Leptin expression in hypothalamic PVN reverses dietary obesity and hyperinsulinemia but stimulates ghrelin.
OBJECTIVE
In order to circumvent the multiple peripheral effects of hyperleptinemia and leptin resistance, the efficacy of leptin transgene expression in the hypothalamic paraventricular nucleus (PVN) to reinstate the central energy homeostasis in obesity was examined.


METHODS
A recombinant adeno-associated viral vector encoding either leptin (rAAV-lep) or green fluorescent protein (rAAV-GFP) was microinjected into the PVN of obesity-prone rats consuming a high-fat diet (HFD).


RESULTS
rAAV-lep, and not rAAV-GFP, microinjection significantly reduced energy intake and enhanced energy expenditure, thereby resulting in normalization of weight and blood levels of leptin, insulin, free fatty acids, and glucose concomitant with enhanced ghrelin secretion during the extended period of observation.


CONCLUSIONS
Thus, we show, for the first time, that amelioration of leptin insufficiency with enhanced localized leptin availability in the PVN alone can reverse dietary obesity and the attendant hyperinsulinemia and concurrently block the central stimulatory effects of elevated endogenous ghrelin on food intake and adiposity.
Bagnasco
Michela
M
Department of Neuroscience, McKnight Brain Institute, University of Florida, Gainesville, Florida 32610-0244, USA.
Dube
Michael G
MG
Katz
Adi
A
Kalra
Pushpa S
PS
Kalra
Satya P
SP
D000256:Adenoviridae / Q000235:genetics; D002001:Adipose Tissue, Brown / Q000378:metabolism; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D004041:Dietary Fats / Q000378:metabolism; D004435:Eating / Q000502:physiology; D005230:Fatty Acids, Nonesterified / Q000097:blood / Q000378:metabolism; D005260:Female; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D054439:Ghrelin; D006946:Hyperinsulinism / Q000097:blood / Q000235:genetics / Q000378:metabolism / Q000628:therapy*; D007473:Ion Channels; D020738:Leptin / Q000096:biosynthesis* / Q000097:blood / Q000235:genetics; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D008845:Microinjections; D024101:Mitochondrial Proteins; D009765:Obesity / Q000097:blood / Q000235:genetics / Q000378:metabolism / Q000628:therapy*; D010286:Paraventricular Hypothalamic Nucleus / Q000378:metabolism* / Q000502:physiology; D036361:Peptide Hormones / Q000096:biosynthesis* / Q000097:blood; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000071256:Uncoupling Protein 1
D002352:Carrier Proteins; D004041:Dietary Fats; D005230:Fatty Acids, Nonesterified; D054439:Ghrelin; D007473:Ion Channels; D020738:Leptin; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D036361:Peptide Hormones; D012333:RNA, Messenger; D000071256:Uncoupling Protein 1