In summary, we show for the first time that nicotine inactivates hypothalamic AMPK and this effect mediates decreased food intake and BAT activation, likely via the SNS (23,24,38). Whether nicotine administration or smoking activates the AMPK-BAT axis in humans remains to be determined, but it is well known that EE is increased in smokers and that this effect may be mediated in part by the SNS (48). Thus, it is tempting to speculate that negative energy balance induced by cigarette smoking may be mediated by the specific activation of the hypothalamic AMPK-BAT axis, a possibility that will require further investigation. Although nicotine is not considered the most harmful component of cigarette smoke, and in fact has been reported to have potentially beneficial effects on mental health (49,50), our results should not be construed as supporting continued tobacco use as a treatment option. It is noteworthy that our observation provides new insights into the molecular actions of nicotine and suggest that evaluating candidate drugs modulating the hypothalamic AMPK-BAT axis (7,8,41) may provide a more targeted approach to develop new therapeutic targets. These targets may be relevant not just for the treatment of obesity, but also for smoking cessation in humans.
