Insulin Stimulation of Fat Cells is Critical for Obesity
BOSTON — July 9, 2002 — Over a billion people worldwide are classified as overweight and at high risk for developing other serious conditions such as heart disease and diabetes. Faced with this burgeoning health crisis, scientists are striving to gain new insights into mechanisms that govern fat cells, called adipocytes. Two reports published in the July issue of Developmental Cell provide exciting new perspectives about regulation of adipocytes.
In a study led by Dr. C. Ronald Kahn, President of Joslin Diabetes Center, in collaboration with researchers at Joslin and Beth Israel Deaconess Medical Center, mice were bred to lack insulin receptors in their fat cells. Insulin is a hormone that moves sugar (glucose) from the blood into cells where it is used as fuel. Remarkably, these mice had a lean body mass and differed from control mice in that they were protected from obesity associated with age — and overeating. They were also protected from a condition called insulin-resistance that is associated with obesity and leads to diabetes.
Mice without fat cell insulin receptors had two different kinds of adipocytes, small and large. The researchers hypothesize that loss of the adipocyte insulin receptor unmasks differences between two populations of fat cells and that the small adipocytes are somehow protected against excessive fat loading, preventing the mice from becoming obese.
Dr. C. Ronald Kahn is the Mary K. Iacocca Professor of Medicine. Other researchers collaborating in the study were Dr. Barbara B. Kahn, Professor of Medicine at Harvard Medical School; Matthias Blüher, M.D., Kohjiro Ueki, M.D., Ph.D., and Nathan Carter of Joslin; M. Dodson Michael, Ph.D., formerly of Joslin; and Odile D. Peroni, Ph.D., of BIDMC.
A second report, authored by Dr. Johan Auwerx of Strasbourg, France, examined the role of a family of proteins called E2Fs in the process that directs maturation of preadipocytes into adipocytes. E2Fs are known for their roles in regulating cell proliferation, and adipocyte maturation is closely coupled to metabolic regulation, but the relationship between these two facts has been somewhat unclear. Here, the authors show that E2Fs regulate the production of PPARg, a protein that plays crucial roles at several times during adipocyte development. Specifically, E2F1 activates PPARg production at an early stage, when preadipocytes proliferate, while E2F4 represses PPARg during a later stage of development, when preadipocytes differentiate into mature adipocytes. The authors conclude that the E2F proteins play a complex role regulating a balance between increases in cell numbers and final maturation of fat cells.
The novel mechanisms for regulation of adipocytes that are presented in these two reports make a substantial contribution to future studies investigating new methods for controlling obesity and associated metabolic disorders, such as diabetes.
