Mechanistic characterization of the anti-inflammatory function of thermogenic fat for the treatment of metabolic disorders

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PROJECT SUMMARY: Obesity and associated “meta-inflammation” are major risk factors for type-2 diabetes, cardiovascular disease, non-alcoholic fatty liver disease (NAFLD) and cancers. Visceral “white” adiposity drives these deadly sequelae of obesity. In contrast, thermogenic “brown” and “beige” adipose can uniquely catabolize stored fat, and are potently anti-obesogenic. The anti-obesity activity of thermogenic adipocytes requires activation by peripheral signals, and the identification of these signals is key to leveraging the therapeutic potential of these cells. Such thermogenic adipose is also thought to be anti-inflammatory but the mechanistic basis of this is unclear. Understanding the mechanisms that promote this anti-inflammatory function of thermogenic fat would have major therapeutic potential. Thermogenic fat is rich in mitochondria which produce a vast array of metabolites, many of which possess signaling capacity. Interestingly the tricarboxylic acid intermediate succinate is an important signaling molecule that controls both thermogenic adipose function and inflammation. I identified that thermogenic fat has a unique capacity to sequester succinate from the extracellular milieu (through an undefined mechanism) to promote thermogenesis; while immune cells express a G-protein coupled receptor (termed succinate receptor 1), the ligation of which is potently pro-inflammatory. I hypothesize that activation of thermogenic adipose tissue will promote an anti-inflammatory phenotype by altering the levels of important signaling metabolites, such as succinate, that are known to regulate immune cell function. Moreover, I predict manipulation of these signals will aid in the treatment of metabolic disease. Objectives: 1) What is the succinate transport mechanism in thermogenic fat? 2) Can thermogenic fat limit circulating succinate and inflammation in obesity-driven pathologies? 3) Can we manipulate thermogenic fat to modify the pathology of NAFLD? This work will use both in vitro primary brown fat cell culture and in vivo models of visceral adipose expansion and thermogenesis. This will be coupled with liquid-chromatography/mass spectrometry (LCMS), genetic manipulation, and pharmacological methods to clarify the causality between thermogenic fat and inflammatory signaling. My research experience has afforded me with a skill set that is unique in the world, that will allow me to study the metabolic cross-talk between the adipose and immune systems. Working with Drs. Chouchani and Spiegelman, experts in the fields of thermogenesis and metabolism, I will become proficient in the study and manipulation of adipocyte biology and LCMS analysis and these skills will be coupled with my strong background in immunology. The diverse and rich scientific environment at DFCI adds fuel to my enthusiasm to establish myself as an independent investigator and drives my determination to ensure that I make a success of it.