Obese lab mice with severe type 2 diabetes had their blood glucose levels restored to normal and experienced a doubling in physical activity when sensitivity to the hormone leptin was restored to a portion of their hypothalamus.

The dramatic improvements came without any changes in the animals' diets or weight. This means that scientists may have found a way to use the brain itself, rather than diets, conventional weight control measures, or drugs aimed at other organs, to control glucose output and metabolism, as well as increase exercise.

Investigators at Beth Israel Deaconess Medical Center in Boston wanted to see how a big a role in weight and appetite is played by certain neurons in the hypothalamus that are receptive to leptin. Discovered in 1994, leptin is a hormone involved in the central nervous system's regulation of weight and appetite.

One place in the brain where leptin works is an area of the hypothalamus known as the arcuate nucleus. Within this area, two types of neurons receptive to the hormone are agouti-related peptide (AgRP) neurons and pro-opiomelanocortin (POMC) neurons. AgRP neurons stimulate appetite, while POMC neurons suppress it.  

While the Boston researchers knew that leptin in the arcuate nucleus had a role in regulating activity levels and blood sugar, they did not know the level of involvement by POMC neurons in either function. To test their hypothesis that POMC neurons play a greater role than expected, they used genetic manipulation to restore leptin sensitivity to a line of severely obese and diabetic mice that were leptin receptor-deficient.

When scientists placed the enhanced receptiveness capability solely in the POMC neurons, the result were dramatic: Blood sugar levels returned to normal nondiabetic levels, and the animals' activity levels spontaneously doubled. Although the mice began eating 30 percent fewer calories and losing modest amounts of weight, the changes in BG and activity levels occurred independent of diet or drugs.

Nobody is sure just how the POMC neurons are able to do what they do. Researchers think that the neurons somehow make the liver produce less glucose and skeletal muscles increase their uptake of it, with both processes leading to lowered BG levels.

These findings hold out that hope that severely overweight people with type 2 will be able to undergo leptin therapy that lowers their BG levels and appetite and increases their metabolism and desire to exercise-all without having to resort to extreme diets or onerous physical fitness routines.

Results of the study were published in the June 2009 issue of Cell Metabolism.