Chemical characterization of leptin-activated neurons in the rat brain

Leptin has profound effects on food intake, body weight, and neuroendocrine status. The lack of leptin results in hormonal and metabolic alterations a nd a dramatic increase in body weight. Leptin acts in the brain, especially in the hypothalamus; however, the central nervous system sites that respon d to leptin have not been examined comprehensively, In this study, we explo red systematically the distribution of leptin-activated neurons throughout the rat brain. Furthermore, we investigated the chemical identity of subset s of these leptin-activated cells. Fos-like immunoreactivity (Fos-IR) was i nvestigated in the rat brain after two different doses of leptin (1.0 mg/kg and 5.0 mg/kg) at 2 hours and 6 hours after injections. The induction of F os-IR was observed in hypothalamic nuclei, including the paraventricular nu cleus (PVH), the retrochiasmatic area (RCA), the ventromedial nucleus (VMH) , the dorsomedial nucleus (DMH), the arcuate nucleus (Arc), and the ventral premammillary nucleus (PMV). In addition, leptin-induced Fos-IR was found in several nuclei of the brainstem, including the superior lateral and exte rnal lateral subdivisions of the parabrachial nucleus (slPB and elPB, respe ctively), the supragenual nucleus, and the nucleus of the solitary tract (N TS). By using double-labeling immunohistochemistry or immunohistochemistry coupled with in situ hybridization, leptin-activated neurons were found tha t contained cocaine- and amphetamine-regulated transcript mRNA in several h ypothalamic nuclei, including the RCA, Are, DMH, and PMV. In the Arc and DM H, leptin-induced Fos-IR was observed in neurons that expressed neurotensin mRNA. Dynorphin neurons in the VMH and in the Are also expressed Fos-IR. I n the brainstem, we found that cholecystokinin neurons in the slPB and gluc agon-like peptide-1 neurons in the NTS were activated by leptin. We also in vestigated the coexpression of Fos-IR and the long form of the leptin recep tor (OBRb) mRNA. We found double-labeled neurons surrounding the median emi nence and in the RCA, Are, VMH, DMH, and PMV. However, in brainstem sites, very little OBRb mRNA was found; thus, there were very Few double-labeled c ells. These results suggest that leptin stimulates brain pathways containin g neuropeptides that are involved in the regulation of energy balance, auto nomic homeostasis, and neuroendocrine status. J. Comp. Neurol. 423: 261-281 , 2000. (C) 2000 Wiley-Liss, Inc.