Activation of AMPK-Regulated CRH Neurons in the PVH is Sufficient and Necessary to Induce Dietary Preference for Carbohydrate over Fat

Abstract

Food selection is essential for metabolic homeostasis and is influenced by nutritional state, food palatability, and social factors such as stress. However, the mechanism responsible for selection between a high-carbohydrate diet (HCD) and a high-fat diet (HFD) remains unknown. Here, we show that activation of a subset of corticotropin-releasing hormone (CRH)-positive neurons in the rostral region of the paraventricular hypothalamus (PVH) induces selection of an HCD over an HFD in mice during refeeding after fasting, resulting in a rapid recovery from the change in ketone metabolism. These neurons manifest activation of AMP-activated protein kinase (AMPK) during food deprivation, and this activation is necessary and sufficient for selection of an HCD over an HFD. Furthermore, this effect is mediated by carnitine palmitoyltransferase 1c (CPT1c). Thus, our results identify the specific neurons and intracellular signaling pathway responsible for regulation of the complex behavior of selection between an HCD and an HFD. VIDEO ABSTRACT.

Role of oxytocin in the control of stress and food intake

“…[225][226][227] Arcuate AgRP neurones project to the medial amygdala neurones that innervate the posterior bed nucleus of the stria terminalis, and this AgRP-medial amygdala-bed nucleus of the stria terminalis pathway has been shown to be involved in fasting-induced behavioural changes in mice. 231 Glucocorticoid administration has also been shown to increase food intake, especially intake of carbohydrates and proteins, in humans 232 possibly via activation of brain reward systems. Furthermore, NPY has anxiolytic actions.…”

“…A CRH1 receptor antagonist has been reported to suppress stress-induced eating in humans, 230 and CRH neurones have been shown to induce preference for a high-carbohydrate diet in mice. 231 Glucocorticoid administration has also been shown to increase food intake, especially intake of carbohydrates and proteins, in humans 232 possibly via activation of brain reward systems. 187 Social defeat stress has been shown to facilitate ghrelin release and stress-induced hyperphagia is impaired in ghrelin receptor-deficient mice.…”

Hypothalamic AMPK and energy balance

“…Interestingly, the two models exhibited different phenotypes: while POMC AMPKα2 KO mice developed obesity due to hyperphagia, AgRP AMPKα2 KO mice developed an age‐dependent lean phenotype . Current evidence has also shown that AMPK in the paraventricular nucleus of the hypothalamus (PVH) modulates dietary preference for carbohydrate over fat, expanding the role of hypothalamic AMPK on feeding control. However, despite the undeniable role of AMPK in the modulation of feeding, several recent studies might indicate that the effects of hypothalamic AMPK observed on body weight changes are more likely associated with an altered energy expenditure than to a modification of food intake …”

Hypothalamic AMPK as a Mediator of Hormonal Regulation of Energy Balance

“…Hypothalamic AMPK modulates the functions of different neuronal populations (such as POMC and NPY/AgRP neurons), thereby controlling appetite and energy consumption to maintain energy homeostasis [ 45 , 46 ]. In addition, hypothalamic AMPK has been shown to control dietary selection, first- and second-phase insulin secretion, lipid metabolism, and hepatic gluconeogenesis, all of which are crucial for energy balance at the whole-body level [ 47 , 48 , 49 , 50 ]. Early studies revealed that pharmacological or adenovirus-mediated activation of AMPK in the medial hypothalamus significantly promotes food intake as a result of increased transcriptional levels of NPY and AgRP [ 51 , 52 ].…”