We next focused on other central components that could mediate the effects of nicotine on energy balance. Nicotine-treated rats showed a marked decrease in phosphorylation of hypothalamic AMPKα (pAMPKα) and its molecular target ACCα (pACCα) compared with vehicle-treated rats (Fig. 2E). The reduction in pAMPKα levels was associated with unaltered protein concentrations of the nonphosphorylated isoforms of AMPKα1 and AMPKα2. ACCα levels were reduced in the hypothalamus of nicotine-treated rats (Fig. 2E). AMPK is regulated in a tissue-specific fashion, normally opposite between brain and peripheral tissues. For example, AMPK activation promotes fatty acid oxidation and glucose uptake in skeletal muscle, whereas conversely, hepatic AMPK activity inhibits fatty acid and cholesterol synthesis. In the hypothalamus AMPK activation elicits feeding and inhibits EE (8,11,14–18). Thus, we analyzed the effect of nicotine on the AMPK pathway in liver and skeletal muscle. Our data show that 48-h nicotine treatment did not induce changes in this metabolic pathway either in liver (Supplementary Fig. 1A) or muscle (Supplementary Fig. 1B).
