Distinct physiologic and neuronal responses to decreased leptin and mild hyperleptinemia

Leptin acts on specific populations of hypothalamic neurons to regulate fee ding behavior, energy expenditure, and neuroendocrine function. It is not k nown, however, whether the same neural circuits mediate leptin action acros s its full biologic dose-response curve, which extends over a broad range, from low levels seen during starvation to high levels characteristic of obe sity. Here, we show that the characteristic fall in leptin with fasting cau ses a rise in neuropeptide Y (NPY) messenger RNA (mRNA), as well as a fall in POMC and cocaine and amphetamine-regulated transcript (CART) mRNAs. Sc i nfusion of leptin sufficient to maintain plasma levels within the physiolog ic range during the fast prevents changes in the expression of these peptid es, as well as changes in neuroendocrine function, demonstrating that multi ple neural circuits are highly sensitive to small changes in leptin within its low physiologic range. In contrast, a modest elevation of plasma leptin above the normal fed range by constant sc infusion, which produced marked reduction in food intake and body weight, decreased NPY mRNA in the arcuate hypothalamic nucleus but did not affect the levels of mRNAs encoding the a norexigenic peptides alpha-MSH, CART or CRH. These results suggest that the dose response characteristics of leptin on hypothalamic target neurons at the level of mRNA expression are variable, with some neurons (e.g. NPY) res ponding across a broad dose range and others (e.g. POMC and CART) showing a limited response within the low range. These results further suggest that the central targets of leptin that mediate the transition from starvation t o the fed state may be distinct from those that mediate the response to ove rfeeding and obesity.