Endocrine Abstracts (2003) 5 P180

Intra-hypothalamic gene transfer of cocaine and amphetamine regulated-transcript results in increased food intake and weight gain

HL Ward, JV Gardiner, KL Smith, WM Kong, NM Martin, CJ Small, MA Ghatei & SR Bloom

Department of Metabolic Medicine, Imperial College Faculty of Medicine, Hammersmith Campus, London, UK.

Cocaine and amphetamine regulated-transcript (CART) is highly expressed in the hypothalamus and was originally reported to be an endogenous satiety peptide. Intracerebroventricular injection of CART can result in motor abnormalities and recent studies have demonstrated increased food intake after intra-nuclear CART administration. To help clarify the situation CART was over-expressed in the hypothalamus using recombinant adeno-associated virus (rAAV-CART). Recombinant adeno-associated virus encoding enhanced green fluorescent protein (rAAV-EGFP) was used for control injections. rAAV-CART injection into the paraventricular nucleus of male Wistar rats (n=12-15) resulted in increased food intake and body weight gain. 138 days post-injection, at the end of the study (cumulative food intake 3963 plus/minus 46.8 grams rAAV-CART vs. 3725.2 plus/minus 68.1 grams rAAV-EGFP, p<0.05: cumulative body weight gain 281.1 plus/minus 10.8 grams rAAV-CART vs. 244.7 plus/minus 9.0 grams rAAV-EGFP, p<0.05).
Once cumulative body weight gain was statistically different rats underwent dietary manipulations. During a 24-hour fast (day 62-63) rAAV-CART animals lost more weight and consumed more chow during the refeed than controls (fast-induced loss [percentage pre-fast body weight] -5.6 plus/minus 0.2% rAAV-CART vs. -4.9 plus/minus 0.2% rAAV-EGFP, p<0.05 and food intake 9.3 plus/minus 0.4 grams rAAV-CART vs. 7.8 plus/minus 0.4grams rAAV-EGFP at 1 hour, p<0.05). High fat feeding was commenced 93 days post-injection. At the end of the study rAAV-CART treated animals had higher leptin concentrations 22.0 plus/minus 2.1 nanograms/millilitre rAAV-CART vs. 16.1 plus/minus1.4 nanograms/millilitre rAAV-EGFP, p<0.05. These data provide further evidence that CART has an orexigenic role in the hypothalamic feeding circuits.

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