Whole body and hematopoietic cell-specific deletion of G-protein coupled receptor 65 (GPR65) improves insulin sensitivity in diet-induced obese mice

• Published in: Molecular metabolism (Germany) Vol. 97; p. 102169
• Main Authors: Zhou, Yingjiang, Bae, EunJu, Hoffman, Simon S., Oh, Da Young, Smith, Gordon I., Klein, Samuel, Talukdar, Saswata
• Format: Journal Article
• Language: English
• Published: Germany Elsevier GmbH 01.07.2025; Elsevier
• Subjects: Adipose Tissue - metabolism; Animals; Diet, High-Fat - adverse effects; GPR65; Humans; Hyperinsulinemic-euglycemic clamp; Inflammation; Insulin resistance; Insulin Resistance - genetics; Insulin Resistance - physiology; Liver - metabolism; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Obese; Muscle, Skeletal - metabolism; Obesity; Obesity - metabolism; Original; Receptors, G-Protein-Coupled - genetics; Receptors, G-Protein-Coupled - metabolism; Signal Transduction; Obesity; Insulin resistance; Inflammation; Hyperinsulinemic-euglycemic clamp; GPR65
• ISSN: 2212-8778; 2212-8778
• DOI: 10.1016/j.molmet.2025.102169

Acidic extracellular microenvironments, resulting from enhanced glycolysis and lactic acid secretion by immune cells, along with metabolic acidosis may interfere with the insulin signaling pathway and contribute to the development of insulin resistance. In the present study, we investigated the role of G protein-coupled receptor GPR65, an extracellular pH sensing protein, in modulating insulin resistance. We measured GPR65 expression in the adipose tissue (AT) of subjects with varying metabolic health states. We utilized whole-body and hematopoietic cell-specific GPR65 knockout (KO) mice to investigate the mechanism underlying the associations between GPR65, inflammatory response, and insulin resistance. Elevated GPR65 expression was observed in the AT of subjects with obesity, compared to their lean counterparts, and was inversely correlated with insulin resistance. In GPR65 KO mice, improved insulin sensitivity and decreased hepatic lipid content were observed, attributed to concomitant increases in mitochondrial activity and fatty acid β-oxidation in liver. GPR65 KO mice also exhibited increased Akt phosphorylation in skeletal muscle, suppressed proinflammatory gene expression in AT, and decreased serum cytokine levels, collectively suggesting the anti-inflammatory effects of GPR65 depletion. This was further confirmed by observations of decreased macrophage chemotaxis towards AT in vitro, and depressed inflammatory signaling pathway activation in bone marrow-derived dendritic cells from GPR65 KO mice. Additionally, hematopoietic lineage-specific GPR65 KO mice exhibited improved whole body insulin sensitivity in clamp studies, demonstrating GPR65 signaling in immune cells mediates this effect. Our data suggests that macrophage-specific GPR65 signaling contributes to inflammation and the development of insulin resistance. •In humans, GPR65 expression is increased in individuals with obesity, and inversely correlated with insulin sensitivity.•GPR65 KO improves whole-body insulin sensitivity in mice on high-fat diet.•GPR65 KO drives anti-inflammatory macrophage polarization and reduces chemotaxis.•GPR55 KO in hematopoietic cells is sufficient to improve insulin sensitivity in mice on high-fat diet.