Role of Ces1f/TGH-2 in adiposity and hepatic steatosis upon fasting

This is the authors' abstract. We don't add key points for this paper.

Adaptive response to fasting plays an important role in whole-body energy metabolism under nutritional stress. Carboxylesterases comprise a family of serine esterases that hydrolyze xenobiotic compounds and endogenous lipids. Of particular interest in view of energy metabolism are human carboxylesterase 1/triacylglycerol hydrolase (CES1/TGH), and its mouse counterparts, Ces1d/TGH-1 and Ces1f/TGH-2. These esterases are unique in that they are highly expressed in the liver and adipose tissues and have substantial TGH activity. Notably, Ces1d and Ces1f are PPARα targets and regulated by fasting. While deficiency of Ces1d or pharmacological inhibition of Ces1d/Ces1f in mice has been shown to ameliorate features of metabolic syndrome, the physiological role of Ces1f has not been clarified in vivo. Here we show that Ces1f plays an important role in whole-body and hepatic fat metabolism upon fasting in a diet-dependent manner. On a normal diet, Ces1f-deficient (Ces1f-/-) mice presented with increased adiposity and exacerbated hepatic steatosis. On a high-fat diet, Ces1f-/- mice presented with decreased adiposity and ameliorated hepatic steatosis. Mechanistically, the differential balance between decreased adipose TGH activity and, possibly, increased liver fatty acid oxidation (FAO) in Ces1f-/- at least partially explains the diet-context dependency. Decreased adiposity in Ces1f-/- mice under a high-fat diet was associated with improved glucose tolerance. Collectively, these findings revealed the unique role of Ces1f in whole-body response to fasting by modulating adipocyte lipolysis and, at least partially, hepatic FAO genes. Our study provides a molecular foundation for understanding CES1 inhibitors, which have potential therapeutic implications for metabolic diseases and liver cancer. (250 words).