance, yet the underlying mechanisms influencing excess lipid accumulation in adipose tissue macrophage are not well-understood. Global deletion of the ubiquitin ligase SIAH2 improves glucose tolerance and insulin sensitivity while reducing adipose tissue inflammation with obesity. While Siah2 mRNA is expressed in preadipocytes and adipocytes, recent snRNA-sequencing data show Siah2 is broadly expressed in adipose tissue immune cells, including macrophage. Here, we generated a macrophage-specific SIAH2 deletion mouse model to assess the role of macrophage SIAH2 in the relationship between adipose tissue expansion and insulin resistance with a high-fat dietary challenge. Loss of SIAH2 in macrophage robustly increased glucose intolerance and insulin resistance without relative increases in body weight, serum lipids or lipid accumulation in skeletal muscle or liver in male mice compared to wild-type male mice fed a high-fat, but not a low-fat diet. The physiological changes in the male mice were associated with increased adipose tissue inflammation and increased lipid accumulation in the adipose tissue macrophage. Macrophage Siah2 depletion also increased the expression of Cd36, Trem2, Tyrobp, Hilpda1 in adipose tissue. Using the M1-like, M2-like paradigm of proinflammatory and anti-inflammatory macrophage, we found that Siah2 mRNA is stimulated by a proinflammatory lipid and suppresses expression of selected PPARγ target genes involved in lipid metabolism and inflammation. These findings place SIAH2 as a lipid-stimulated stress response protein that functions to regulate lipid accumulation in adipose tissue macrophage and the associated obesity-induced systemic insulin resistance.
    Keywords:  PPARgamma; SIAH2; adipose tissue; cell signaling; inflammation; insulin resistance; macrophages; obesity; ubiquitin
    DOI:  https://doi.org/10.1016/j.jlr.2026.100999
  4. Cell Metab. 2026 Feb 17. pii: S1550-4131(26)00012-4. [Epub ahead of print]
    Deletion of Mfn2 in endothelial cells triggers a mitohormetic response that improves systemic metabolism and healthspan in mice.
    Iñigo Chivite, Erika Monelli, Margalida Munar-Gelabert, Alicia G Gómez-Valadés, Abdiel Alvarado-Diaz, Macarena Pozo, Luis Varela, Sara Ramírez, Roberta Haddad-Tóvolli, Miriam Toledo, Júlia Fos-Domènech, Francisco Díaz-Castro, Iasim Tahiri, Pau García-Ramón, Mariana Ferreira, Chloé van Gelder, Anne Abot, Óscar Osorio-Conles, José Antonio Valer, Arnaud Obri, Maria Milà-Guasch, Jorge Alvarez Luis, Pilar Villacampa, Elena Eyre, Jordi Altirriba, Sabrina Genßler, Markus Haake, Christine Schuberth-Wagner, Xavier Remesar, Antonio Zorzano, Pablo M Garcia-Rovés, Francesc Ventura, Josep Vidal, Claude Knauf, Rubén Nogueiras, Tamas L Horvath, Katrien De Bock, Mariona Graupera, Marc Claret.
      Endothelial cells (ECs) are key metabolic gatekeepers, yet their role in metabolic health remains unclear. Given their central involvement in energy metabolism, mitochondria are ideally positioned to enable ECs to adapt to ever-changing metabolic requirements. Here, we explore the hypothesis that mitochondrial dynamics proteins in ECs influence whole-body metabolic status. Genetic deficiency of Mfn2 in ECs (Mfn2iΔEC), but not of Mfn1iΔEC, induces a mitohormetic response in the adipose vasculature, enhancing antioxidant defenses, mitochondrial fitness, and lipid oxidation, ultimately improving metabolic outcomes. Cultured ECs secrete the mitokine growth differentiation factor 15 (GDF15) via a forkhead box O1 (FOXO1)-dependent axis, a response also observed under stress conditions in vivo. Notably, Mfn2iΔEC mice exhibited elevated endothelial and circulating GDF15 levels, and neutralization of GDF15 partly attenuated their metabolic benefits. Consistent with mitohormetic activation, Mfn2iΔEC mice showed protection against diet-induced obesity and delayed age-related decline. Hence, vascular mitohormetic adaptations emerge as a novel mechanism promoting systemic metabolic health.
    Keywords:  GDF15; aging; diabetes; endothelial cells; mitochondria; mitofusin; mitohormesis; obesity
    DOI:  https://doi.org/10.1016/j.cmet.2026.01.012
  5. Nat Metab. 2026 Feb 18.
    Adipocyte NADH dehydrogenase reverses circadian and diet-induced metabolic syndrome.
    Chelsea Hepler, Nathan J Waldeck, Benjamin J Weidemann, Biliana Marcheva, You-Jia Chen, Jacqueline Hecker, Ziming Zhu, Rino Nozawa, Joseph V Mastroni, Anneke K Thorne, Colleen R Reczek, Jonathan Cedernaes, Kathryn M Ramsey, Clara B Peek, Grant D Barish, Navdeep S Chandel, Joseph Bass.
      Circadian clocks are internal timing systems that enable organisms to anticipate and adapt to daily environmental changes. These rhythms arise from a transcription-translation feedback loop in which CLOCK and BMAL1 regulate the expression of thousands of genes, including their repressors PER and CRY. Disruption of circadian rhythms contributes to obesity, metabolic disease and cancer, yet how the clock maintains metabolic homeostasis remains limited. Here we report that the clock regulates oxidative metabolism in adipocytes through diurnal complex I respiration. Disrupting the clock in male mice via adipocyte-specific genetic deletion or high-fat-diet feeding reduces complex I respiration in adipocytes, leading to suppression of the peroxisome proliferator-activated receptor and insulin signalling pathways. In contrast, restoring complex I function by expressing yeast NDI1 in adipocytes protects against diet-induced and circadian-induced metabolic dysfunction independently of weight gain. These findings reveal that adipocyte circadian disruption impairs metabolic health through mitochondrial complex I dysfunction, establishing clock control of complex I as a key regulator of metabolic homeostasis.
    DOI:  https://doi.org/10.1038/s42255-026-01464-5
  6. FASEB J. 2026 Feb 28. 40(4): e71579
    Gpr75 Deletion in Adipocytes Protects From Diet-Induced Obesity: Changes in Glucose Homeostasis and Inflammatory Responses.
    Sakib Hossain, Elizabeth Villegas, Catherine Liapes, Nahid Sultana, Dorina Krasniqi, Danielle Diegisser, Ana Castro, Comfort Williams, Artiom Gruzdev, Darryl C Zeldin, Victor Garcia, Michal Laniado Schwartzman.
      Loss of function G-protein coupled receptor 75 (GPR75) variants in humans are associated with leanness, and Gpr75 null mice are protected from diet-induced obesity (DIO). However, the mechanisms underlying this protection are largely unknown. Here, we investigated the contribution of adipocyte-derived Gpr75 to DIO. Adipocyte-specific Gpr75 knockout (adipo-Gpr75-/-) male and female mice and their wild-type (WT) littermates were placed on a high-fat diet (HFD) for 14 weeks. Metabolic parameters including body weight, energy intake and expenditure, activity, and glucose metabolism were monitored before and after diet feeding. While WT mice obtained a diabetogenic phenotype on HFD, the adipo-Gpr75-/- counterparts were protected. This protection showed sexual dimorphism. Female adipo-Gpr75-/- mice displayed a 50% (p < 0.001) decrease in weight gain and adiposity compared to WT, whereas male adipo-Gpr75-/- gained weight like WT mice. Interestingly, both male and female adipo-Gpr75-/- mice exhibited improved glucose handling compared to WT, which was correlated to decreased adiposity, abrogated adipose tissue inflammation, and increased insulin sensitivity in skeletal muscle. Importantly, no differences in food intake were observed; however, adipo-Gpr75-/- mice exhibited increased activity and energy expenditure, regardless of sex. Taken together, these findings demonstrate that deletion of GPR75 specifically in adipocytes is sufficient to confer protection against DIO and suggest that adipocyte-derived GPR75 contributes importantly to the pathogenesis of DIO potentially by mechanisms that may include promotion of inflammation, impairment of insulin signaling, and disruption of metabolic homeostasis.
    Keywords:  GLP‐1; GPR75; diabetes; insulin sensitivity; obesity; sex differences
    DOI:  https://doi.org/10.1096/fj.202504597R
  7. J Gerontol A Biol Sci Med Sci. 2026 Feb 14. pii: glag034. [Epub ahead of print]
    Benefits of Oral Nitrite Supplementation on Mitochondrial Respiration and Physical Function In Older Adults.
    Daniel E Forman, Subashan Perera, Sruti Shiva, Nancy W Glynn, Tara Teahan Stakich, Sofhia V Ramos, Giovanna Distefano, Cody Wolf, Angelina Kendi, Adam Sterczala, Ian J Sipula, Fiona M Bello, Michael J Jurczak, Frank C Sciurba, Mark T Gladwin, Anne B Newman, Paul M Coen.
       BACKGROUND: Age-associated decline in mitochondrial oxidative capacity is associated with increased risk of disease, frailty, and disability. Oral nitrite and nitrate supplementation have been demonstrated to improve mitochondrial energetics and physical function in younger adults, but effects in older adults (age ≥70 years) remain unclear.
    METHODS: Randomized, placebo controlled, double-blind, 2-arm trial with a parallel group design to examine the effect of 20 mg sodium nitrite supplements administered three times a day for 12 weeks versus placebo in older (age ≥70 years) sedentary adults. Change in muscle mitochondrial respiration (complex I and II supported maximal oxidative phosphorylation [CI&II MaxOXPHOS]) was the primary outcome. Platelet bioenergetics, cardiorespiratory fitness, and other physical function measures were also assessed.
    RESULTS: 64 adults (75.7 ± 5.7 years) completed the trial. Nitrite supplementation was not associated with improvements in skeletal muscle mitochondrial respiration, nor improvements in exercise capacity and physical function. However, platelet mitochondrial respiration changed significantly following an acute dose of oral nitrite. Notably, while nitrite levels increased 16 to 30-fold in plasma following an acute dose, levels increased only 1.6 fold in skeletal muscle.
    CONCLUSIONS: The divergent response of skeletal muscle versus platelet mitochondrial respiration in response to nitrite supplementation suggest tissue-specific pharmacokinetics and pharmacodynamics that likely impact on the efficacy of nitrite supplementation. Results also suggest there may be age-related changes in drug delivery, metabolism, and mitochondrial responsiveness compared to nitrite/nitrate previously demonstrated in younger adults.
    Keywords:  Gerotherapeutics; Mitochondrial respiration; Nitric oxide signaling; Pharmocodynamics; Physical function; aging; exercise capacity; geroscience; mitochondrial respiration; nitrite
    DOI:  https://doi.org/10.1093/gerona/glag034
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