Nutrient-sensing growth hormone secretagogue receptor in macrophage programming and meta-inflammation

作者：Da Mi Kim, Jong Han Lee, Quan Pan, Hye Won Han, Zheng Shen, Sahar Eshghjoo, Chia‐Shan Wu, Wanbao Yang, Ji Yeon Noh, David W. Threadgill, Shaodong Guo, Gus A. Wright, Robert C. Alaniz, Yuxiang Sun · 发表于：Molecular Metabolism · 年份：2023 · DOI：10.1016/j.molmet.2023.101852 · 被引用次数：24 · 研究领域：Adipokines, Inflammation, and Metabolic Diseases、Regulation of Appetite and Obesity、Immune cells in cancer

Obesity-associated chronic inflammation, aka meta-inflammation, is a key pathogenic driver for obesity-associated comorbidity. Growth hormone secretagogue receptor (GHSR) is known to mediate the effects of nutrient-sensing hormone ghrelin in food intake and fat deposition. We previously reported that global GHSR ablation protects against diet-induced inflammation and insulin resistance, but the site(s) of action and mechanism are unknown. Macrophages are key drivers of meta-inflammation. To unravel the role of GHSR in macrophages, we generated myeloid-specific Ghsr knockout mice (LysM-Cre;Ghsrf/f). LysM-Cre;Ghsrf/f and control Ghsrf/f mice were subjected to 5 months of high-fat diet (HFD) feeding to induce obesity. In vivo, metabolic profiling of food intake, physical activity, and energy expenditure, as well as glucose and insulin tolerance tests (GTT and ITT) were performed. At termination, peritoneal macrophages (PMs), epididymal white adipose tissue (eWAT), and liver were analyzed by flow cytometry and histology. For ex vivo studies, bone marrow-derived macrophages (BMDMs) were generated from the mice and treated with palmitic acid (PA) or lipopolysaccharide (LPS). For in vitro studies, macrophage RAW264.7 cells with Ghsr overexpression or Insulin receptor substrate 2 (Irs2) knockdown were studied. We found that Ghsr expression in peritoneal macrophages was increased under HFD feeding. In vivo, HFD-fed LysM-Cre;Ghsrf/f mice exhibited significantly attenuated systemic infl...