bims-mimead Biomed News
on Adipose tissue and metabolic disease
Issue of 2026–08–16
eight papers selected by
Rachel M. Handy, University of Guelph and Universiteit Mastricht
  1. Exercise intensity modulates interorgan communication and is associated with cardiometabolic health outcomes in humans.
  2. GDF15 suppresses liver inflammation independently of weight loss through neuroendocrine glucocorticoid signaling.
  3. Temporal multi-omic analysis uncovers sex-biased molecular programs underlying skeletal muscle adaptation to endurance training.
  4. Insulin resistance is associated with mammary mitochondrial dysfunction at the onset of human lactation.
  5. Nr4a3 Deficiency Disrupts MEK1-ERK1/2-Drp1 Signaling, Driving Adiposity and Glucose Intolerance in Male Mice.
  6. Impaired adipogenesis and lipid storage capacity in subcutaneous adipose tissue of patients with PMOS.
  7. Human Loss-of-Function ZNRF3 Mutation Impairs Adipose Thermogenesis and Drives Subcutaneous Fat Expansion.
  8. Intermittent fasting promotes remodeling of neural and vascular networks in visceral white adipose tissue.
  1. Cell Rep Med. 2026 Aug 13. pii: S2666-3791(26)00405-2. [Epub ahead of print] 102988
    Exercise intensity modulates interorgan communication and is associated with cardiometabolic health outcomes in humans.
    Luke Olsen, Javier Botella, Douglas Barrows, Ethan Romero, Kaitlyn Baird, Mutsumi Katayama, Ece Kilic, Christopher Peralta, Nadège Zanou, Henry Sanford, Laurie Farrell, Christopher L Axelrod, Kaja Plucińska, Jeanne Walker, Lu Yan, Katie Fredrickson, Olivier Pourquie, Jeremy M Robbins, Ekaterina V Vinogradova, Henrik Molina, Nicolas Place, John P Kirwan, Juleen R Zierath, Anna Krook, Robert E Gerszten, David J Bishop, Paul Cohen.
      Exercise is an integral therapy for many cardiometabolic diseases, including obesity, type 2 diabetes, and hypertension. Despite its broad health benefits, the circulating factors that mediate exercise adaptations in humans remain incompletely defined, particularly across different exercise intensities. Here, we conducted 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 found that exercise intensity distinctly influenced the plasma proteome and metabolome in untrained and trained participants. By integrating multi-organ gene and protein expression datasets with in vitro and in vivo tissue sampling, we mapped regulated proteins to their predicted tissues of origin and destination. Muscle fibers and adipocytes were particularly sensitive to exercise intensity and observed to undergo broad secretory and transcriptomic changes. Moreover, we leveraged a large-scale plasma-phenome database to identify intensity-dependent proteins associated with cardiometabolic health and disease, highlighting how exercise intensity differentially shapes interorgan communication and organismal health.
    Keywords:  exercise; interorgan crosstalk; metabolism; moderate-intensity exercise; physiology; sprint-interval exercise
    DOI:  https://doi.org/10.1016/j.xcrm.2026.102988
  2. Cell Metab. 2026 Aug 10. pii: S1550-4131(26)00281-0. [Epub ahead of print]
    GDF15 suppresses liver inflammation independently of weight loss through neuroendocrine glucocorticoid signaling.
    Dongdong Wang, Maria Joy Therese Jabile, Fiorella Di Pastena, Logan K Townsend, Elham Ahmadi, Annabelle Hoegl, Alice Payne, Declan C T Lavoie, Battsetseg Batchuluun, Jaya Gautam, Marisa R Morrow, James S V Lally, Rune E Kuhre, Sebastian B Jørgensen, Gregory R Steinberg.
      Growth differentiation factor 15 (GDF15) is strongly associated with metabolic dysfunction-associated steatohepatitis (MASH), yet whether it promotes or protects against liver injury remains unclear. Using thermoneutral mouse models that closely resemble human MASH, genetic deletion of GDF15 or its receptor GFRAL selectively worsened hepatic inflammation and fibrosis without altering steatosis or insulin resistance. Conversely, recombinant GDF15 reduced liver inflammation and fibrosis more effectively than matched caloric restriction despite identical reductions in food intake, body weight, and steatosis, demonstrating weight-loss-independent hepatoprotection. These effects required GFRAL but were independent of β-adrenergic signaling. Instead, GDF15 activated the hypothalamic-pituitary-adrenal (HPA) axis, increasing circulating corticosterone and hepatic glucocorticoid receptor signaling. Spatial transcriptomics and RNA sequencing demonstrated that GDF15 remodeled the hepatic immune-fibrotic niche by suppressing inflammatory macrophages, plasma B cells, and activated stellate cells while promoting pro-resolving immune programs. Together, these findings identify a GDF15-GFRAL-HPA axis that restrains liver inflammation independently of weight loss.
    Keywords:  GFRAL; HPA; Kupffer cells; MASLD; RNA sequence; caloric restriction; glucocorticoid receptor; hypothalamic-pituitary-adrenal axis
    DOI:  https://doi.org/10.1016/j.cmet.2026.07.008
  3. Cell Rep. 2026 Aug 12. pii: S2211-1247(26)00901-0. [Epub ahead of print]45(8): 117823
    Temporal multi-omic analysis uncovers sex-biased molecular programs underlying skeletal muscle adaptation to endurance training.
    MoTrPAC study group
      Exercise training confers broad health benefits, yet molecular regulators of skeletal muscle adaptation, particularly sex-specific mechanisms, remain incompletely understood. Integrating new and previously published multi-omics data from the molecular transducers of physical activity consortium (MoTrPAC), we characterized metabolomic, epigenomic, transcriptomic, proteomic, and post-translational modification (PTM) responses to 1-8 weeks of endurance exercise training in male and female rat gastrocnemius. While transcriptomic and proteomic responses were largely sex-concordant, there were distinct sex-specific training-induced PTM signatures, particularly in the redox proteome. Females exhibited decreased mitochondrial protein cysteine oxidation alongside increased oxidation of glycolytic proteins relative to males, suggesting sex-biased subcellular reactive oxygen species (ROS) dynamics. Multi-omic factor analysis (MOFA) identified coordinated sex-concordant molecular programs and further supported female-specific mechanisms of redox buffering with training. Together, these findings indicate that sex-specific skeletal muscle exercise adaptations are particularly evident at the PTM level in rats, and identify future avenues for precision exercise health and medicine.
    Keywords:  CP: Metabolism; PTMs; cysteine oxidation; endurance exercise; exercise training; mitochondrial remodeling; multi-omics; post-translational modifications; sex differences; skeletal muscle, proteomics
    DOI:  https://doi.org/10.1016/j.celrep.2026.117823
  4. J Clin Invest. 2026 Aug 13. pii: e197311. [Epub ahead of print]
    Insulin resistance is associated with mammary mitochondrial dysfunction at the onset of human lactation.
    Xin Meng, Taha Elajnaf, Hussam Rostom, Michelle Ma, Annalee Furst, Bryony R Davies, Isabella R Honess, Gaurav Pandey, Isadora C Furigo, Craig L Doig, Jayne F Martin Carli, Rajesh V Thakker, Lars Bode, Kelsey E Johnson, Fadil M Hannan.
      Insulin resistance (IR) has emerged as a risk factor for lactation insufficiency and delays the onset of milk secretion after childbirth, termed secretory activation (SA). This may cause inadequate infant weight gain and early breastfeeding cessation. However, the mechanisms underlying delayed SA in insulin resistant women are unknown. To investigate this, we characterized the mammary transcriptomes and IR-related hormones of 75 breastfeeding women with healthy term infants during postpartum days 1-5. Participants were divided into IR tertiles based on plasma leptin-to-adiponectin ratio measurements. Those in the highest tertile had later SA onset with greater neonatal weight loss during postpartum days 1-5. Transcriptomic analysis on postpartum day 2 (n=4 high IR vs. n=8 low IR participants) showed transient suppression of mammary insulin and prolactin signaling genes, increased pro-inflammatory gene expression and altered expression of >200 mammary mitochondrial genes. These alterations were absent on postpartum days 3-5. Cultured mammary epithelial cells (MECs) treated with insulin showed upregulation of prolactin signaling and oxidative phosphorylation (OXPHOS) genes, with imaging and bioenergetic studies demonstrating that insulin promotes mitochondrial biogenesis and OXPHOS. Thus, our findings delineate roles for insulin in mammary bioenergetics and highlight mitochondrial dysfunction as a mechanism for delayed SA in insulin resistant women.
    Keywords:  Endocrinology; Insulin; Metabolism; Mitochondria; Reproductive biology; Transcriptomics
    DOI:  https://doi.org/10.1172/JCI197311
  5. Am J Physiol Endocrinol Metab. 2026 Aug 09.
    Nr4a3 Deficiency Disrupts MEK1-ERK1/2-Drp1 Signaling, Driving Adiposity and Glucose Intolerance in Male Mice.
    Peter N Ellsworth, Kate E Whalen, Jared D Carter, Jacob A Herring, Kavan H Hess, Kristopher L Wieland, Drake C Watkins, Jeremy Y Saito, Erik D Marchant, Nathan D Marchant, Nathan D Walker, Garritt L Page, Yang Cao, Qin Yang, Benjamin T Bikman, Jeffery S Tessem.
      Obesity is strongly associated with elevated blood glucose levels, glucose intolerance, insulin resistance and type 2 diabetes. The Nr4a family of orphan nuclear receptors are essential for proliferation, cell survival, mitochondrial function, and fuel utilization in a tissue dependent manner. Nr4a3 overexpression has been shown to decrease blood glucose levels and improve glucose tolerance. Here we present the effects of full body Nr4a3 deletion in mice fed a standard chow diet. We demonstrate that male and female Nr4a3 knock out mice fed a standard chow diet have elevated non-fasting blood glucose and impaired glucose tolerance. Male Nr4a3 knock out mice have increased body weight, without changes in body length, food intake, movement or energy expenditure. Interestingly, male, but not female, Nr4a3 knock out mice have increased weight of all adipose depots with increased adipocyte cell size. Furthermore, male Nr4a3 mice have impaired adipose mitochondrial respiration, with normal liver and soleus respiration. Finally, we show a significant decrease in Drp1 mRNA, Drp1 protein, and phosphorylated DRP1 levels. These data suggest that Nr4a3 loss impairs expression of the key mitochondrial fission gene Drp1, resulting in impaired adipose mitochondrial respiration and ultimately increasing adipocyte size, adipose depot mass, and body mass. These data demonstrate that Nr4a3 is critical for proper adipocyte function.
    Keywords:  Adipose tissue; Drp1; Glucose tolerance; Mitochondrial Respiration; Nr4a3
    DOI:  https://doi.org/10.1152/ajpendo.00322.2025
  6. JCI Insight. 2026 Aug 10. pii: e199981. [Epub ahead of print]11(15):
    Impaired adipogenesis and lipid storage capacity in subcutaneous adipose tissue of patients with PMOS.
    Adeline Divoux, Edina Erdos, Katie L Whytock, Timothy F Osborne, Steven R Smith.
      Women with PMOS (formally termed PCOS) have an overall increased prevalence of metabolic syndrome (MetS) and central obesity. To help determine whether there might be changes in s.c. adipose tissue (SAT) associated with these abnormalities, we performed single-nuclei and scRNA-seq on SAT biopsies from 15 premenopausal PMOS women with signs of insulin resistance and 17 healthy BMI-matched controls. In SAT from PMOS versus control we observed a higher ratio of fibrotic versus insulin sensitive adipocytes and a higher ratio of mesenchymal stem cells (MSCs) to preadipocytes. Further in silico analysis suggested that preadipocytes in PMOS are more inflammatory and have a reduced capacity for differentiation. Slit homolog 2 (SLIT2), which is expressed at higher levels in MSC from PMOS, decreased adipogenesis in cell culture assays likely through its interaction with the Roundabout homolog 1 and homolog 2 (ROBO1/2) receptor expressed on the surface of preadipocytes. These new observations are consistent with higher SLIT/ROBO signaling, leading to reduced differentiation in the SAT of PMOS as an underlying mechanism for the aberrant ectopic fat accumulation and the development of MetS in PMOS.
    Keywords:  Adipose tissue; Cell biology; Extracellular matrix; Human stem cells; Metabolism
    DOI:  https://doi.org/10.1172/jci.insight.199981
  7. Diabetes. 2026 Aug 14. pii: db251108. [Epub ahead of print]
    Human Loss-of-Function ZNRF3 Mutation Impairs Adipose Thermogenesis and Drives Subcutaneous Fat Expansion.
    Ningning Zhang, Peng Lu, Yangyi Tong, Zhiwen Cao, Yinmeng Zhu, Yujia Gong, Nan Yin, Ruikai Yang, Muye Tong, Na Chen, Yuxiao Zhao, Chao Wu, Qian Li, Zhongyun Zhang, Xinyuan Zhou, Dongqin Gu, Yansong Liu, Qianyun Cheng, Zhiguo Zhang, Jieli Lu, Yufang Bi, Yong Geng, Weiqing Wang, Guang Ning, Jie Hong, Weiqiong Gu, Ruixin Liu, Jiqiu Wang.
       ARTICLE HIGHLIGHTS: A rare loss-of-function variant in ZNRF3 (p.V228L) is enriched in individuals with obesity and is associated with increased subcutaneous white adipose tissue (sWAT) accumulation and lower fasting glucose levels. Both adipocyte-specific Znrf3 knockout and global variant knock-in impair sWAT browning, increase sWAT expansion, and improve glucose tolerance in mice. These findings establish ZNRF3 as a genetic regulator of fat distribution and thermogenic capacity, informing precise phenotyping of obesity. GWAS has implicated ZNRF3 in human fat distribution, yet its role in adipose tissue biology remains unknown.
    DOI:  https://doi.org/10.2337/db25-1108
  8. iScience. 2026 Aug 21. 29(8): 117028
    Intermittent fasting promotes remodeling of neural and vascular networks in visceral white adipose tissue.
    Nathaniel Vo, Annie Yew, Qiwei Zhang, Sean Jeong, Jacques Togo, Jin G Park, Hoon-Ki Sung.
      Intermittent fasting (IF) improves metabolic health, in part by remodeling white adipose tissue (WAT), yet the underlying mechanisms remain elusive. Here, we show that IF induces coordinated neurovascular remodeling in visceral WAT, marked by increased angiogenesis and sympathetic innervation. Using tissue clearing and three-dimensional imaging, we find that a 16-week IF regimen increases vascular density and sympathetic nerve fiber branching in perigonadal WAT. Transcriptomic profiling reveals the upregulation of neurotrophic factors, including neuregulin 4 (Nrg4), and browning-associated gene programs. WAT explants from IF-treated mice promote neurite branching in SH-SY5Y neuron-like cells, an effect blunted by ErbB inhibition. In vivo ErbB inhibition further attenuates IF-induced sympathetic remodeling. Human visceral adipose RNA-seq analysis shows a strong positive correlation between NRG4 expression and browning gene signatures. These findings support NRG4-ErbB signaling as a contributor to sympathetic remodeling, linking adipose neurotrophic signaling to metabolic benefits and therapeutic potential in obesity-related disorders.
    Keywords:  NRG4; adipose tissue remodeling; angiogenesis; intermittent fasting; neuregulin 4; sympathetic innervation
    DOI:  https://doi.org/10.1016/j.isci.2026.117028
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