Researchers Identify Link Between Obesity And Type 2 Diabetes

[Guest guest]

Source: Beth Israel Deaconess Medical Center

(http://www.bidmc.harvard.edu/)

Date: Posted 1/18/2002

Researchers Identify Link Between Obesity And Type 2 Diabetes

BOSTON - Researchers at Beth Israel Deaconess Medical Center (BIDMC) have

identified a mechanism that helps explain how the hormone leptin acts to

metabolize fatty acids in muscle, establishing for the first time a novel

molecular link between obesity and diabetes, and creating the possibility of a

new target for the development of drugs to help manage both conditions. The

study appears in the Jan. 17 issue of the journal Nature.

Discovered in 1994, leptin first gained widespread attention as a " satiety

signal " or appetite suppressant. Initial studies revealed that the hormone,

which is produced in fat cells, travels through the bloodstream and interacts

with receptors in the brain to provide a " signal " that the body has consumed

enough food and should stop eating.

Since then, however, scientists have demonstrated that leptin's role is not

confined to suppressing appetite. Leptin receptors have also been identified in

the T-cells of the immune system and in new blood vessels, and, as this new

research suggests, the hormone has also been shown to play an important role in

metabolism. " Leptin is a master regulator of our bodies' hormonal systems, "

explains Barbara Kahn, M.D., Chief of Endocrinology at Beth Israel Deaconess and

Professor of Medicine at Harvard Medical School. " It probably evolved as a

regulator that could be suppressed to protect people and animals when no food

was available. " Kahn served as the study's senior author. BIDMC researcher

Yasuhiko Minokoshi, M.D., Ph.D., is the first author. Impaired fuel metabolism

is a well-known factor in obesity as well as type 2 diabetes. When fatty acids

in muscle and the liver are not sufficiently utilized, their buildup not only

impairs the body's ability to burn calories, but also leads to insulin

resistance, which increases a person's risk of developing diabetes. This new

research focuses on the enzyme 5'-AMP activated protein kinase (AMPK), a

molecule that had previously been identified as a " fuel gauge " which acts on key

enzymes in both cholesterol metabolism and glycogen synthesis. Kahn and her

colleagues hypothesized that AMPK might also be serving as a " signaling pathway "

for leptin, enabling the hormone to metabolize fatty acids in muscle.

To test their hypothesis, the researchers injected laboratory mice with leptin.

They discovered that the hormone was indeed activating AMPK in muscle when

administered either directly into a peripheral vein or into the brain's

hypothalamus. This novel effect was the same in experiments conducted outside

the body, when muscle was removed from the mice and incubated with leptin. In

addition, by blocking the nerves to the animals' legs, the researchers showed

that leptin was exerting an indirect effect on muscle by way of the brain and

sympathetic nervous system.

These results demonstrated that while there was an early activation of AMPK that

resulted from leptin's direct effect on skeletal muscle, later, more sustained,

activation was indirectly taking place via the central nervous system. " We

discovered that leptin, by way of AMPK, was inhibiting another enzyme, acetylCoA

carboxylase (ACC), which had the result of increasing fat metabolism, " explains

Kahn. Together with results of an earlier study showing that mice grew very lean

when the ACC enzyme was removed, these findings suggest that the AMPK pathway

could be a particularly promising target for drug treatments for obesity and

diabetes.

" AMPK is a heterotrimeric enzyme, " Kahn adds. " This means that it contains three

sections, alpha, beta and gamma, each of which contains two or three isoforms.

Our study showed that a single isoform - alpha 2 - is the key to leptin's

effects on fatty acid oxidation in muscle. " This finding is important, she

emphasizes, because the greater the degree of molecular specificity, the greater

the likelihood of success in developing new drugs without adverse side effects.

The incidence of obesity and type 2 diabetes has escalated tremendously over the

past decade. A new report from the U.S. Surgeon General finds that 61 percent of

American adults currently meet the scientific definition of " overweight " or

" obese, " putting them at risk of developing type 2 diabetes, one of the leading

causes of death and disability in this country. Diabetes affects 16 million

individuals throughout the United States, and can lead to heart attack, stroke,

atherosclerosis and peripheral blood vessel disease, among other serious

conditions. " Since the discovery of leptin, we've known that it's a fascinating

and important hormone, " says Kahn. " Now we know that the AMPK pathway is a key

mechanism for leptin's effects to mobilize fatty acids rather than deposit them.

This provides important clues to help reduce the likelihood that obese patients

will develop diabetes, and may lead to ways to reduce insulin resistance and its

accompanying cardiovascular morbidity in people with diabetes and obesity. "

Study co-authors include Young-Bum Kim, Ph.D., Odile D. Peroni, Ph.D., and

Corinna Muller, of Beth Israel Deaconess Medical Center, and Lee G. D. Fryer,

Ph.D., and Carling, Ph.D., of Hammersmith Hospital, London.

The study was funded by grants from the National Institutes of Health (NIH).

Beth Israel Deaconess Medical Center is a major patient care, research and

teaching affiliate of Harvard Medical School and a founding member of CareGroup

Healthcare System. Beth Israel Deaconess is the fourth largest recipient of

National Institutes of Health research funding among independent U.S. hospitals.