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.
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.