bims-mimead 2026-04-05 papers

Issue of 2026–04–05
four papers selected by
Rachel M. Handy, University of Guelph

Nat Metab. 2026 Apr 03.

Irisin ameliorates obesity and insulin resistance via adipose tissue IL-33 and regulatory T cells.

Mu A, Gang Wang, Nathan W Zammit, Laura Roth, Yasheng Maierhaba, Dina Bogoslavski, Chufan Cai, P Kent Langston, Qiuyang Zhang, Inna S Afonina, Rudi Beyaert, Bruce M Spiegelman, Diane Mathis.

Irisin is an exercise-induced myokine that confers multiple physiological benefits, including browning of subcutaneous adipose tissue in mice. However, the underlying cellular and molecular mechanisms of irisin's effects on obesity are unclear. Here, we show that irisin modulates adipose tissue inflammation by increasing interleukin (IL)-33 production and preserving ST2+ regulatory T cells in white adipose tissues. Administered chronically to high-fat-diet-fed male mice, irisin preserves visceral adipose tissue (VAT) levels of ST2+ regulatory T cells, an important immunomodulatory population that usually contracts after long-term high-fat-diet feeding. This protection results from increases in IL-33-producing mesenchymal stromal cells and IL-33 levels in VAT. These effects are primary, as irisin directly induces IL-33 expression in cultured VAT mesenchymal stromal cells. Irisin-mediated changes in VAT IL-33 dynamics are accompanied by IL-33-dependent upregulation of thermogenic gene expression in subcutaneous adipose tissue. These irisin-driven cell-cell and inter-tissue interactions improve obesity and glucose intolerance, and increase energy expenditure, with no reduced food intake and muscle loss in obese mice.

DOI: https://doi.org/10.1038/s42255-026-01491-2

Obesity (Silver Spring). 2026 Mar 31.

Adipose Tissue-Targeted Delivery of Rosiglitazone With Iron Oxide Nanoparticles Ameliorates Insulin Resistance in Male Mice.

Jakob E Ostberg, Zeeshan Ahmed, Katayoun Saatchi, Parleen K Pandher, Yamna Rahim, Urs O Häfeli, Sarah L Gray.

OBJECTIVE: This study aimed to assess iron oxide magnetic nanoparticles (MNPs) for adipose tissue-targeted therapeutics to restore adipose tissue function and insulin sensitivity in obesity.
METHODS: The insulin-sensitizing effects of rosiglitazone and known adverse effects were leveraged for this proof-of-concept assessment of adipose tissue drug targeting. Rosiglitazone was adsorbed to alendronic acid-coated MNPs (rosiMNPs) and a biocompatible magnet implanted in the right inguinal white adipose tissue (ingWAT) of obese, insulin resistant male mice. Following rosiMNP treatment (1.5 mg/kg/day, 18 days), insulin sensitivity and adipose tissue health were assessed.
RESULTS: RosiMNPs restored insulin sensitivity as well as systemic rosiglitazone (1.5 mg/kg/day, 18 days), with a shift in adipocyte size compatible with PPARγ-induced adipocyte hyperplasia and no increase in circulating adiponectin. PPARγ target genes were induced in ingWAT with rosiMNPs or systemic rosiglitazone, but only in liver and gonadal WAT of systemically treated mice. Additionally, iron accumulation was shown in the right, targeted ingWAT depot, but not in the left, untargeted ingWAT, kidney, or liver, suggesting targeting was achieved. Unfortunately, the dose and duration of systemic treatment were ineffective at inducing changes in kidney.
CONCLUSIONS: Results demonstrate the potential benefits of adipose tissue-targeted therapeutics to improve adipose tissue function to restore insulin sensitivity to prevent the metabolic complications of obesity.

Keywords: PPAR gamma; adipose tissue; insulin resistance; nanotechnology; obesity

DOI: https://doi.org/10.1002/oby.70182

Mol Metab. 2026 Apr 01. pii: S2212-8778(26)00045-1. [Epub ahead of print] 102361

Extracellular vesicles carrying surface-anchored adiponectin prevent obesity-related metabolic complications by enhancing insulin sensitivity.

Adiponectin (Adpn) is a potent insulin-sensitizing adipokine with therapeutic promise for type 2 diabetes (T2D) and metabolic dysfunction-associated steatohepatitis (MASH). Its clinical use is limited by challenges in producing stable, bioactive high-molecular weight forms. Adipocyte-derived extracellular vesicles (EVs) naturally carry oligomeric Adpn on their surface, enhancing hormone stability and activity. Here, we engineered EVs displaying membrane-anchored Adpn (EVPP-Adpn) and control EVs lacking Adpn (EVCTL), and evaluated their metabolic effects in high fat diet (HFD)-induced obesity mice. EVPP-Adpn were purified from HEK293T cells stably transfected with a chimeric Adpn fused to a transmembrane domain and a pilot peptide (PP) directing it to EVs ; EVCTL were produced from non-transfected cells. HFD-fed male and female mice received intraperitoneal EV injections for six weeks. EVPP-Adpn improved glucose tolerance and insulin sensitivity, promoted adipocyte lipid storage through insulin-regulated lipogenesis and alleviated MASH features (liver steatosis, inflammation and fibrosis). EVPP-Adpn lowered circulating ceramides and reduced FGF21, indicating improved hepatic metabolism, and activated AKT and AMPK pathways in liver and skeletal muscle, consistent with increased adiponectin signaling. These results demonstrate that surface-anchored Adpn EVs restore tissue-specific insulin signaling and improve obesity-related metabolic dysfunctions, highlighting their potential as a novel biotherapeutic strategy for T2D and MASH.

Keywords: Extracellular vesicles; MASH; MASLD; bioengineering; exosomes; obesity; type 2 diabetes

DOI: https://doi.org/10.1016/j.molmet.2026.102361

Diabetes. 2026 Mar 30. pii: db251132. [Epub ahead of print]

LEAP2 Reduces Ad Libitum Food Intake and Attenuates Postprandial Glucose Excursions in Men With Obesity.

Anders Englund, Andreas H Lange, Christoffer A Hagemann, Hüsün S Kizilkaya, Mette M Rosenkilde, Bolette Hartmann, Jens J Holst, Flemming Dela, Asger B Lund, Lærke S Gasbjerg, Filip K Knop.

The naturally occurring peptide, liver-expressed antimicrobial peptide 2 (LEAP2), has gained interest as a ghrelin receptor antagonist. We previously reported reduced food intake and plasma glucose-lowering effects of LEAP2 infusion in lean healthy men; however, the effects of this competitive antagonist and inverse agonist of the ghrelin receptor in men with obesity have not been investigated. In the current study, 20 men with obesity were enrolled in a randomized, double-blind, placebo-controlled, crossover study comprising two experimental visits, each involving a ∼5-h intravenous infusion of LEAP2 (infusion rate 40 pmol/kg/min) or placebo during which a liquid mixed meal test and a subsequent ad libitum meal test were performed. The LEAP2 infusion resulted in a fivefold increase in plasma concentrations of LEAP2 compared with placebo. The infusion lowered postprandial plasma glucose levels and reduced ad libitum food intake by ∼12%. We conclude that a continuous intravenous LEAP2 infusion reduces glycemia and food intake in men with obesity, supporting further exploration of LEAP2's therapeutic potential in obesity and related metabolic conditions.
ARTICLE HIGHLIGHTS: Liver-expressed antimicrobial peptide 2 (LEAP2), a ghrelin receptor antagonist and inverse agonist, reduces food intake and improves markers of dysmetabolism in preclinical studies and in lean men; however, the effects of LEAP2 in obesity is unknown. We investigated the effects of exogenous LEAP2 on ad libitum food intake and metabolic parameters in men with obesity. We found that LEAP2 reduces ad libitum food intake and reduces postprandial plasma glucose concentration, revitalizing the ghrelin receptor as a potential target in the treatment of obesity and its related conditions.

DOI: https://doi.org/10.2337/db25-1132