Hypothalamic pro-opiomelanocortin gene delivery ameliorates obesity and glucose intolerance in aged rats.
OBJECTIVE
Age-related obesity is associated with impaired hypothalamic pro-opiomelanocortin (Pomc) gene expression. We assessed whether overproduction of POMC in the hypothalamus ameliorates age-related obesity in rats.


METHODS
Recombinant adeno-associated virus (rAAV) encoding Pomc (rAAV-Pomc) or control vector was delivered bilaterally into the basomedial hypothalamus of aged obese rats with coordinates targeting the arcuate nucleus. Energy balance, glucose metabolism, brown adipose tissue thermogenesis and mRNA levels of hypothalamic neuropeptides and melanocortin receptors were assessed.


RESULTS
Forty-two days after Pomc gene delivery, hypothalamic Pomc expression increased 12-fold while agouti-related protein and neuropeptide Y mRNA levels remained unchanged. Using a punch technique, we detected the highest Pomc RNA level in the arcuate nucleus. Pomc overexpression reduced food consumption from day 10 after vector injection, but this anorexic effect abated by day 30. In contrast, there was a steady decrease in body weight without apparent attenuation. Pomc gene delivery decreased visceral adiposity and induced uncoupling protein 1 in brown adipose tissue in aged rats. Serum NEFA and triglyceride levels were also diminished by rAAV-Pomc treatment. Improved glucose metabolism and insulin sensitivity were observed on day 36 but not day 20 after Pomc gene delivery. The expression of hypothalamic melanocortin 3 and 4 receptor decreased by 17% and 25%, respectively in rAAV-Pomc rats.


CONCLUSIONS
This study demonstrates that targeted Pomc gene therapy in the hypothalamus reduces body weight and visceral adiposity, and improves glucose and fat metabolism in aged obese rats. Thus long-term activation of the central melanocortin system may be a viable strategy to combat age-related obesity and diabetes.
Li
G
G
Department of Pharmacology and Therapeutics, University of Florida College of Medicine, Gainesville, FL, USA.
Zhang
Y
Y
Wilsey
J T
JT
Scarpace
P J
PJ
D002001:Adipose Tissue, Brown / Q000187:drug effects / Q000378:metabolism; D000375:Aging / Q000502:physiology; D054369:Agouti-Related Protein; D000818:Animals; D001835:Body Weight / Q000235:genetics; D002784:Cholesterol / Q000097:blood; D000229:Dependovirus / Q000235:genetics; D004435:Eating; D005230:Fatty Acids, Nonesterified / Q000097:blood; D015316:Genetic Therapy / Q000379:methods; D005822:Genetic Vectors / Q000235:genetics / Q000494:pharmacology; D005947:Glucose / Q000378:metabolism; D018149:Glucose Intolerance / Q000235:genetics*; D005951:Glucose Tolerance Test / Q000379:methods; D007031:Hypothalamus / Q000187:drug effects*; D036341:Intercellular Signaling Peptides and Proteins; D020738:Leptin / Q000097:blood; D008297:Male; D009478:Neuropeptide Y / Q000187:drug effects / Q000235:genetics; D009765:Obesity / Q000235:genetics / Q000378:metabolism / Q000628:therapy*; D036361:Peptide Hormones / Q000187:drug effects / Q000235:genetics; D011333:Pro-Opiomelanocortin / Q000008:administration & dosage* / Q000235:genetics*; D051381:Rats; D011916:Rats, Inbred F344; D044104:Receptor, Melanocortin, Type 3 / Q000187:drug effects / Q000235:genetics; D044105:Receptor, Melanocortin, Type 4 / Q000187:drug effects / Q000235:genetics; D014280:Triglycerides / Q000097:blood
C515197:AGRP protein, rat; D054369:Agouti-Related Protein; D005230:Fatty Acids, Nonesterified; D036341:Intercellular Signaling Peptides and Proteins; D020738:Leptin; D009478:Neuropeptide Y; D036361:Peptide Hormones; D044104:Receptor, Melanocortin, Type 3; D044105:Receptor, Melanocortin, Type 4; D014280:Triglycerides; D011333:Pro-Opiomelanocortin; D002784:Cholesterol; D005947:Glucose