Scientists in the US have identified a mechanism that helps explain how the hormone leptin acts to metabolise fatty acids in muscle.
The study establishes for the first time a novel molecular link between obesity and diabetes, and creates the possibility of a new target for the development of drugs to help manage both conditions, researchers at Beth Israel Deaconess Medical Center (BIDMC) write in the January 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 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," explained 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."
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 utilised, their build-up 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 hypothesised that AMPK might also be serving as a "signalling pathway" for leptin, enabling the hormone to metabolise 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," explained Kahn in a statement. Kahn maintained that their findings suggest that the AMPK pathway could be a particularly promising target for drug treatments for obesity and diabetes.