bims-mimead Biomed News
on Adipose tissue and metabolic disease
Issue of 2026–03–15
six papers selected by
Rachel M. Handy, University of Guelph
  1. Defining the vascular niche of human adipose tissue across metabolic states.
  2. Immune cells regulate circulating adipocyte extracellular vesicle levels in response to metabolic shifts.
  3. A druggable redox switch on SHP1 controls macrophage inflammation.
  4. Plasma GDF15 increases during hyperinsulinemic hypoglycemia in humans with post-bariatric hypoglycemia and after insulin exposure in mice.
  5. Gut Microbiota-Derived Extracellular Vesicles in Patients With Obesity Undergoing Gastric Bypass Surgery.
  6. Vagal Activity and Fat Oxidation Basal Correlates in Older Active Postmenopausal Women: A Cross-Sectional Study.
  1. Nat Metab. 2026 Mar 12.
    Defining the vascular niche of human adipose tissue across metabolic states.
    Ibrahim AlZaim, Mohamed N Hassan, Maja Schröter, Luca Mannino, Katarina Dragicevic, Marie Balle Sjogaard, Joseph Festa, Lolita Dokshokova, Sophie Weinbrenner, Blanca Tardajos Ayllon, Bettina Hansen, Rikke Kongsgaard Rasmussen, Julie N Christensen, Olivia Wagman, Ruby Schipper, Min Cai, Wouter Dheedene, Anja Bille Bohn, Jean Farup, Lin Lin, Samuele Soraggi, Anna Dalsgaard Thorsen, Amanda Bæk, Henrik Holm Thomsen, Maximilian von Heesen, Lena-Christin Conradi, Paul Evans, Carolina E Hagberg, Joerg Heeren, Margo Emont, Evan D Rosen, Aernout Luttun, Anders Etzerodt, Lucas Massier, Mikael Rydén, Niklas Mejhert, Matthias Blüher, Konstantin Khodosevich, Robert A Fenton, Bilal N Sheikh, Niels Jessen, Laura P M H de Rooij, Joanna Kalucka.
      Adipose tissue homeostasis depends on an intact vascular network that ensures adequate nutrient delivery and immune regulation. In obesity, vascular dysfunction, particularly within endothelial cells (ECs), contributes to inflammation and metabolic disease progression, yet the cellular organization of the human adipose vasculature remains poorly defined. Here we show, using single-cell RNA sequencing of nearly 70,000 vascular cells from human subcutaneous adipose tissue of 65 individuals, that the adipose vasculature is highly heterogeneous and consists of seven canonical EC subtypes. In addition, we identify a distinct population of ECs that display mixed endothelial, mesenchymal, adipocytic and immune transcriptional features. Computational analyses and whole-mount imaging support their presence and suggest that they emerge through endothelial-to-mesenchymal transition. Comparative analyses further reveal inflammatory and fibrotic vascular signatures in obesity and type 2 diabetes. Together, this atlas delineates the cellular complexity of the human adipose vasculature and highlights its contribution to metabolic disease.
    DOI:  https://doi.org/10.1038/s42255-026-01475-2
  2. Cell Metab. 2026 Mar 10. pii: S1550-4131(26)00051-3. [Epub ahead of print]
    Immune cells regulate circulating adipocyte extracellular vesicle levels in response to metabolic shifts.
    Snigdha Tiash, Saket Awadhesbhai Patel, Marjori Russo, Anusha Suresh, Bo Pang, Yun-Ling Pai, Wentong Jia, Rachael L Field, Terri Pietka, Nada A Abumrad, Gordon I Smith, Dmitri Samovski, Samuel Klein, Jonathan R Brestoff, Clair Crewe.
      Extracellular vesicles (EVs) are now recognized as potent mediators of inter-organ signaling and are implicated in the pathogenesis of obesity and associated comorbidities. Despite a recent surge in functional information about EVs, we still lack a basic understanding of how endogenous EV levels are controlled to regulate inter-organ signaling. New flow cytometry technologies have allowed us to study the regulation of circulating endogenous EVs from metabolically relevant cell types such as adipocytes (adipocyte-derived EVs [adipoEVs]). We provide evidence for a paradigm of EV regulation in which tissue-resident immune cells, predominantly macrophages, clear EVs released by local tissue cells or those entering the tissue from circulation, an activity that determines circulating EV levels. In obesity, EV uptake by adipose tissue immune cells is reduced, leading to increased circulating adipoEVs and reduced adipoEV clearance rates. This work shows that tissue immune cells gate tissue EV entry into the circulation, making them key regulators of inter-organ EV signaling.
    Keywords:  adipocyte; exosomes; extracellular vesicles; insulin resistance; inter-organ signaling; macrophage; mitochondria; obesity; spectral flow cytometry; type 2 diabetes
    DOI:  https://doi.org/10.1016/j.cmet.2026.02.008
  3. Nat Chem Biol. 2026 Mar 12.
    A druggable redox switch on SHP1 controls macrophage inflammation.
    Mei Ying Ng, Meredith N Nix, Guangyan Du, Ivan Davidek, Nils Burger, Sanghee Shin, Sean Toenjes, Haruna Takeda, Megan Cheah Xin Yan, Bingsen Zhang, Haopeng Xiao, Shelley M Wei, Hyuk-Soo Seo, Sirano Dhe-Paganon, Thomas E Wales, John R Engen, Evanna L Mills, Jianwei Che, Tinghu Zhang, Nathanael S Gray, Edward T Chouchani.
      Immunological proteins are major disease targets, yet most remain undrugged. Post-translational redox modification of cysteine residues has emerged as an important mode of immune cell regulation, particularly in macrophage cytokine responses. Here we develop a strategy for systematic discovery and small-molecule functionalization of redox-regulated cysteines on immunological proteins. Using deep redox proteomics, we annotate 788 in vivo redox-regulated cysteines across diverse immune-relevant protein domains. We demonstrate how these sites enable cysteine-directed pharmacology through discovery of a novel cysteine activation site on the immune regulator SHP1. Targeting C102, we develop a highly selective covalent agonist, SCA, which binds the N-SH2 domain to relieve autoinhibition and activate SHP1. In mouse and human macrophages, SCA selectively engages SHP1 C102, antagonizing interleukin-1 receptor-associated kinase signaling and lipopolysaccharide-induced proinflammatory cytokine production. Together, this work identifies a druggable cysteine redox switch controlling macrophage cytokine responses and provides a compendium of redox-regulated sites for therapeutic development.
    DOI:  https://doi.org/10.1038/s41589-026-02163-8
  4. Cell Rep Med. 2026 Mar 09. pii: S2666-3791(26)00073-X. [Epub ahead of print] 102656
    Plasma GDF15 increases during hyperinsulinemic hypoglycemia in humans with post-bariatric hypoglycemia and after insulin exposure in mice.
    Rafael Ferraz-Bannitz, Lei Pei, Hanna Wang, Berkcan Ozturk, Pilar Casanova Querol, Alessandra Gonçalves da Cruz, Tyler M Cook, Hamayle Saeed, Leila Osterwalder, Lindsay Poulos, Hany Saifeldin, Cameron Cummings, Maryam Farahmandsadr, Alessandra Amore, Amanda Sheehan, Donald C Simonson, Darleen A Sandoval, Mary-Elizabeth Patti.
      Post-bariatric hypoglycemia (PBH), characterized by excessive postprandial incretin and insulin secretion, is a common complication of bariatric surgery. Here, we investigate the relationship between PBH and growth differentiation factor 15 (GDF15) in individuals with PBH after Roux-en-Y gastric bypass (RYGB), post-RYGB individuals who remain asymptomatic (Asx), and individuals with overweight/obesity but without history of surgery (Ow/Ob). Fasting plasma GDF15 is higher in PBH vs. Ow/Ob and further increases postprandially, coinciding with hypoglycemia symptoms. During a hyperinsulinemic hypoglycemic clamp, GDF15 progressively increases in PBH and correlates with hypoglycemia survey symptoms, including weakness, difficulty concentrating, feeling cold, and tingling lips. In mice, insulin-induced hypoglycemia also results in elevated GDF15 levels, and exogenous recombinant GDF15 (rGDF15) reduces food intake in response to hypoglycemia. Our data suggest that GDF15 modulates the counterregulatory response to hypoglycemia in both PBH individuals and mice and that elevated GDF15 levels contribute to hypoglycemia-related postprandial symptoms. This study was registered at ClinicalTrials.gov (NCT04428866).
    Keywords:  GDF15; counterregulatory response; hypoglycemia; hypoglycemia symptoms; post-bariatric hypoglycemia
    DOI:  https://doi.org/10.1016/j.xcrm.2026.102656
  5. Mol Microbiol. 2026 Mar 12.
    Gut Microbiota-Derived Extracellular Vesicles in Patients With Obesity Undergoing Gastric Bypass Surgery.
    Jenni Hekkala, Anna Kaisanlahti, Mysore V Tejesvi, Jenni Turunen, Nikke Virtanen, Sonja Karikka, Pande Putu Erawijantari, Anatoliy Samoylenko, Genevieve Bart, Seppo Vainio, Leo Lahti, Janne Hukkanen, Terhi Ruuska-Loewald, Vesa Koivukangas, Justus Reunanen.
      Human gut microbiota is associated with obesity. Gut microbiota-derived extracellular vesicles (EVs), lipid coated nanoparticles secreted by bacteria, have been suggested as a communication mechanism between gut microbiota and the host. This study characterized the effect of Roux-en-Y gastric bypass (RYGB) on gut microbiota and gut microbiota-derived EVs in patients with obesity. Fecal samples were collected from 30 recruited patients at baseline and 6 months after surgery. EVs were isolated from fecal samples, and their origin and protein content were analyzed. The number of unique proteins was increased in gut microbiota-derived EVs after the surgery as compared to baseline. A significant difference in both microbiota composition (p = 0.001; PERMANOVA) and microbiota-derived EVs (p = 0.001; PERMANOVA) was observed in response to surgery. Based on 16S rRNA gene sequencing data, a random forest classifier accurately classified both gut microbiota (AUC = 0.93) and EVs (AUC = 0.80) to baseline and after surgery groups. This study found that gastric bypass surgery altered both the composition and characteristics of gut microbiota and gut microbiota-derived EVs in patients with obesity. Thus, gut microbiota-derived EVs may play a role in obesity and influence the health effects of bariatric surgery beyond the gut. Trial Registration: ClinicalTrials.gov identifier: NCT00950003.
    Keywords:  extracellular vesicles; gastric bypass surgery; gut microbiota; nanoparticles; obesity
    DOI:  https://doi.org/10.1111/mmi.70064
  6. Sports Med Open. 2026 Mar 12. pii: 29. [Epub ahead of print]12(1):
    Vagal Activity and Fat Oxidation Basal Correlates in Older Active Postmenopausal Women: A Cross-Sectional Study.
    Jordi Monferrer-Marín, Ainoa Roldán, Jørn Wulff Helge, Cristina Blasco-Lafarga.
       BACKGROUND: Heart Rate Variability at rest has been recently associated with metabolic outcomes alongside exercise, which in turn have been associated with energy expenditure, muscle power and fat mass. This study aimed to analyse the relationship at rest between autonomic function and metabolic outcomes, in physically active postmenopausal women. We hypothesised that, autonomic function is more strongly associated with Fat oxidation than basal metabolic rate. In sixty-one active postmenopausal women (67.9 ± 5.3 years; 40.3 ± 4.3 kg muscle mass) basal metabolic rate and Heart Rate Variability analysis was recorded simultaneously for 30 min with participants resting supine under standardised activity and diet conditions.
    RESULTS: Root Mean Square of Successive Differences of heart beats (RMSSD) and Total power showed a predictive value for resting Fat oxidation (β = 0.46; β = 0.26), explaining 30% of the variance. Including traditional predictors such as energy expenditure increased explained variance to 57.5%. In this model, RMSSD association disappeared, Total power (β = 0.88) became the strongest predictor, and together with energy expenditure (β = 0.53), showed significant associations with FATox. Respiratory exchange ratio only correlated with RMSSD (β = - 0.54) in the isolated Heart Rate Variability model, without basal metabolic rate associations. Box plots of RMSSD quartiles revealed a difference in fat-oxidation between the highest and lowest quartiles, a pattern not seen for Total power.
    CONCLUSION: Baroreflex activity and fat oxidation associate at rest in active postmenopausal women with preserved cardiovascular function. Total power emerges as the strongest Heart Rate Variability predictor of baseline Fat oxidation in the multivariable models. Stratification by RMSSD quartiles revealed graded differences in fat oxidation rates across levels of vagal modulation.
    TRIAL REGISTRATION: Clinical Trials, NCT06336070. https://clinicaltrials.gov/study/NCT06336070 Registered: 4 April 2024.
    Keywords:  Autonomic nervous system; Baroreflex; Energy expenditure; Heart rate variability; Metabolic flexibility; Total power; Vagus nerve
    DOI:  https://doi.org/10.1186/s40798-026-01004-1
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