Divergent Regulation of Proopiomelanocortin Neurons by Leptin in the Nucleus of the Solitary Tract and in the Arcuate Hypothalamic Nucleus

Abstract

(4,5). POMC neurons produce several neuropeptides derived from the POMC-polypeptide precursor, including the melanocortins ␣-, ␤-, and ␥-melanocyte-stimulating hormone (MSH), which are ligands for the melanocortin-3 and -4 receptors (MC3/4R) (6,7). A separate population of leptin-responsive cells in the ARC is the agouti-related peptide-producing (AgRP) neurons, which coexpress neuropeptide Y. AgRP is an antagonist of the melanocortin peptides at the MC3/4R (8). In contrast to POMC neurons, AgRP/neuropeptide Y neurons are inhibited by leptin (9). These opposing signaling effects are consistent with the negative actions of leptin on energy balance, since MC3/4R agonists inhibit energy intake while AgRP and neuropeptide Y strongly promote feeding. Together, the POMC, AgRP-, and MC3/4R-expressing cells comprise the core of the central melanocortin system (7).␤-Endorphin, a ligand of the opioid receptors, is also derived from the POMC polypeptide precursor via posttranslational processing (10). Compared with the melanocortin system, less is known about the specific role(s) of the opioid system in regulation of energy balance by leptin. However, in contrast to earlier reports, some more recent genetic data suggest that ␤-endorphin, like the melanocortins, may act to inhibit weight gain (11). It is therefore possible that all these POMC-derived peptides may act in concert to affect body weight and food intake in response to leptin.It has been clearly demonstrated that leptin can regulate intracellular signaling in hypothalamic POMC neurons, including stimulation of phosphorylation of the signaltransducer and activator of transcription 3 (STAT3) transcription factor (12), induction of suppressor-of-cytokinesignaling 3 (SOCS-3) mRNA, and activation of c-Fos protein expression (13). In addition, leptin positively regulates ARC POMC mRNA levels (14,15), rapidly stimulates neuronal firing rates, and decreases the membrane potential (16), leading to release of mature POMC-derived neuropeptides (17,18).Leptin also acts directly on several brain regions outside the hypothalamus, including the nucleus of the solitary tract (NTS) in the caudal brainstem, as has been demonstrated by the localization of ObRb mRNA, rapid activation of STAT3 phosphorylation (P-STAT3), induction SOCS-3 gene expression, and stimulation of c-Fos in this brain region in response to leptin administration in rodents (12,19 -21). Furthermore, intra-NTS injection of leptin decreases food intake and body weight of rats (21), as has also been demonstrated by leptin injection into the arcuate of the hypothalamus (22) AgRP, agouti-related peptide-producing; ARC, arcuate nucleus; CCK, cholecystokinin; IHC, immunohistochemistry; MC3/4R, melanocortin-3 and -4 receptors; MSH, melanocyte-stimulating hormone; NTS, nucleus of the solitary tract; POMC, proopiomelanocortin; STAT3, signal-transducer and activator of transcription 3.

Differential effects of fasting and leptin on proopiomelanocortin peptides in the arcuate nucleus and in the nucleus of the solitary tract

“…Our data indicate that fasting alters the biosynthesis of POMCderived peptides in the NTS, although biosynthesis is not directly regulated by leptin. Recently, it was shown that fasting-induced reduction of pomc mRNA in the in the NTS was not reversed by leptin (26). These findings support our transcription data.…”

“…However, our results strongly indicate that this effect of leptin is not mediated by POMC-related peptides produced in the NTS. Different from our study and Huo et al (26), another laboratory suggested that peripheral administration of leptin induced pSTAT3 activation in about 30% of the POMC-EGFP neurons in the NTS (12). Although the phosphorylation of STAT3 is valid and widely used to indicate leptin signaling, pSTAT3 could participate in other signaling pathways independent of the biosynthesis of POMC.…”

Identification of neuronal subpopulations that project from hypothalamus to both liver and adipose tissue polysynaptically

“…Common neuronal populations in the NTS. NPY-and POMC-expressing cells are present in the NTS, and colocalization of POMC with GFP expression here has been confirmed in POMC-GFP mice (14). We confirmed the colocalization of NPY with GFP expression in the NTS of NPY-GFP mice.…”

Hindbrain leptin receptor stimulation enhances the anorexic response to cholecystokinin

“…Neurons in several feeding-relevant caudal brain stem nuclei, including the nucleus of the solitary tract (NTS, an area thought to be involved in satiety), express the long (signaling) form of the leptin receptor (7,13). Peripheral injection of leptin induces phosphorylation of STAT3 (pSTAT3, a marker of leptin receptor activation) in NTS cells (9,10), as well as in hypothalamic populations, adding strength to the suggestion that leptin acts directly on hindbrain sites. Furthermore, leptin injected into the dorsal vagal complex (DVC, which contains the NTS, area postrema, and dorsal motor nucleus of the vagus nerve) reduces food intake and body weight at doses that are subthreshold for such effects following ventricular administration (7).…”