Melanocortin activation of nucleus of the solitary tract avoids anorectic tachyphylaxis and induces prolonged weight loss.
To examine the role of the brain stem melanocortin system in long-term energy regulation, we assessed the effects of overproduction of proopiomelanocortin (POMC) in the caudal brain stem of F344xBN rats with adult-onset obesity. Recombinant adeno-associated viral vector encoding POMC gene was delivered to the nucleus of solitary tract (NTS) in the hindbrain, and food intake, body weight, glucose and fat metabolism, brown adipose tissue thermogenesis, and mRNA levels of neuropeptides and melanocortin receptors were assessed. POMC delivery resulted in sustained reduction in food intake and body weight over 42 days and improved insulin sensitivity. At death, in recombinant adeno-associated viral vector-POMC-treated rats vs. control rats, alpha-melanocyte-stimulating hormone in NTS increased nearly 21-fold, whereas hypothalamic alpha-melanocyte-stimulating hormone remained unchanged. Visceral adiposity decreased by 37%; tissue triglyceride content diminished by 26% and 47% in liver and muscle, respectively; serum triglyceride and nonesterified fatty acids were reduced by 35% and 34%, respectively; phosphorylation of acetyl-CoA carboxylase was elevated by 63% in soleus muscle; brown adipose tissue uncoupling protein 1 increased by 30%; and melanocortin 3 receptor expression declined by 60%, whereas neuropeptide Y, agouti-related protein, and MC4 receptor mRNA levels were unchanged in the NTS. In conclusion, POMC overexpression in the NTS produces a characteristic unabated hypophagia that is uniquely different from the anorexic tachyphylaxis following POMC overexpression in the hypothalamus. The sustained anorectic response may result from absence of compensatory elements in the NTS, such as increased agouti-related protein expression, suggesting melanocortin activation of the brain stem may be a viable strategy to alleviate obesity.
Li
Gang
G
Department of Pharmacology and Therapeutics, University of Florida College of Medicine, Gainesville, Florida 32610, USA.
Zhang
Yi
Y
Rodrigues
Enda
E
Zheng
Donghang
D
Matheny
Michael
M
Cheng
Kit-Yan
KY
Scarpace
Philip J
PJ
D050154:Adiposity / Q000235:genetics; D000818:Animals; D030801:Animals, Genetically Modified; D000855:Anorexia / Q000139:chemically induced / Q000517:prevention & control*; D001069:Appetite Regulation / Q000235:genetics; D001835:Body Weight; D004734:Energy Metabolism / Q000235:genetics; D005786:Gene Expression Regulation; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D020738:Leptin / Q000097:blood; D008297:Male; D053486:Melanocortins / Q000235:genetics* / Q000378:metabolism; D009765:Obesity / Q000235:genetics / Q000378:metabolism / Q000628:therapy; D011333:Pro-Opiomelanocortin / Q000235:genetics / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D017552:Solitary Nucleus / Q000378:metabolism*; D013618:Tachyphylaxis / Q000235:genetics; D013997:Time Factors; D015431:Weight Loss / Q000235:genetics*; D000521:alpha-MSH / Q000235:genetics / Q000378:metabolism
D020738:Leptin; D053486:Melanocortins; D000521:alpha-MSH; D011333:Pro-Opiomelanocortin