2019 - 2023
Obesity promotes chronic inflammation in peripheral tissues such as adipose tissue and liver, which leads to a wide range of metabolic dysfunctions, a phenomenon called â€œmeta-inflammationâ€. Macrophages are key immune-modulators of meta-inflammation, comprised of two subtypes: the pro-inflammatory M1 and anti-inflammatory M2. Reprograming macrophage polarization is thought to have great potential for treatment of obesity-induced inflammation and metabolic dysfunctions. However, the regulatory mechanisms of macrophage polarization are not well understood. Gut hormone ghrelin is differentially regulated by different type of nutrients, and it increases obesity and insulin resistance. G-protein-coupled receptor Growth hormone secretagogue receptor (GHS-R) is a known ghrelin receptor. Our studies with GHS-R global deletion mice have shown that GHS-R is an essential metabolic regulator; its signaling activation is indicative of systemic metabolic and inflammatory state. We have reported that GHS-R ablation protects against diet-induced obesity and insulin resistance in aging. We also have evidence that GHS-R has cell-autonomous effect in macrophages, and knockdown of GHS-R shifts macrophages toward M2 spectrum. In this proposal, we hypothesize that GHS-R is a key sensor and regulator of macrophages; in response to metabolic/inflammatory insults, GHS-R metabolically reprograms macrophages toward pro-inflammatory polarization, which subsequently leads to inflammation and lipid accumulation in adipose tissue and liver. We will unravel the roles and pertinent mechanisms of GHS-R in macrophage polarization using our newly-generated myeloid-specific GHS-R knockout mice. The following comprehensive and complementary Specific Aims will be conducted: 1. Determine whether GHS-R promotes pro-inflammatory polarization of macrophages, and increases inflammation and lipid deposition in adipose tissue and liver (in vivo studies). 2. Examine whether GHS-R regulates macrophage polarization via cell-autonomous action, and promotes inflammation of adipocytes and hepatocytes via paracrine action (ex vivo studies). 3. Investigate molecular mechanisms involved in GHS-R mediated macrophage polarization. We postulate that GHS-R metabolically reprograms macrophages; GHS-R, via insulin signaling, modulates signaling pathways governing fatty acid oxidation, glucose metabolism, and mitochondrial function. This proposal will shed light on a new paradigm for regulating macrophage phenotypic switch, and likely uncover a novel regulatory mechanism linking nutrient sensing, inflammation and metabolism. This proposal will also provide â€œproof-of-conceptâ€ evidence on whether targeting GHS-R in macrophages would be a unique and powerful strategy for combating obesity and inflammation.