Central leptin gene therapy fails to overcome leptin resistance associated with diet-induced obesity.
The objective of this study was to determine if central overexpression of leptin could overcome the leptin resistance caused by 100 days of high-fat feeding. Three-month old-F344XBN male rats were fed either control low fat chow (Chow), which provides 15% of energy as fat, or a high-fat/high-sucrose diet (HF), which provides 59% of energy as fat. Over several weeks, the HF-fed animals spontaneously split into two groups of animals: those that became obese on the HF diet (DIO) and those that did not gain extra weight on the HF diet [diet resistant (DR)]. After 100 days of HF feeding, animals were given a single intracerebroventricular injection containing 5.75E10 particles of rAAV encoding leptin (rAAV-leptin) or control virus (rAAV-con). Chow animals responded robustly to rAAV-leptin, including significant anorexia, weight loss, and lipopenia. In contrast, DIO were completely unresponsive to rAAV-leptin. DR rats responded to rAAV-leptin, but in a more variable fashion than Chow. Unlike what was observed in Chow, the anorectic response to rAAV-leptin rapidly attenuated and was no longer significant by day 14 postvector delivery. Both DIO and DR animals were found to have reduced long-form leptin receptor expression and enhanced basal P-STAT-3 in the hypothalamus with respect to Chow. rAAV-leptin caused an increase in STAT3 phosphorylation and proopiomelanocortin expression in the hypothalamus and an increase in uncoupling protein-1 in brown adipose tissue in both Chow and DR animals, but failed to do so in DIO. This suggests that central overexpression of leptin is not a viable strategy to reverse diet-induced obesity.
Wilsey
Jared
J
Geriatric Research, Education and Clinical Center, Dept. of Veterans Affairs Medical Center, Gainesville, FL 32608-1197, USA.
Zolotukhin
Sergei
S
Prima
Victor
V
Scarpace
Philip J
PJ
D002001:Adipose Tissue, Brown / Q000378:metabolism; D000818:Animals; D001835:Body Weight; D002352:Carrier Proteins / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D004041:Dietary Fats / Q000494:pharmacology; D004435:Eating; D005230:Fatty Acids, Nonesterified / Q000097:blood; D015870:Gene Expression; D015316:Genetic Therapy; D007473:Ion Channels; D020738:Leptin / Q000097:blood / Q000235:genetics*; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D024101:Mitochondrial Proteins; D009478:Neuropeptide Y / Q000235:genetics; D009765:Obesity / Q000209:etiology / Q000378:metabolism* / Q000628:therapy*; D010101:Oxygen Consumption; D011333:Pro-Opiomelanocortin / Q000235:genetics; D051381:Rats; D011914:Rats, Inbred BN; D011916:Rats, Inbred F344; D011956:Receptors, Cell Surface / Q000235:genetics; D054411:Receptors, Leptin; D050796:STAT3 Transcription Factor; D015534:Trans-Activators / Q000378:metabolism; D019076:Transgenes / Q000502:physiology; D017211:Treatment Failure; D000071256:Uncoupling Protein 1
D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D004041:Dietary Fats; D005230:Fatty Acids, Nonesterified; D007473:Ion Channels; D020738:Leptin; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D009478:Neuropeptide Y; D011956:Receptors, Cell Surface; D054411:Receptors, Leptin; D050796:STAT3 Transcription Factor; C494088:Stat3 protein, rat; D015534:Trans-Activators; C000604373:Ucp1 protein, rat; D000071256:Uncoupling Protein 1; D011333:Pro-Opiomelanocortin