Hypothalamic Leptin Gene Therapy and Caloric Restriction Have Differential Effects on Energy Intake and Energy Partitioning in Adult Female Rats

Abstract

ObjectivesWeight gain during middle age is associated with several chronic diseases. Dieting is a common but often ineffective long-term strategy for stabilizing body weight at optimal levels for health. Similar to humans, middle-aged rats exhibit progressive weight gain and are a useful model for evaluating strategies for controlling weight. The adipokine leptin is an important regulator of appetite and energy expenditure but peripheral hyperleptinemia is associated with leptin resistance and may contribute to chronic inflammation. Here we compared the effects of increasing leptin levels selectively in the hypothalamus using gene therapy with conventional caloric restriction (CR) on weight gain, food consumption, serum leptin, abdominal white adipose tissue, and bone marrow adipose tissue in nine-month-old female rats. MethodsRats (n = 16) were implanted with a cannula in the 3rd ventricle of the hypothalamus and injected with adeno-associated virus encoding a recombinant rat gene for leptin (rAAV-lep) and maintained on standard rat chow for 18 weeks. A control group (n = 15) was calorically restricted (CR) to match the weight of the rAAV-lep group. ResultsBoth approaches were effective in preventing weight gain. However, rAAV-lep rats consumed 16% more food and had higher brown adipose tissue Ucp-1 mRNA expression than CR rats. Additionally, compared to CR rats, rAAV-lep rats had lower abdominal white adipose tissue mass, lower serum leptin levels, and lower bone marrow adiposity. ConclusionsHypothalamic leptin gene therapy and CR, while equally effective in preventing weight gain, differ in their effects on energy intake, expenditure and body composition. Our findings suggest that increasing hypothalamic leptin levels has advantages (e.g., desirable body composition and unrestricted food intake) over conventional CR as a strategy for preventing age-related weight gain. Funding SourcesNIH AR060913.