Central leptin gene therapy suppresses body weight gain, adiposity and serum insulin without affecting food consumption in normal rats: a long-term study.
The weight-reducing effects of leptin are predominantly mediated through the hypothalamus in the brain. Gene therapy strategies designed for weight control have so far tested the short-term effect of peripherally delivered viral vectors encoding the leptin gene. In order to circumvent the multiple peripheral effects of hyperleptinemia and to overcome the age-related development of leptin resistance due to multiple factors, including defective leptin transport across the blood brain barrier, we determined whether delivery of viral vectors directly into the brain is a viable therapeutic strategy for long-term weight control in normal wild-type rats. A recombinant adeno-associated virus (rAAV) vector encoding rat leptin (Ob) cDNA was generated (rAAV-betaOb). When administered once intracerebroventricularly (i.c.v.), rAAV-betaOb suppressed the normal time-related weight gain for extended periods of time in adult Sprague-Dawley rats. The vector expression was confirmed by immunocytochemical localization of GFP and RT-PCR analysis of leptin in the hypothalamus. This sustained restraint on weight gain was not due to shifts in caloric consumption because food-intake was similar in rAAV-betaOb-treated and rAAV-GFP-treated control rats throughout the experiment. Weight gain suppression, first apparent after 2 weeks, was a result of reduced white fat depots and was accompanied by drastically reduced serum leptin and insulin concentrations in conjunction with normoglycemia. Additionally, there was a marked increase in uncoupling protein-1 (UCP1) mRNA expression in brown adipose tissue, thereby indicating increased energy expenditure through thermogenesis. Seemingly, a selective enhancement in energy expenditure following central delivery of the leptin gene is a viable therapeutic strategy to control the age-related weight gain and provide protection from the accompanying multiple peripheral effects of hyperleptinemia and hyperinsulinemia.
Dhillon
H
H
Department of Physiology, College of Medicine, Box 100274, University of Florida, Gainesville, FL 32610-0274, USA.
Kalra
S P
SP
Prima
V
V
Zolotukhin
S
S
Scarpace
P J
PJ
Moldawer
L L
LL
Muzyczka
N
N
Kalra
P S
PS
D000256:Adenoviridae / Q000235:genetics; D000273:Adipose Tissue / Q000378:metabolism* / Q000503:physiopathology; D002001:Adipose Tissue, Brown / Q000378:metabolism; D000375:Aging / Q000097:blood / Q000235:genetics / Q000502:physiology; D000818:Animals; D001823:Body Composition / Q000235:genetics; D002352:Carrier Proteins / Q000378:metabolism; D005247:Feeding Behavior; D005260:Female; D015316:Genetic Therapy / Q000379:methods; D005822:Genetic Vectors / Q000008:administration & dosage / Q000235:genetics; D049452:Green Fluorescent Proteins; D007031:Hypothalamus / Q000378:metabolism; D007150:Immunohistochemistry; D007276:Injections, Intraventricular; D007328:Insulin / Q000097:blood*; D007329:Insulin Antagonists / Q000008:administration & dosage*; D007473:Ion Channels; D020738:Leptin / Q000008:administration & dosage / Q000096:biosynthesis / Q000097:blood / Q000235:genetics*; D008164:Luminescent Proteins / Q000032:analysis; D008565:Membrane Proteins / Q000378:metabolism; D024101:Mitochondrial Proteins; D009765:Obesity / Q000235:genetics / Q000517:prevention & control*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D000071256:Uncoupling Protein 1; D015430:Weight Gain / Q000235:genetics*
D002352:Carrier Proteins; D007328:Insulin; D007329:Insulin Antagonists; D007473:Ion Channels; D020738:Leptin; D008164:Luminescent Proteins; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D012333:RNA, Messenger; C000604373:Ucp1 protein, rat; D000071256:Uncoupling Protein 1; D049452:Green Fluorescent Proteins