Saturday, May 10, 2025
5/10/2025
Feed-forward regulation between GPR120 and PPAR gamma. - PROJECT SUMMARY/ABSTRACT Pathologic expansion of white adipose tissue (WAT) in obesity is characterized by adipocyte hypertrophy, inflammation, and fibrosis; however, factors triggering this maladaptive remodeling are largely unknown. Moreover, adipose precursor cells (APCs) exhibit reginal variation in response to obesity, for unclear reason. In the next funding cycle, we will focus on the healthy adipogenesis and test the hypothesis that the potential to recruit new adipocytes from PDGFRβ+ APCs determine WAT health in obesity. We manipulate levels of PPARγ, the master regulator of adipogenesis with or without GPR120 stimulation, in APCs of adult mice to determine whether increasing the adipogenic capacity of APCs through GPR120 stimulation-mediated PPARγ overexpression results in healthy WAT expansion in obesity. In addition to examine the negative effect of loss of mural cell GPR120 in WAT expansion upon high-fat diet feeding, we also hypothesize the precise molecular mechanism that how GPR120 activation drives modulation of PPARγ activity in APCs and inhibition of inflammation in fibro-inflammatory progenitor cells (FIPs) under obese condition. The concept, which we suggested in the previous funding cycle, that the combination of PPARγ and GPR120 activation has been shown as additive effects as well as using much lower doses of PPARγ agonist, TZDs to mitigate unwanted side effects in combination with GPR120 agonist, compound A (CpdA). Thus, in this renewal application, we determine the effect of the PPARγ and GPR120 activation in healthy WAT remodeling is dependent on mural cell PPARγ and GPR120 feed-forward regulation with GPR120 stimulation-mediated anti-inflammatory effects. Our studies highlight the potential for APCs to be targeted pharmacologically to improve metabolic health in obesity.
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