Leptin Increases Hypothalamic Pro-opiomelanocortin mRNA Expression in the Rostral Arcuate Nucleus

Abstract

Melanocortins are peptides, cleaved from the pro-opiomelanocortin (POMC) precursor, that act in the brain to reduce food intake and are potential mediators of leptin action. In the forebrain, melanocortins are derived from POMC-containing neurons of the hypothalamic arcuate nucleus. To test the hypothesis that these POMC neurons are regulated by leptin, we used in situ hybridization to determine whether reduced leptin signaling (as occurs in fasting), genetic leptin deficiency (in obese ob/ob mice), or genetic leptin resistance (in obese db/db mice) lower expression of POMC mRNA. We further hypothesized that leptin administration would raise hypothalamic POMC mRNA levels in leptin-deficient animals, but not in mice with defective leptin receptors. In wild-type mice (n = 12), fasting for 48 h lowered POMC mRNA levels in the rostral arcuate nucleus by 53%, relative to values in fed controls (n = 8; P < 0.001). Similarly, arcuate nucleus POMC mRNA levels were reduced by 46 and 70% in genetically obese ob/ob (n = 6) and db/db mice (n = 6), respectively, as compared with wild-type mice (n = 5) (P < 0.01 for both comparisons). Five daily intraperitoneal injections of recombinant murine leptin (150 microg) raised levels of POMC mRNA in the rostral arcuate nucleus of ob/ob mice (n = 8) by 73% over saline-treated ob/ob control values (n = 8; P < 0.01), but was without effect in db/db mice (n = 6). In normal rats, two injections of a low dose of leptin (3.5 microg) into the third cerebral ventricle (n = 15) during a 40-h period of fasting also increased POMC mRNA levels in the rostral arcuate nucleus to values 39% greater than those in vehicle-treated controls (n = 14; P = 0.02). We conclude that reduced central nervous system leptin signaling owing to fasting or to genetic defects in leptin or its receptor lower POMC mRNA levels in the rostral arcuate nucleus. The finding that leptin reverses this effect in ob/ob, but not db/db, mice suggests that leptin stimulates arcuate nucleus POMC gene expression via a pathway involving leptin receptors. These findings support the hypothesis that leptin signaling in the brain involves activation of the hypothalamic melanocortin system.

AgRP(83–132) and SHU9119 differently affect activity-based anorexia

“…Up-regulation of POMC mRNA contrasts with the widely described down-regulation of anorexigenic neuropeptides during food restriction (Schwartz et al, 1997) and is probably a result of a unique situation of limited food access along with physical activity. Previously, we observed that physical activity per se does not result in up-regulation of POMC gene expression (Hillebrand et al, 2005c;.…”

Caloric restriction: Impact upon pituitary function and reproduction

“…POMC can be differentially cleaved by proteases to generate an array of hormones (adrenocorticotrophic hormone [ACTH], lipotropin, corticotrophin-like intermediate peptide [CLIP], melanocyte-stimulating hormone [MSH] and β-endorphin) that exert multiple effects crucial in linking the organism's metabolic state to its reproductive capacity. The expression of POMC mRNA is significantly reduced by CR implemented upon rats, mice and also primates (Bergendahl et al, 1992;Koegler et al, 2001;Schwartz et al, 1997;Mizuno et al, 1998). The proteolytic cleavage products themselves of POMC have differential effects on the reproductive axis, e.g.…”

Body weight is regulated by the brain: a link between feeding and emotion

“…For example, most of POMC-expressing Arc neurons coexpress Ob-Rb mRNA. 73 Leptin increases POMC mRNA in the Arc 74 and induces the expression of c-fos and SOCS-3 mRNA in Arc POMC neurons. 65,66 In addition, POMC mRNA in the Arc is markedly reduced in leptin-deficient ob/ob mice as well as in fasted rodents (when leptin levels rapidly fall).…”

“…75,76 The decrease in POMC expression is prevented by leptin administration. [74][75][76] Finally, leptin directly depolarizes POMC neurons. 69 Of importance, a-MSH acts as an agonist for the melanocortin-4 receptor (MC4-R), 70,77,78 a Gs-proteincoupled receptor distributed in the CNS.…”