Enhancing energy and glucose metabolism by disrupting triglyceride synthesis: Lessons from mice lacking DGAT1

Hubert C Chen

doi:10.1186/1743-7075-3-10

Abstract

Although the ability to make triglycerides is essential for normal physiology, excess accumulation of triglycerides results in obesity and is associated with insulin resistance. Inhibition of triglyceride synthesis, therefore, may represent a feasible strategy for the treatment of obesity and type 2 diabetes. Acyl CoA:diacylglycerol acyltransferase 1 (DGAT1) is one of two DGAT enzymes that catalyze the final reaction in the known pathways of mammalian triglyceride synthesis. Mice lacking DGAT1 have increased energy expenditure and insulin sensitivity and are protected against diet-induced obesity and glucose intolerance. These metabolic effects of DGAT1 deficiency result in part from the altered secretion of adipocyte-derived factors. Studies of DGAT1-deficient mice have helped to provide insights into the mechanisms by which cellular lipid metabolism modulates systemic carbohydrate and insulin metabolism, and a better understanding of how DGAT1 deficiency enhances energy expenditure and insulin sensitivity may identify additional targets or strategies for the treatment of obesity and type 2 diabetes.

Highlights

Triglycerides are neutral lipids consisting of a glycerol backbone and three long-chain fatty acids
In addition to representing a major form of stored energy in the adipose tissue and skeletal muscle, triglycerides are an integral component of lipoprotein particles synthesized by the liver and small intestine, skin sebum secreted by sebaceous glands, and milk produced by mammary glands
An increase in insulin sensitivity is confirmed by results from hyperinsulinemic-euglycemic clamp studies (Figure 1C), in which Dgat1-/- mice require a ~20% higher glucose infusion rate than WT mice to maintain euglycemia [4]

Summary

Introduction

Triglycerides (triacylglycerols) are neutral lipids consisting of a glycerol backbone and three long-chain fatty acids. Transplantation of WT adipose tissue into Dgat1-/- mice did not adversely affect their resistance to diet-induced obesity or enhanced response to insulin These results provide strong evidence that the altered endocrine function of Dgat1-/- WAT has beneficial effects on systemic energy and glucose metabolism. The disruption of enzymes in the anabolic process of lipid uptake and storage (e.g., lipoprotein lipase, DGAT1) is more likely to enhance tissue glucose disposal or insulin secretion, whereas disruptions of enzymes in the catabolic process (e.g., hormone-sensitive lipase) tend to impair insulin action or secretion [13] In these various knockout models, glucose disposal does not appear to have a strong correlation with levels of plasma free fatty acids, which have been hypothesized to be an important correlative of insulin resistance. Curr Opin Clin Nutr Metab Care 2002, 5:359-363

14. Shulman GI

Findings

12. Reitman ML