AMPK controls feeding by directly regulating neuropeptide expression in the ARC (16–18) and also regulates EE by modulating thermogenesis in BAT via the SNS (7,8,41). In this study we aimed to investigate whether nicotine-induced negative energy balance was mediated by specific modulation of the hypothalamic AMPK pathway. Our findings show that nicotine decreases body weight through its combined effects of hypophagia and increased thermogenesis in BAT, in addition to driving elevated locomotor activity and increased lipid mobilization (demonstrated by a lower RQ). In keeping with former reports (3,19–22,39,40), nicotine also decreased the expression of ARC orexigenic neuropeptides such as AgRP and NPY and increased POMC expression. Our data indicate that at the same dose that caused anorexia, nicotine inhibited the hypothalamic AMPK pathway. This effect, as well as the aforementioned actions, was reversed by nicotine cessation and antagonism of α3β4 nicotinic acetylcholine receptors, which have recently been demonstrated to be involved in the action of nicotine in the hypothalamus (3). Together, these results suggest the existence of a mechanistic link between hypothalamic AMPK function and nicotine-induced changes in energy homeostasis.
