355-OR: Targeting a Lipid Droplet Hydrolase-Mediated Lipid Signaling for Treatment of Type 2 Diabetes

Abstract

Lipid droplets (LDs) are cytosolic organelles that serve as the major energy reservoir in adipocytes. Excessive accumulation of neutral lipids in LDs has been linked to obesity-associated type 2 diabetes. The dynamics of LDs is regulated by multiple proteins bound to their surfaces. Recently, carboxylesterase 1d (Ces1d) was identified as a LD-targeting lipid hydrolase. It has been showed that blockage of Ces1d in adipose tissue led to not only decreased lipolysis, but also impaired β-adrenergic signaling-stimulated thermogenesis. The goal of the current study is to define the mechanism governing the function of Ces1d on lipid metabolism. The hypothesis is that the LD-targeting Ces1d generates free fatty acids (FFA) “third messenger” that trigger specific lipid signaling in adipose tissue which further affect the whole-body metabolic homeostasis. To test this hypothesis, an adipose tissue specific Ces1d knockout mouse model (Adipo-Ces1d KO) was generated. Mass Spectrometry analysis revealed that circulating docosahexaenoic acid (DHA, C22:6 n=3), an established PPARγ ligand, was dramatically decreased in Adipo-Ces1d KO mice. The production of DHA was confirmed by an in vitro lipid digestion assay on the recombinant Ces1d. Lack of DHA signaling further led to decreased transactivation of PPARγ in adipose tissue of the Adipo-Ces1d KO mice. As a result, the expression of thermogenic gene, UCP1 was significantly downregulated. The result agrees with previous observation that Adipo-Ces1d KO mice lost their ability to defense body temperature when exposed to coldness. More interestingly, the Adipo-Ces1d KO mice gained more body weight with increased fat mass during a HFD challenge, suggesting they experienced decreased energy expenditure in the whole process. The findings thus highlight the key role of a novel lipid signaling pathway mediated by Ces1d in energy expenditure and hence pinpoint it as a potential target for treatment of obesity-induced type 2 diabetes. Disclosure X.Li: None. K.Sun: None. Funding National Institutes of Health (R56DK124419, R01DK129815)