Overexpression of CART in the PVN increases food intake and weight gain in rats.

Abstract

Cocaine- and amphetamine-regulated transcript (CART) codes for a hypothalamic neuropeptide, CART (55-102), which inhibits food intake. Intracerebroventricular injection of CART (55-102) reduces appetite, but also results in motor abnormalities. More recently, studies have demonstrated that administration of CART directly into the paraventricular nucleus (PVN) increases food intake. To investigate the role of CART in the regulation of energy balance in the PVN, we used recombinant adeno-associated virus (rAAV) to overexpress CART in the PVN. Male Wistar rats were injected with either rAAV-encoding CART (rAAV-CART) or rAAV-encoding enhanced green fluorescent protein (rAAV-EGFP) as a control. Food intake and body weight were measured regularly. Animals were fed on normal-chow diet for the first 93 days of the study. After this point, they were fed on high-fat diet. Animals were killed 138 days postinjection and blood and tissues were collected for analysis. Overexpression of CART in the PVN resulted in increased cumulative food intake and body weight gain compared with rAAV-EGFP controls when fed normal chow. These changes became significant at day 65 and 79, respectively and were accentuated on a high-fat diet. A 4% increase in food intake was observed in rAAV-CART animals on a normal-chow diet and a 6% increase when fed a high-fat diet. At the end of the study, rAAV-CART-treated animals had higher circulating leptin concentrations in accord with their higher body weight. These data provide further evidence that hypothalamic CART plays an orexigenic role.