bims-mimead 2026-04-19 papers

Issue of 2026–04–19
five papers selected by
Rachel M. Handy, University of Guelph

Am J Physiol Endocrinol Metab. 2026 Apr 16.

Exercise ameliorates adipose tissue insulin resistance by activating the lactate/GPR81 signaling pathway in DIO-IR mice.

Yihsuan Lin, Ge Song, Yue Chen, Chunyu Liang, Zhen Ni, Lijing Gong, Yi Yan.

Growing evidence indicates that both exogenous lactate administration and physical exercise improve insulin resistance (IR). This study investigates, from a novel perspective, whether exercise-induced lactate serves as a signaling molecule to ameliorate adipose tissue IR and explores the underlying mechanisms. Using diet-induced obese and insulin-resistant (DIO-IR) mice subjected to high-lactate exercise training, insulin-resistant 3T3-L1 (IR-3T3-L1) adipocytes treated with lactate, and a GPR81-overexpressing cell line, we demonstrate three key findings: First, high-lactate exercise training markedly alleviated adipose tissue and systemic IR in DIO-IR mice. Second, acute high-lactate exercise mirrored the effects of L-lactate injection by elevating circulating and epididymal white adipose tissue (eWAT) lactate concentrations, concomitantly upregulating GPR81 and glucose uptake signaling expression while modulating adipokine secretion. Mechanistically, lactate/GPR81 signaling potentiated glucose uptake in IR-3T3-L1 adipocytes via the IRS1-AKT-GLUT4 pathway. Collectively, these results demonstrate that exercise-induced lactate enhances glucose uptake signaling and rebalances adipokine secretion. It may act as a signaling molecule that upregulates the specific receptor GPR81, thereby alleviating adipose tissue and systemic insulin resistance in diet-induced obese insulin-resistant (DIO-IR) mice. Our findings uncover a previously unrecognized link between exercise metabolism and adipose tissue homeostasis, highlighting lactate as a potential therapeutic target for IR-related metabolic disorders.

Keywords: GPR81; adipose tissue; exercise; insulin resistance; lactate

DOI: https://doi.org/10.1152/ajpendo.00321.2025

J Vis Exp. 2026 Mar 27.

Modeling Adipocyte Insulin Resistance Using Mouse Subcutaneous Adipose Tissue-derived Stromal Vascular Fraction.

Mengyao Wan, Shuo Jiang, Xiaodi Liang.

Insulin resistance in adipose tissue is a central feature of metabolic disorders such as type 2 diabetes, yet many in vitro models rely on immortalized cell lines that incompletely reflect the cellular complexity of native adipose tissue. The goal of this protocol is to establish a reproducible and experimentally accessible method for modeling adipocyte insulin resistance using primary adipocytes derived from the stromal vascular fraction (SVF) of mouse subcutaneous adipose tissue. The protocol describes the isolation of SVF cells by enzymatic digestion, their adipogenic differentiation into lipid-laden mature adipocytes, and the subsequent induction of insulin resistance using dexamethasone. Insulin resistance is operationally defined and validated through functional and molecular readouts, including reduced insulin-stimulated glucose uptake and consumption, as well as decreased phosphorylation of key insulin signaling proteins in the PI3K-AKT pathway. By retaining SVF-derived cellular heterogeneity, this approach provides a primary-cell-based system that supports investigation of adipocyte insulin signaling under conditions that more closely approximate adipose tissue physiology than conventional cell lines. This protocol is intended for researchers seeking a standardized platform to study mechanisms of adipocyte insulin resistance or to evaluate metabolic interventions, while acknowledging that readouts reflect responses from a mixed SVF-derived culture rather than a purified adipocyte population.

DOI: https://doi.org/10.3791/69769

Cell Metab. 2026 Apr 14. pii: S1550-4131(26)00105-1. [Epub ahead of print]

The weight-loss-independent hepatoprotective benefits of semaglutide are orchestrated by intrahepatic sinusoidal endothelial GLP-1 receptors.

Maria J Gonzalez-Rellan, Cristina Riobello, Susanna Fang, Eloisa Martins da Silva, Jacqueline A Koehler, Rui Shang, Rola Hammoud, Xiemin Cao, Marta Varela-Rey, Daniel J Drucker.

Glucagon-like peptide-1 (GLP-1) medicines improve metabolic liver disease through weight-loss-dependent and -independent actions. Here, we interrogated semaglutide's action in mice with metabolic dysfunction-associated steatohepatitis (MASH). In Glp1rWnt1-/- mice resistant to GLP-1RA-induced weight loss, semaglutide improved steatosis, fibrosis, and immune remodeling. GEM-X Flex-seq localized Glp1r expression to pericentral liver sinusoidal endothelial cells (ECs) (LSECs) and CD8+ T cells. EC Glp1r deletion in Glp1rTie2-/- mice or AAV8-Cre-mediated hepatic EC Glp1r knockdown substantially abrogated semaglutide's hepatic benefits despite preserved weight loss. Transcriptomic profiling revealed that Glp1r+ LSECs adopt a stress-responsive phenotype in MASH that is reversed by semaglutide. Glp1r+ LSECs function as dominant contributors to semaglutide-regulated circuits linked to injury and repair involving VWF, SELE, CEACAM, and BMP. Molecular profiling revealed semaglutide-coordinated transcriptional and protein-level reversal of disease signatures. Together, the data using mouse models of MASH reveal an EC-specific, weight-loss-independent, semaglutide-regulated, GLP-1R-dependent intrahepatic network for improving liver health.

Keywords: GLP-1; LSEC; MASH; diabetes; inflammation; liver; obesity; semaglutide

DOI: https://doi.org/10.1016/j.cmet.2026.03.011

Trends Endocrinol Metab. 2026 Apr 15. pii: S1043-2760(26)00092-5. [Epub ahead of print]

A fuel partitioning perspective on appetite suppression by GLP-1 receptor agonists.

Mark I Friedman, Jens Lund.

Appetite suppression by glucagon-like peptide-1 receptor agonists (GLP-1RAs) is thought to result from direct actions on neural circuits controlling food intake. In this article, we (1) propose that a shift in fuel partitioning toward fat oxidation caused by GLP-1RAs contributes to appetite suppression and (2) explore potential lines of research to test this hypothesis.

Keywords: GLP-1 receptor agonists; fat oxidation; food intake; fuel partitioning; obesity

DOI: https://doi.org/10.1016/j.tem.2026.03.013

Nat Commun. 2026 Apr 11.

Adipocytes signal to recruit specific mRNAs from surrounding cells to restore expression deficits.

Clair Crewe, Christy M Gliniak, Toshiharu Onodera, Shiuhwei Chen, Jan-Bernd Funcke, May-Yun Wang, Snigdha Tiash, Yun-Ling Pai, Marjori Russo, Saket Awadhesbhai Patel, Ze Yu, Yi-Cian Zheng, Alex Larkin, Chao Xing, Laurent Gautron, Chun-Kan Chen, Chen Liu, Philipp E Scherer.

Extracellular vesicles (EVs) are nano-sized, membrane-delimited, particles released by cells that carry signaling macromolecules. A major pathway of EV production is potentiated by neutral sphingomyelinase 2 (SMPD3/nSMAse2), an enzyme that generates ceramide from sphingomyelin. In our attempt to study this pathway in adipocytes of male mice, we discover that the elimination of SMPD3 from adipocytes in vivo triggers a signal to surrounding immune cell-like preadipocytes to release EVs that carry SMPD3 mRNA. This results in a widespread increase in SMPD3 mRNA in purified null adipocytes without a change in the transcripts of other enzymes involved in ceramide metabolism. These results point to a selective mechanism by which specific mRNA molecules are acquired from the microenvironment to a level that can restore expression of mRNA and protein in a cell that is depleted of the corresponding genetic information.

DOI: https://doi.org/10.1038/s41467-026-71740-1