In a recent issue of Minokoshi and colleagues

In a recent issue of , Minokoshi and colleagues have added more light to our understanding of the role of hypothalamic AMPK in the regulation of energy balance. Previous seminal work from the same group suggested that AMPK in the PVH might be involved in the modulation of feeding . Here, they show that mice stereotaxically treated in the PVH with lentiviruses encoding a constitutively active AMPK (CA-AMPK) gained more weight when fed a normal laboratory chow, demonstrating that activation of AMPK in this nucleus is important for energy balance. Notably, when fed a high-fat diet (HFD), CA-AMPK mice gained less weight than controls, which prompted investigation into the food intake patterns in these mice maintained in different diets, namely, standard laboratory chow, high-carbohydrate diet (HCD), and HFD. Their data showed that HCD was preferred by mice in two-diet choice experiments, independently of the source of carbohydrates (sucrose or cornstarch) or fat (lard or coconut oil) and the nutritional state of the mice (fed or fasted) (). This effect was mainly due to differences in the feeding during the dark phase and did not affect the total caloric intake of the mice, when compared with their controls . To investigate the molecular underpinnings of this effect, the authors looked into the possible involvement of fatty YM 155 oxidation in the PVH, since it is known that AMPK plays a major role in regulating this process , . Their data showed that the effect of AMPK activation was mediated by carnitine palmitoyltransferase 1c (CPT1c), as demonstrated by the fact that genetic knockdown or pharmacological blockage of CPT1c promoted an increase in HFD after refeeding , a situation that normally increases carbohydrate intake. Finally, by using a combination of colocalization, pharmacological, virogenetic, pharmacogenetic, and electrophysiology studies, they identified a subclass of corticotropin-releasing hormone (CRH)-positive neurons in the rostral region of the PVH as the key neuronal population where the effect of AMPK on carbohydrate preference takes place. Specifically, the activation of the AMPK–CPT1c axis promoted a Ca-induced activation of CRH neurons, which is necessary for HCD choice behavior . The importance of these findings is that although a role of the PVH in macronutrient selection has been known, the molecular mechanisms mediating this action were unclear. This is of relevance, because the preference of palatable HFD meals has increased in the current world, which is having an impact in the obesity pandemic. The progression of obesity relies on a persistent state of positive energy balance. For this reason, it seems reasonable that many strategies for treating obesity have been focused only in decreasing food intake. However, to date, all drugs that exclusively and directly target appetite have failed, among other reasons because of the compensatory decreases in EE. Therefore, it is imperative to have a deeper understanding of the major homeostatic mechanisms modulating energy homeostasis. The new evidence presented in this study shows that besides its function regulating homeostatic food intake , and EE , , AMPK plays a major role in food predilection . The fact that one single molecule may control all these aspects makes it an interesting and unique candidate for obesity treatment , suggesting that the targeting of AMPK in specific sets of neurons might be considered as the force for a more rational design of drugs to combat the dark side of metabolic disease, that is, obesity and its comorbidities. Acknowledgments The author thanks Dr Johan Fernø (University of Bergen, Norway) for English language editing. This work has received funding from Xunta de Galicia (2015-CP079), Ministry of Economy and Competitiveness (SAF2015-71026-R), and Atresmedia. CIBER de Fisiopatología de la Obesidad y Nutrición is an initiative of ISCIII. The funders had no role in decision to publish, or preparation of the manuscript.