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| Leptin increases hypothalamic pro-opiomelanocortin mRNA expression in the rostral arcuate nucleus |
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| Author(s): Schwartz MW, Seeley RJ, Woods SC, Weigle DS, Campfield LA, Burn P, Baskin DG |
| Source: DIABETES Volume: 46 Issue: 12 Pages: 2119-2123 Published: DEC 1997 |
| Times Cited: 506 References: 29 |
| Abstract: Melanocortins are peptides, cleaved hom 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 Cin 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 mild-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 mild-type mice (n = 5) (P < 0.01 for both comparisons). Five daily intraperitoneal injections of recombinant murine leptin (150 pg) 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 mu g) 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 Cn = 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. |
| Document Type: Article |
| Language: English |
| Reprint Address: Schwartz, MW (reprint author), UNIV WASHINGTON, PUGET SOUND VA HLTH CARE SYST, DEPT MED, 1660 S COLUMBIAN WAY, SEATTLE, WA 98108 USA |
Addresses:
1. UNIV WASHINGTON, PUGET SOUND VA HLTH CARE SYST, DEPT PSYCHOL, SEATTLE, WA 98108 USA
2. UNIV WASHINGTON, PUGET SOUND VA HLTH CARE SYST, DEPT BIOL STRUCT, SEATTLE, WA 98108 USA
3. UNIV WASHINGTON, HARBORVIEW MED CTR, SEATTLE, WA 98104 USA
4. HOFFMANN LA ROCHE INC, DEPT METAB DIS, NUTLEY, NJ 07110 USA |
| Publisher: AMER DIABETES ASSOC, 1660 DUKE ST, ALEXANDRIA, VA 22314 |
| Subject Category: Endocrinology & Metabolism |
| IDS Number: YH805 |
| ISSN: 0012-1797 |
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