OBESITY AND HORMONE ACTION
The Link Between Obesity and Diabetes
Obesity is a major risk factor for type 2 diabetes and is closely associated with the metabolic syndrome—a cluster of disorders linked to insulin resistance and central obesity, including impaired glucose tolerance, circulating lipid abnormalities and fatty liver, hypertension and increased risk of cardiovascular disease. More than 60 million Americans either are obese or have the metabolic syndrome. It is now clear that this link is related in large part to the effects of adipocytes and their secretions on metabolism and insulin action.
Different Types of Fat with Different Functions
Adipose tissue occurs in multiple forms, which serve several different functions in the body. White fat is the predominant adipose tissue in the body and the major site of energy storage via triglyceride accumulation. Brown fat is found only in selected locations and is specialized for energy expenditure. In addition, white fat in certain depots, especially in intra-abdominal (visceral) areas, results in “apple-shaped” obesity associated with insulin resistance and the metabolic syndrome, whereas accumulation of subcutaneous white fat in the hips and thighs, i.e., “pear-shaped” obesity, is not linked to these problems.
Section researchers study the molecular and genetic basis of brown and white fat development and their relationship to insulin resistance and the metabolic syndrome. In addition, there is a focus on the molecular mechanisms of insulin action and insulin resistance. The section has close collaborations with the Section on Cellular and Molecular Physiology, the Section on Clinical Research and Joslin’s Clinical Obesity Program.
Factors Controlling Development of White and Brown Fat
Obesity is characterized by increases in both adipocyte number and size. Although much is known about factors controlling food intake and their relationship to obesity, little is known about the factors that control the development of white or brown fat cells themselves, why white fat accumulates to varying extents in different depots, and to what extent these white fat cells may be functionally different.
Section researchers study the development of both brown and white fat in in vivo and in tissue culture. These studies show that the precursor cells for each type are different and respond to different hormonal regulation. Current research shows that insulin, insulin-like growth factor 1 (IGF-1) and certain bone morphogenetic proteins (BMPs) may play a role in the commitment of mesenchymal stem cells to these two different adipocyte lineages, and thus could provide novel therapeutics in obesity.
Studies in both rodents and humans also show that fundament developmental and patterning genes, such as Hox genes, may play an important role in control over fat development in different depots and the differences between visceral and subcutaneous fat. In humans, expression of several of these developmental genes is closely correlated with body mass index and waist-hip ratio, a measure of intra-abdominal versus subcutaneous fat. Efforts are under way to isolate the various types of white fat cell precursors, trace the lineage of fat cells during development, and determine how each type of fat accumulation affects metabolism.
Obesity, Insulin Resistance and Metabolic Syndrome
Another major focus is understanding insulin action, insulin resistance and how these are linked to obesity, type 2 diabetes and the metabolic syndrome. Using sophisticated genetic approaches, researchers have “knocked out” specific molecules in the insulin signaling network in different tissues and determined how these forms of insulin resistance alter metabolism. These studies reveal many novel aspects of insulin action. For example, knocking out the insulin receptor in fat results in mice that are lean, resistant to developing obesity and diabetes, and have increased longevity. Insulin resistance specifically in the liver can lead to a range of alterations in glucose and lipid metabolism and a tendency to gallstone formation, three key features of the insulin resistance syndrome. Finally, knockout of insulin action in the brain in mice results in increased appetite, mild obesity and altered hepatic glucose metabolism. Using this approach, it is also possible to define new targets for type 2 diabetes therapy that might overcome the insulin resistance and reduce obesity.
Insulin, Diabetes and Control of Gene Expression
Section researchers take the lead in the use of genomics to study diabetes and obesity through the Diabetes Genome Anatomy Project (DGAP)— a unique multi-investigator project representing seven different institutions. The overall goal of DGAP is to identify the sets of genes and proteins involved in insulin action, obesity, insulin resistance and the predisposition to type 2 diabetes, as well as the secondary changes in gene expression that occur in response to the metabolic abnormalities present in diabetes in both human and rodent tissues.
Section Investigators:
C. Ronald Kahn, M.D.
Yu-Hua_Tseng,_Ph.D.
