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

Evidence from laboratory and animal studies provides groundwork for understanding mechanisms and potential before human studies continue.

• Level A · Stronger Clinical Evidence
• Level B · Emerging clinical evidence with positive signals
• Level C · Early human research exploring benefits
• Level D · Scientific groundwork from lab and animal studies
• Emerging · Emerging topic under active research

Abstract (original English)

Objective 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. Methods 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. Results 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 m

Evidence level

Evidence from laboratory and animal studies provides groundwork for understanding mechanisms and potential before human studies continue.

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