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 ?meta-inflammation?. Macrophages are key immune-modulators of meta-inflammation, comprised of 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. Growth hormone secretagogue receptor (GHS-R), is known to bind to nutrient-sensing obesogenic gut hormone ghrelin. 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 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. We hypothesize that GHS-R is a key regulator of macrophage polarization; GHS-R reprograms macrophages toward pro-inflammatory state under diet-induced obesity, leading 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 and re-expression mice. The following comprehensive and complementary Specific Aims will be conducted:
Aim 1. Determine whether macrophage GHS-R promotes pro-inflammatory polarization of macrophages under diet-induced obesity, increasing inflammation and lipid deposition in adipose tissue and liver (In vivo studies).
Aim 2. Examine whether GHS-R controls macrophage polarization via cell-autonomous action, and promotes inflammation in adipocytes and hepatocytes via paracrine action (Ex vivo studies).
Aim 3. Investigate molecular mechanisms by which GHS-R regulates macrophage polarization. We anticipate that GHS-R has a crucial role in macrophage polarization and meta-inflammation in adipose tissues and liver. Specifically, we predict that GHS-R, via insulin signaling, reprograms signaling pathways of fatty acid oxidation and glycolysis, in turn regulating the expression of pro-inflammatory cytokines. 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 ?proof-of-concept? evidence whether targeting GHS-R in macrophages would be an unique and powerful strategy for combating obesity and inflammation.
Obesity is associated with chronic inflammation in adipose tissue and liver. We have shown that global ablation of GHS-R promotes macrophage phenotypic switch toward an anti-inflammatory state, and attenuates diet-induced adipose tissue inflammation and steatohepatitis. The goal of this proposal is to understand the roles and underpinning mechanisms of GHS-R in macrophage polarization, and delineate effects of macrophage GHS-R on metabolic functions of peripheral tissues.