Head: C. Ronald Kahn, MD

Molecular mechanisms that control of body weight and feeding behavior.

Obesity is a major risk factor for type 2 diabetes and is closely linked to other components of the metabolic syndrome, including insulin resistance, dyslipidemia, hypertension, fatty liver, and increased risk of cardio-vascular disease. Obesity develops when energy intake exceeds energy expenditure. The development of obesity depends in part on the balance between food intake and caloric utilization, but also on the balance between white adipose tissue, which functions to store energy, and brown adipose tissue, specialized for energy expenditure. In addition, while it is known that white fat in different depots plays differential roles in the development of insulin resistance and diabetes -- i.e. intra-abdominal (visceral) adiposity is associated with insulin resistance and high risk of diabetes while the accumulation of subcutaneous white fat in the hips and thighs is not -- little is known about the fundamental factors that led to development of these different types of fat. Nor is it understood why white fat accumulates to different extents in different depots.

Research in the Section on Obesity attempts to determine factors leading to obesity, alterations of energy balance and their links to insulin resistance and the metabolic syndrome. In addition, there is a major focus on insulin action, insulin resistance and the genetics of diabetes and obesity. This Section’s efforts utilize a broad range of technologies, going from cellular studies to animal studies and to humans, with extensive use of cell and molecular biology, genetics, genomics, proteomics, RNA knockdown, gene-targeting and clinical studies.


Kahn lab:

Using a variety of genetic approaches, including whole body gene-knockout, combinatorial knockouts and tissue-specific knockouts in mice and cell lines, the Kahn lab has defined the role of different molecules in the insulin-signaling network in different tissues, and has determined how these forms of insulin resistance alter metabolism. These studies have revealed many novel aspects of insulin action. For example, knocking-out the insulin receptor in fat results in mice that are lean, resistant to development of obesity and diabetes, and have increased longevity. Insulin resistance in the liver, on the other hand, can lead to alterations in cholesterol metabolism and formation of gallstones, two other features of the insulin resistance syndrome. Indeed, interfering with different parts of the insulin signaling pathway in liver, using interference by shRNAs differentially affects glucose and lipid metabolic pathways in the liver, and this appears to be via differential involvement of the Akt and atypical PKC pathways. Knockout of insulin action in brain results in increased appetite, obesity and altered hepatic glucose metabolism, demonstrating an important central control of these processes.

In addition to the studies of insulin action and insulin resistance, there is now a major focus on development of adipose tissue in different depots and the use of gene-expression to profiling to help provide new insights into these areas or research. Recent studies in both rodents and humans have shown that fundamental developmental and patterning genes, such as Hox genes, Shox2, Engrailed-1 and others, may play an important role in control over development of fat in different depots. 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 vs subcutaneous fat. Efforts are underway to isolate the different types of white and brown fat cell precursors, trace the lineage of fat cells during development using in vivo markers of differentiation, and to determine how these different fat depots have such different effects on metabolism through fat transplantation and other studies.
Current foci of research include: