Leptin - Can obese mice lead to lean people?

In a study by Considine, et. al. published in February (1996} in The New England Journal of Medicine (NEJM 1996, 334: 292-2951, this was addressed. In the study, they measured the leptin concentrations in lean and obese individuals and in obese individuals placed on a liquid protein diet of 800 calories/day (Optifast). Also measured was the effect of food consumption on leptin concentrations in both normal-weight and obese individuals.

The results were somewhat surprising.  Unlike the genetically obese mice, it was found that obese humans had (on average) leptin levels 4 times higher than non-obese individuals! When obese individuals were reduced by 10% of their initial body weights, the serum leptin level decreased by 55% (on average). The leptin concentration did increase slightly during weight maintenance but were still much lower than the initial levels. When leptin concentrations were studied before and after meals in both normal-weight and obese individuals, it was found that the concentration did not change significantly before or after meals in the respective subjects.

If human obesity were associated with low leptin levels, it would be (theoretically) possible to treat human obesity with supplemental leptin. Human obesity appears to result from a much more complex mechanism and is not associated with a lack of leptin production. Recent clinical trials, however, have shown that large doses of leptin can result in some weight loss in obese individuals.

It is known that abnormalities in a region of the brain known as the hypothalamus are sometimes associated with severe obesity. It is also known that in most animal models of obesity, a hypothalamic peptide known as neuropeptide Y will stimulate food intake (primarily carbohydrate) and stimulate secretion of insulin and cortisol which in turn lead to fat accumulation.

When genetically obese mice are administered leptin, the level of neuropeptide Y falls markedly and is associated with marked weight reduction. This has lead to attempts to suppress neuropeptide Y production in animals.  Animals have been bred that do not produce normal neuropeptide Y. Unfortunately, this did not have the dramatic effect on weight and appetite that was expected.

Further studies on leptin, neuropeptide Y, and other neuropeptides and hormones are ongoing.