Hypothalamic pathways underlying the endocrine, autonomic, and behavioral effects of leptin.

Leptin affects body weight by decreasing food intake, activating the sympathetic nervous system and regulating neuroendocrine function. This type of regulation is a hallmark of hypothalamic control, which typically integrates autonomic, endocrine and behavioral responses. We have performed a series of experiments investigating hypothalamic pathways underlying these actions of leptin. We found that leptin activates neurons that coexpress pro-opiomelanocortin (POMC) and cocaine- and amphetamine-regulated transcript (CART) mRNA. These neurons innervate several sites, including sympathetic preganglionic neurons in the spinal cord, neurons in the paraventricular hypothalamic nucleus (PVH), and melanin-concentrating hormone and orexin neurons in the lateral hypothalamic area (LHA). Following leptin administration, POMC neurons express both Fos and suppressor of cytokine signalling-3 (SOCS-3) mRNA. In contrast, leptin induced SOCS-3 expression in neuropeptide Y (NPY) neurons but not Fos, suggesting that leptin acts differentially on NPY and POMC cells. We also investigated potential downstream targets of leptin responsive NPY and POMC neurons by assessing the distribution of the melanocortin 4 receptor (MC4-R) mRNA and Y1 and Y5 NPY receptor mRNA in chemically defined neurons. We found dense MC4-R mRNA expression in several sites including the PVH and LHA. Using dual-label in situ hybridization we found that MC4-R mRNA is coexpressed in PVH cells expressing pro-TRH mRNA. We also found Y1 and Y5 NPY receptor mRNA in the PVH in patterns very similar to that of MC4R, suggesting that these receptors may be coexpressed on at least some PVH neurons. These results provide a neuroanatomic framework explaining the endocrine, autonomic and behavioral effects of leptin.