News & Research

    Boston University, Boston, Massachusetts

Regulation of Lipolysis via the TSC1/2-RHEB-mTORC1 Pathway

General Research Subject: Type 2 Diabetes

Focus: Adipocytes, Insulin Action\Metabolism, Integrated Physiology\Insulin Resistance

Type of Grant: Basic Science

Project Start Date: July 1, 2011

Project End Date: June 30, 2014

Research Description

One of the key physiological functions of insulin in the organism is to inhibit lipolysis and to promote accumulation and storage of triglycerides in fat tissue.  In patients with insulin resistance and type 2 diabetes, insulin cannot suppress lipolysis, and availability of free fatty acids (FFA) exceeds energy requirements of the body.  As a result, FFA are accumulated in the form of various lipid products in non-adipose peripheral tissues, such as liver, pancreas and skeletal muscle, causing and aggravating type 2 diabetes, cardiovascular disease and other hazardous metabolic conditions.

A recently discovered lipase, ATGL, is responsible for the bulk of triacylglycerol hydrolase activity in cells and represents the rate-limiting lipolytic enzyme.  Thus, in order to exert its full effect on lipolysis, insulin should somehow suppress ATGL.  To this end, we have discovered a novel pathway of regulation of lipolysis by insulin which has to do with the transcriptional control of ATGL expression.  This pathway is mediated by the insulin- and nutrient-sensitive mammalian Target of Rapamycin Complex 1, or mTORC1.  We now propose to follow up on these findings by performing experiments in vitro and in vivo in order to determine the molecular mechanism and physiological significance of this regulatory pathway.  Since dyslipidemia represents a major causative factor for the development of insulin resistance, we expect that our work will lead to the discovery of new medications and treatments.

Research Profile

What area of diabetes research does your project cover? What role will this particular project play in preventing, treating and/or curing diabetes?

One of the key physiological functions of insulin in the organism is to inhibit lipolysis and to promote accumulation and storage of triglycerides in fat tissue.  In patients with insulin resistance and type 2 diabetes, insulin cannot suppress lipolysis, and availability of free fatty acids (FFA) exceeds energy requirements of the body.  As a result, FFA are accumulated in the form of various lipid products in non-adipose peripheral tissues, such as liver, pancreas and skeletal muscle, causing and aggravating type 2 diabetes, cardiovascular disease and other hazardous metabolic conditions.

A recently discovered lipase, ATGL, is responsible for the bulk of triacylglycerol hydrolase activity in cells and represents the rate-limiting lipolytic enzyme.  Thus, in order to exert its full effect on lipolysis, insulin should somehow suppress ATGL.  To this end, we have discovered a novel pathway of regulation of lipolysis by insulin which has to do with the transcriptional control of ATGL expression.  This pathway is mediated by the insulin- and nutrient-sensitive mammalian Target of Rapamycin Complex 1, or mTORC1.  We now propose to follow up on these findings by performing experiments in vitro and in vivo in order to determine the molecular mechanism and physiological significance of this regulatory pathway.  Since dyslipidemia represents a major causative factor for the development of insulin resistance, we expect that our work will lead to the discovery of new medications and treatments.

If a person with diabetes were to ask you how your project will help them in the future, how would you respond?

The etiology of diabetes mellitus is difficult to understand, most probably because it is associated with very basic abnormalities in the cell physiology.  We are trying to uncover the molecular mechanisms of insulin action in a hope to produce a rational treatment for the disease.

Why is it important for you, personally, to become involved in diabetes research? What role will this award play in your research efforts?

Diabetes research is extremely rewarding in many ways.  To me, it provides a unique opportunity to combine modern basic science with a real chance to help patients.  This award from ADA will allow us to explore the molecular nature of insulin resistance.  We have obtained novel promising results, and we intend to follow up on these studies in future.

In what direction do you see the future of diabetes research going?

I believe that basic research in diabetes should be more oriented on the cell biological aspects of regulated membrane and protein traffic.  These problems include biogenesis and secretion of insulin-containing granules in beta-cells, formation and insulin-dependent translocation of Glut4-containing membrane vesicles in fat and muscle and regulated secretion from adipocytes, including secretion of non-proteinaceous products, such as fatty acids.  Our progress can and will benefit from recent achievements in the field of signal transduction and membrane traffic that may be adopted to diabetes-related studies.