Chronic low-grade inflammation is a hallmark of obesity, which is directly linked to nonalcoholic Fatty Liver Disease (NAFLD) and systemic insulin resistance. Ghrelin receptor, a growth hormone secretagogue receptor (GHS-R), mediates the stimulatory effect of ghrelin on food intake and fat deposition. We previously reported that global ablation of GHS-R in mice decreases adipose inflammation, and GHS-R knockdown in macrophage cell line reduces the expression of pro-inflammatory cytokine genes. To determine the physiological role of GHS-R in macrophages, we generated myeloid-specific GHS-R knockout mice (LysM-Cre;Ghsrf/f). Under diet-induced obesity (DIO), LysM-Cre;Ghsrf/f mice showed reduced circulating inflammatory cytokine levels, attenuated insulin resistance, but no change in body weight. Moreover, DIO-induced NAFLD was ameliorated in LysM-Cre;Ghsrf/f mice, showing reduced inflammation and lipid accumulation in the liver. To understand the regulatory mechanism of macrophage GHS-R in NAFLD pathogenesis and systemic inflammation and insulin sensitivity, we conducted ex vivo studies using bone marrow-derived macrophages (BMDMs). GHS-R deficient BMDMs showed reduced macrophage pro-inflammatory polarization and decreased expression of pro-inflammatory cytokine genes; consistently, exhibiting elevated mitochondrial respiration and improved mitochondrial dynamics. Moreover, the primary hepatocytes treated with conditioned media from BMDMs of LysM-Cre;Ghsrf/f mice showed gene expression of reduced inflammatory cytokines and increased insulin signaling. Taken together, our findings reveal that GHS-R is an important immunometabolic regulator and governs macrophage polarization through regulating mitochondrial function and cellular metabolism of macrophages, moderating hepatic and systemic inflammation and insulin sensitivity. GHS-R antagonist may present a novel therapeutic strategy for the metabolic disorders such as NAFLD.
D. Kim: None. J. Lee: None. Q. Pan: None. J. Noh: None. H. Wang: None. H. Han: None. C. Wu: None. S. Guo: None. Y. Sun: None.
American Diabetes Association (1-15- BS-177 to Y.S.); National Institutes of Health