bims-mimead Biomed News
on Adipose tissue and metabolic disease
Issue of 2026–01–04
six papers selected by
Rachel M. Handy, University of Guelph
  1. Influence of obesity and insulin resistance with hepatic steatosis on the human plasma lipidome.
  2. Multi-omic definition of metabolic obesity through adipose tissue-microbiome interactions.
  3. Pharmacological Inhibition of Pyruvate Dehydrogenase Kinase 4 Enhances Insulin Sensitivity in Mouse Models of Diabetes and Obesity.
  4. Phosphoproteomics of aged insulin-resistant bone identifies P70S6K phosphorylation of AFF4 as a gene-specific transcriptional regulator.
  5. Sex Differences in Body Weight Regulation and Hepatic Insulin Signaling Following Bariatric Surgery and Postoperative Diet in Obese Rats.
  6. Obese plasma transfer accelerates cellular aging in the C57BL/6 mouse model.
  1. J Lipid Res. 2025 Dec 26. pii: S0022-2275(25)00232-9. [Epub ahead of print] 100969
    Influence of obesity and insulin resistance with hepatic steatosis on the human plasma lipidome.
    Max C Petersen, Gordon I Smith, Aaron M Armando, Xiong Su, Oswald Quehenberger, Edward A Dennis, Samuel Klein.
      Insulin resistance accompanied by hepatic steatosis is a common complication of obesity. In an effort to identify plasma lipids that could be biomarkers or causes of insulin resistance with steatosis in people with obesity, we evaluated the plasma lipidome in three distinct groups separated by adiposity, hepatic steatosis, and insulin sensitivity, assessed by using the hyperinsulinemic-euglycemic clamp procedure: i) insulin-sensitive lean (ISL, n=13); ii) insulin-sensitive obese (ISO, n=14); and iii) insulin-resistant obese with hepatic steatosis (IROS, n=13). We evaluated 759 complex lipid species in 16 subclasses (including phospholipids, glycerolipids, sphingolipids, acylcarnitines, and cholesteryl esters) and 84 eicosanoids in fasting plasma samples. Total abundances of each lipid subclass (sum of species) in the ISO group were not different than values in the ISL group, whereas phosphatidylethanolamines, triglycerides, and diacylglycerols were more abundant in the IROS than in the ISO group. The abundances of only 5 individual complex lipid species were different between the ISL and ISO groups, whereas the abundances of 23 lipids were different between the ISO and IROS groups. More complex lipids were associated with insulin sensitivity (n=124) than obesity per se (n=7). In contrast, plasma eicosanoids were not different between the ISO and IROS groups, but were greater in both groups with obesity than in the ISL group. We conclude that insulin resistance with hepatic steatosis is associated with alterations in the plasma complex lipidome, independent of adiposity, in people with obesity, whereas adiposity has a greater impact than insulin resistance on plasma eicosanoid concentrations.
    Keywords:  complex lipids; eicosanoids; insulin resistance; lipidomics; obesity
    DOI:  https://doi.org/10.1016/j.jlr.2025.100969
  2. Nat Med. 2026 Jan 02.
    Multi-omic definition of metabolic obesity through adipose tissue-microbiome interactions.
    Rima M Chakaroun, Meenakshi Pradhan, Elias Björnson, Daniel Arvidsson, Jonatan Fridolfsson, Anders Gummesson, Marc Schoeler, Matthias Mitteregger, Gustav J Smith, Ingrid Larsson, Mats Börjesson, Matthias Blüher, Mathias Uhlén, Michael Stumvoll, Göran Bergström, Valentina Tremaroli, Fredrik Bäckhed.
      Obesity's metabolic heterogeneity is not fully captured by body mass index (BMI). Here we show that deep multi-omics phenotyping of 1,408 individuals defines a metabolome-informed obesity metric (metBMI) that captures adipose tissue-related dysfunction across organ systems. In an external cohort (n = 466), metBMI explained 52% of BMI variance and more accurately reflected adiposity than other omics models. Individuals with higher-than-expected metBMI had 2-5-fold higher odds of fatty liver disease, diabetes, severe visceral fat accumulation and attenuation, insulin resistance, hyperinsulinemia and inflammation and, in bariatric surgery (n = 75), achieved 30% less weight loss. This obesogenic signature aligned with reduced microbiome richness, altered ecology and functional potential. A 66-metabolite panel retained 38.6% explanatory power, with 90% covarying with the microbiome. Mediation analysis revealed a bidirectional, metabolite-centered host-microbiome axis, mediated by lipids, amino acids and diet-derived metabolites. These findings define an adipose-linked, microbiome-connected metabolic signature that outperforms BMI in stratifying cardiometabolic risk and guiding precision interventions.
    DOI:  https://doi.org/10.1038/s41591-025-04009-7
  3. J Obes Metab Syndr. 2025 Dec 31.
    Pharmacological Inhibition of Pyruvate Dehydrogenase Kinase 4 Enhances Insulin Sensitivity in Mouse Models of Diabetes and Obesity.
    Min-Ji Kim, Bitna Ha, Ran Ryeong Kim, Jung-Yi Lee, Chae Won Lim, Jin Hee Ahn, In-Kyu Lee, Jae-Han Jeon.
       Background: Insulin resistance is a central feature of type 2 diabetes mellitus (T2DM), which remains a major global health burden with limited therapies that directly address upstream molecular defects. Pyruvate dehydrogenase kinase 4 (PDK4), a regulator of glucose and lipid metabolism, has emerged as a promising therapeutic target. Here, we evaluated the metabolic effects of GM-10395, an orally available PDK4 inhibitor, in preclinical models of insulin resistance.
    Methods: We evaluated the metabolic effects of GM-10395, an orally available PDK4 inhibitor, in preclinical models of insulin resistance. In alpha mouse liver 12 (AML12) hepatocytes, we assessed protein kinase B (AKT) phosphorylation, mitochondrial reactive oxygen species (ROS), and oxygen consumption rate (OCR). In vivo, long-term oral administration of GM-10395 (8 weeks in KKAy mice [n=6 per group] and 5 weeks in diet-induced obesity [DIO] mice [n=6 per group]) was evaluated for effects on glucose tolerance, glycosylated hemoglobin, lipid profiles, and liver histology.
    Results: GM-10395 restored AKT phosphorylation, reduced ROS generation, and normalized OCR in palmitate-treated AML12 cells. In both KKAy and DIO mice, GM-10395 significantly improved glucose tolerance and reduced hepatic steatosis. Serum lipid analysis revealed reductions in low-density lipoprotein cholesterol and triglycerides, with histology confirming decreased lipid deposition. Enhanced insulin signaling, evidenced by increased phosphorylated AKT (pAKT)/total AKT (tAKT) ratios in liver, muscle, and adipose tissues, was consistently observed.
    Conclusion: GM-10395 improves systemic glucose and lipid homeostasis by restoring insulin sensitivity via PDK4 inhibition. These results support GM-10395 as a promising oral therapeutic candidate for insulin resistance in T2DM.
    Keywords:  Fatty liver; Insulin resistance; Phosphorylation; Pyruvate dehydrogenase kinase 4; Type 2 diabetes mellitus
    DOI:  https://doi.org/10.7570/jomes25086
  4. Nat Commun. 2025 Dec 31.
    Phosphoproteomics of aged insulin-resistant bone identifies P70S6K phosphorylation of AFF4 as a gene-specific transcriptional regulator.
    Mriga Dutt, Luoping Liao, Hani Jieun Kim, Ronnie Blazev, Audrey Chan, Hitesh Kore, Ayenachew Bezawork-Geleta, Li Dong, Isela Sarahi Rivera, Natalie K Y Wee, Jeffrey Molendijk, Julian P H Wong, Vanessa R Haynes, Veronica Uribe, Gordon S Lynch, Kelly A Smith, Magdalene K Montgomery, Matthew J Watt, Pengyi Yang, Garron T Dodd, Stephin J Vervoort, Natalie A Sims, Benjamin L Parker.
      Insulin action on the skeleton is essential for bone development and whole-body energy metabolism, however a global view of signaling in this tissue is lacking. Furthermore, whether there are signaling differences that drive the gene-specific activation under insulin-resistant (IR) or ageing conditions is unknown. Here, we perform a phosphoproteomic analysis of insulin signaling in the bones of young, lean, insulin-sensitive versus old, obese, IR mice revealing a rewiring of phosphorylation. We target dysregulated phosphoproteins in a zebrafish functional genomic screen of bone development and mineralization revealing candidates important for skeletal formation. One of these is ALF Transcription Elongation Factor 4 (AFF4), the core scaffold of the Super Elongation Complex and we show that phosphorylation of S831 on AFF4 is an insulin-dependent substrate of P70S6K and attenuated in aged, IR bone. Phosphorylation of S831 is defective in IR osteoblasts and associated with reduced transcriptional elongation at discrete locations in the genome. Mechanistically, we show phosphorylation of S831 increases recruitment of chromatin remodelers, ENL/AF9 to crotonylated histone via the YEATS domain, and promotes gene-specific activation. Our analysis identifies regulators of insulin action on the skeleton, further uncovering a mechanism of IR via locus-specific changes in transcriptional elongation and gene activation.
    DOI:  https://doi.org/10.1038/s41467-025-68106-4
  5. Obes Surg. 2025 Dec 28.
    Sex Differences in Body Weight Regulation and Hepatic Insulin Signaling Following Bariatric Surgery and Postoperative Diet in Obese Rats.
    Tanja Jevdjovic, Predrag Vujovic, Andjela Milicevic, Iva Lakic, Samir Muhovic, Aida Topic, Amina Valjevac, Tamara Dakic.
       INTRODUCTION: The global obesity prevalence demands new strategies for its treatment. We evaluated sleeve gastrectomy (SG) and biliopancreatic diversion (BD) effects on body weight and hepatic insulin signaling outcomes in high-fat diet (HFD)-induced obese rats, with attention to postoperative diet and sex.
    METHODS: Wistar rats received a four-week HFD, then underwent SG or BD. Postoperatively, half of each experimental group remained on HFD and half switched to standard chow for four weeks. Serum glycemia and insulin as well as hepatic GLUT1/GLUT2, IR, p-IR (Tyr1361), Akt, and p-Akt (Ser473) were assessed.
    RESULTS: SG and BD produced comparable weight loss. However, a switch to standard chow yielded additional weight loss only in females. Postoperative diet did not alter glycemia, aligning with weight-independent, surgery-driven mechanisms. Serum insulin was unchanged in males but decreased in females after SG/BD, with a further decline on chow. At the hepatic level, IR abundance increased in both sexes, whereas IR activation was surgery/diet-sensitive only in males. Conversely, p-Akt/Akt rose with chow only in females, indicating enhanced hepatic insulin sensitivity without a requisite increase in IR phosphorylation.
    CONCLUSION: Both procedures significantly reduced body weight and lowered blood glucose in males and females. Switching to standard chow further enhanced weight loss and insulin sensitivity in females. Hepatic glucose transporter and signaling responses varied by sex, surgery, and postoperative diet. These findings underscore sex-related, independent effects of surgery and postoperative diet and argue for tailored nutritional management after bariatric procedures.
    Keywords:  Biliopancreatic diversion; GLUTs; Insulin signaling; Liver; Obesity; Sleeve gastrectomy
    DOI:  https://doi.org/10.1007/s11695-025-08471-7
  6. Immun Ageing. 2025 Dec 29. 22(1): 54
    Obese plasma transfer accelerates cellular aging in the C57BL/6 mouse model.
    Shabnam Shahabi Nejad, Hamid Zand, Samira Rastgoo, Leyli Zahra Bahreini Boroujeni, Mehdi Abedini Najafabadi, Saman Asadi, Reyhane Hamishe Bahar, Ghazaleh Shimi.
       BACKGROUND: Obesity induces chronic inflammation and cellular senescence, contributing to metabolic and immune dysfunction. This study investigates the effects of plasma obtained from obese and non-obese C57BL/6 donor mice on senescence and inflammation markers in recipient mice.
    METHODS: Recipient C57BL/6 mice received intraperitoneal injections of 150 μl of pooled plasma from either obese (PO group) or non-obese (PNO group) donors once weekly for four weeks. Body weight, epididymal adiposity index, and thymus index were recorded. Senescence-associated β-galactosidase (SA-β-gal) activity was assessed in epididymal white adipose tissue (eWAT) and peripheral blood mononuclear cells (PBMCs). Gene expression of p16, interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α) was quantified using quantitative real-time polymerase chain reaction (qRT-PCR). Plasma concentrations of IL-6 and TNF-α were measured using enzyme-linked immunosorbent assay (ELISA).
    RESULTS: Mice in the PO group showed significantly increased SA-β-gal activity in eWAT (P < 0.05) and PBMCs (P < 0.001) compared to the PNO group. In eWAT, p16 expression was significantly elevated (P = 0.019; log₁₀-fold change: 1.48). In PBMCs, IL-6 (P < 0.001; log₁₀-fold change: 0.90), p16 (P < 0.001; log₁₀-fold change: 1.41), and TNF-α (P < 0.001; log₁₀-fold change: 2.83) expressions were significantly upregulated in the PO group. No significant differences were observed in plasma cytokines, body weight, epididymal adiposity, or thymus index.
    CONCLUSIONS: These results indicate that the pro-inflammatory and pro-senescence effects of obese plasma are not limited to the original donor but can actively transfer aging-related changes and immune dysfunctions to healthy recipient tissues, highlighting the need for further therapeutic exploration.
    Keywords:  Aging; Cytokines; Immunosenescence; Inflammation; Obesity; Senescence
    DOI:  https://doi.org/10.1186/s12979-025-00547-3
This page is being maintained by Thomas Krichel. It was last updated on 2026‒01‒12 at 12:19.