| dc.description.abstract | Metabolically triggered inflammation is termed “meta-inflammation,” which underlies the pathological processes of many metabolic dysfunctions. In both inflammatory processes of chronic inflammation and bacterial endotoxin-induced acute inflammation, macrophages have been shown to exhibit critical regulatory activity at all stages of inflammatory tissue responses. The ghrelin receptor, a.k.a. growth hormone secretagogue receptor (GHS-R), mediates the stimulatory effects of ghrelin on food intake and fat deposition. In this study, we investigated the roles of macrophage GHS-R in macrophage programming and meta-inflammation under physiological and pathological conditions.
We generated myeloid-specific GHS-R knockout mice (LysM-Cre;Ghsrf/f) and tested the mice under different inflammatory conditions; normal physiological condition, lipopolysaccharide (LPS)-induced acute inflammatory condition, and high fat diet (HFD)-induced low grade chronic inflammatory condition. Under physiological conditions, myeloid-specific GHS-R did not alter body weight, tissue weight, or metabolic profile. Interestingly, systemic pro-inflammatory cytokines were down-regulated in RD-fed myeloid-specific GHS-R deleted mice. Therefore, we further studied the role of GHS-R under pathological conditions; LPS-induced acute inflammation and HFD-induced chronic inflammation. We found that myeloid-specific GHS-R deletion protects against LPS-induced lethal endotoxemia and pro-inflammation in serum and macrophages by reducing M1-macrophage polarization. In addition, myeloid-specific GHS-R deletion reduces hepatic inflammation in a paracrine manner. Under chronic inflammatory conditions, fewer infiltrated macrophages were found in epididymal white adipose tissue (eWAT) and liver of HFD-fed LysM-Cre;Ghsrf/f mice, which suggests a down-regulated inflammatory state in these tissues. Reduced lipolysis in eWAT and serum-free fatty acid (FFA) was detected in HFD-fed LysM-Cre;Ghsrf/f mice, which indicates ameliorated liver steatosis in HFD-feeding. The regulatory effect of macrophage GHS-R on hepatic inflammation was in a paracrine manner by reducing M1-macrophage polarization, which is regulated by IRS2-PI3Kδ-AKT2 through PKA-CREB. Consistent with the macrophage phenotype change, elevated mitochondrial respiration, fatty acid oxidation (FAO), and reduced glycolysis were detected in GHS-R deleted macrophages.
These findings reveal that GHS-R is an important immune-metabolic regulator of macrophages. GHS-R governs macrophage infiltration, polarization, and cellular metabolic-programming, thus moderating tissue inflammation and systemic insulin sensitivity. Our findings suggest that GHS-R antagonists may present a novel therapeutic strategy for metabolic disorders such as endotoxemia and insulin resistance. | en |
