Ghrelin Receptor in Macrophages: A Key Mediator of Both Non-shivering Thermogenesis in Brown Fat and Adipose Inflammation in White Fat?
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Obesity is a major cause of insulin resistance (reduced responsiveness to insulin), which leads to diabetes. There are two types of fat: white fat stores energy and brown fat burns energy. Brown fat is recently found in adult humans, and declining of heat production in brown fat leads to obesity. Macrophages (a type of immune cells) are linked to obesity and insulin resistance. Recent studies show that anti-inflammatory macrophages promote heat production in brown fat. Increasing brown fat heat-producing ability by enhancing anti-inflammatory macrophages could be a novel means to combat obesity. Ghrelin is a circulating hormone known to stimulate appetite and promote obesity. Ghrelin's effect is mediated by its receptor, GHS-R. We made a "global GHS-R null" mouse model with the ghrelin receptor deleted in all tissues. Our data showed that these "null" mice are lean and more insulin-responsive. More interestingly, we have found that the null mice have more anti-inflammatory macrophages and generate more heat in brown fat. We hypothesize that GHS-R deletion activates anti-inflammatory macrophages, which in turn increases heat production in brown fat and decreases inflammation in white fat. This proposal will investigate the direct effects of GHS-R in macrophages, as well as its associated effects in brown and white fat. The studies in this proposal will allow us to determine whether obesity can be attenuated by suppressing GHS-R expression in macrophages, and gain insight to whether GHS-R blockers have the potential to be a new class of anti-obesity drug.........