Acute leptin deficiency, leptin resistance, and the physiologic response to leptin withdrawal

JM Montez, A Soukas, E Asilmaz… - Proceedings of the …, 2005 - National Acad Sciences
JM Montez, A Soukas, E Asilmaz, G Fayzikhodjaeva, G Fantuzzi, JM Friedman
Proceedings of the National Academy of Sciences, 2005National Acad Sciences
Food restriction and weight loss result in reduced plasma leptin, which is associated with a
pleiotropic biologic response. However, because weight loss itself is also associated with
changes in numerous other humoral and metabolic signals, it can be difficult to determine
the precise features of the biologic response to acute leptin deficiency. To study this
response in the absence of changes in nutritional state, we have developed a protocol that
allows such analysis in normal, non-food-restricted animals. Wild-type mice are treated with …
Food restriction and weight loss result in reduced plasma leptin, which is associated with a pleiotropic biologic response. However, because weight loss itself is also associated with changes in numerous other humoral and metabolic signals, it can be difficult to determine the precise features of the biologic response to acute leptin deficiency. To study this response in the absence of changes in nutritional state, we have developed a protocol that allows such analysis in normal, non-food-restricted animals. Wild-type mice are treated with high-dose leptin until fat mass is depleted and, as a consequence, endogenous leptin production is reduced. At this point, exogenous leptin is abruptly withdrawn, thus inducing a state of leptin deficiency in otherwise normal mice. Leptin deficiency is sustained by feeding the animals only as much as they consumed voluntarily before leptin withdrawal. The biologic response to leptin deficiency induced in this manner includes altered neuropeptide levels, decreased energy expenditure, and impaired reproductive and immune function. Replacement of leptin at physiological concentrations after withdrawal of high-dosage leptin blunts, but does not completely block, the hyperphagia and weight regain caused by acute leptin deficiency, nor does it correct the resulting reproductive and immune dysfunction. This suggests that high-dosage leptin treatment induces a state of partial leptin resistance. In aggregate, these studies establish the role of acute hypoleptinemia in regulating energy balance, the immune system, and reproductive function, and further suggest that high-dosage leptin treatment can induce a state of acquired leptin resistance.
National Acad Sciences