Human Carboxylesterase 2 Reverses Obesity-Induced Diacylglycerol Accumulation and Glucose Intolerance

Area of Science:

• Biochemistry
• Metabolic Disease Research
• Enzymology

Background:

• Serine hydrolases are crucial enzymes impacting metabolic health.
• Obesity is linked to dysregulated enzyme activity, particularly in the liver.
• Understanding these enzymatic changes is key to metabolic disease pathophysiology.

Purpose of the Study:

• To investigate the functional role of serine hydrolases in human obesity.
• To identify specific enzymes contributing to metabolic dysfunction in obesity.
• To elucidate the mechanistic link between enzyme activity and obesity-related metabolic disturbances.

Main Methods:

• Activity-based protein profiling of liver biopsies from lean and obese humans.
• In vitro studies using primary human hepatocytes with CES2 knockdown.
• In vivo studies in mice involving adenoviral delivery of human CES2.
• Lipidomic analysis to identify CES2-regulated lipids.

Main Results:

• Obesity is associated with reduced hepatic activity of carboxylesterase 2 (CES2) and arylacetamide deacetylase (AADAC).
• CES2 knockdown in human hepatocytes impaired glucose storage and lipid oxidation.
• Adenoviral CES2 delivery in mice reversed hepatic steatosis, improved glucose tolerance, and reduced inflammation.
• CES2 exhibits triglyceride and diacylglycerol lipase activities, inversely correlating with HOMA-IR and hepatic diacylglycerol.

Conclusions:

• Decreased hepatic CES2 activity is a conserved feature of obesity across species.
• Reduced CES2 plays a causative role in the pathogenesis of obesity and related metabolic disturbances.
• CES2 represents a potential therapeutic target for metabolic diseases like obesity.