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

IF 7 2区医学 Q1 ENDOCRINOLOGY & METABOLISM

Molecular Metabolism Pub Date : 2025-05-17 DOI:10.1016/j.molmet.2025.102169

Yingjiang Zhou , EunJu Bae , Simon S. Hoffman , Da Young Oh , Gordon I. Smith , Samuel Klein , Saswata Talukdar

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引用次数: 0

Abstract

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 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.

Conclusions

Our data suggests that macrophage-specific GPR65 signaling contributes to inflammation and the development of insulin resistance.

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g蛋白偶联受体65 （GPR65）的全身和造血细胞特异性缺失可改善饮食诱导肥胖小鼠的胰岛素敏感性。

慢性、低度炎症是肥胖诱导的胰岛素抵抗病因学的关键因素，肥胖中的促炎巨噬细胞极化促进了有害炎症微环境的发展。重要的是，免疫细胞增强的糖酵解和乳酸分泌导致细胞外空间变成酸性，代谢性酸中毒已被证明可以抑制胰岛素信号传导。在本研究中，我们研究了G蛋白偶联受体GPR65（一种细胞外pH感应蛋白）在调节胰岛素抵抗中的作用。我们观察到，与瘦人相比，代谢健康和不健康的肥胖受试者的脂肪组织（AT）中GPR65的表达升高，这与骨骼肌和肝脏胰岛素抵抗呈负相关。与这些观察结果一致，GPR65 KO小鼠在高胰岛素-血糖钳夹研究中表现出改善的胰岛素敏感性。此外，在GPR65 KO小鼠的肝脏中，我们观察到肝脏脂质含量降低，同时线粒体活性和脂肪酸β氧化增加。GPR65 KO小鼠骨骼肌Akt磷酸化升高，脂肪组织促炎基因表达抑制，血清细胞因子水平降低，提示GPR65缺失具有抗炎作用。GPR65 KO小鼠中巨噬细胞对AT的趋化性降低，骨髓来源树突状细胞炎症信号通路激活降低，进一步证实了这一点。重要的是，在钳夹研究中，造血谱系特异性GPR65 KO小鼠表现出改善的全身胰岛素敏感性，证明免疫细胞中的GPR65信号介导了这种作用。综上所述，我们的数据表明巨噬细胞特异性GPR65信号有助于炎症和胰岛素抵抗的发展。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Molecular Metabolism ENDOCRINOLOGY & METABOLISM-

CiteScore

14.50

自引率

2.50%

发文量

219

审稿时长

43 days

期刊介绍： Molecular Metabolism is a leading journal dedicated to sharing groundbreaking discoveries in the field of energy homeostasis and the underlying factors of metabolic disorders. These disorders include obesity, diabetes, cardiovascular disease, and cancer. Our journal focuses on publishing research driven by hypotheses and conducted to the highest standards, aiming to provide a mechanistic understanding of energy homeostasis-related behavior, physiology, and dysfunction. We promote interdisciplinary science, covering a broad range of approaches from molecules to humans throughout the lifespan. Our goal is to contribute to transformative research in metabolism, which has the potential to revolutionize the field. By enabling progress in the prognosis, prevention, and ultimately the cure of metabolic disorders and their long-term complications, our journal seeks to better the future of health and well-being.