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The hypothalamic AMP-kinase regulates feeding behavior in response to hormonal and nutrient signals. Decrease of AMP-kinase activity in the paraventricular (PVH) and arcuate hypothalamus plays an important role in anorexic effect of leptin. However, the effect of AMP-kinase on long-term energy balance remains to be established. In the present study, we examined the effect of chronic expression of constitutively-active AMP-kinase (CA-AMPK) in the PVH on food intake and body weight in male C57/BL6 mice, using lenti-viral vector with synapsin 1 promotor. CA-AMPK in the PVH significantly increased body weight (CA-AMPK mice: 11.0 ± 1.5 g vs. the control mice: 3.5 ± 0.3 g, during 3 months after the infection). CA-AMPK mice also increased food intake before the increase in body weight (CA-AMPK mice: 14.8 ± 0.9 kcal vs. control mice: 12.9 ± 0.1 kcal/day, I month after the infection). Interestingly, CA-AMPK mice increased food intake only under high carbohydrate diet (lob chow or high sucrose diet) but not under high fat diet (60% Fat). In contrast, the control mice increased the intake of high fat diet but not high carbohydrate diet (intake of high fat diet in CA-AMPK mice: 11.7 ± 0.9 kcal and in the control mice: 16.5 ± 0.9 kcal/day). When both high sucrose and high fat diets were simultaneously available, CA-AMPK mice chose high sucrose diet, whereas the control mice chose high fat diet. CA-AMPK increased the mRNA expression of fatty acid oxidation-related genes in the PVH such as PPAR alpha, FATP1, acyl-CoA synthetase 1 and CPT1c. Direct administration of etomoxir, an inhibitor of CPT-1 and fatty acid oxidation in mitochondria, into the PVH in the CA-AMPK mice, reversed to the high preference for high fat diet. Thus, these findings suggest that AMP-kinase in the PVH regulates not only calorie intake but also the preference for carbohydrate and fat diets. AMP-kinase in the PVH may control the food preference by changing fatty acid metabolism in the nucleus. [ABSTRACT FROM AUTHOR]