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

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

Neurotensin Co-Expressed in Orexin-Producing Neurons in the Lateral Hypothalamus Plays an Important Role in Regulation of Sleep/Wakefulness States

<div><p>Both orexin and neurotensin are expressed in the lateral hypothalamic area (LHA) and have been implicated in the regulation of feeding, motor activity and the reward system. A double label immunofluorescence and <i>in situ</i> hybridization studies showed that neurotensin colocalizes with orexin in neurons of the LHA. Pharmacological studies suggested that neurotensin excites orexin-producing neurons (orexin neurons) through activation of neurotensin receptor-2 (NTSR-2) and non-selective cation channels. <i>In situ</i> hybridization study showed that most orexin neurons express <i>neurotensin receptor-2</i> mRNA but not <i>neurotensin receptor-1</i> (<i>Ntsr-1</i>) mRNA. Immunohistochemical studies showed that neurotensin-immunoreactive fibers make appositions to orexin neurons. A neurotensin receptor antagonist decreased Fos expression in orexin neurons and wakefulness time in wild type mice when administered intraperitoneally. However, the antagonist did not evoke any effect on these parameters in orexin neuron-ablated mice. These observations suggest the importance of neurotensin in maintaining activity of orexin neurons. The evidence presented here expands our understanding of the regulatory mechanism of orexin neurons.</p></div

A neurotensin receptor antagonist SR142948 dose-dependently decreased wakefulness time and duration during the lights on period in wild-type mice, but not in orexin neuron-ablated mice.

<p>Hourly amounts (A, B) and average episode duration (C, D) of awake, non-REM, and REM sleep states (mean±SE) plotted over 4 hr after administration of saline (dotted line) or SR142948 (solid line) in wild-type (n = 27, 14 and 7 for saline, SR 1 mg/kg, and 3 mg/kg, respectively) (A, C) and <i>orexin/ataxin-3</i> mice (n = 14, 14 and 7 for saline, SR 1 mg/kg, and 3 mg/kg, respectively) (B, D). Data for the dark phase are displayed in shaded panels. SR142948 was administered at the start of light or dark periods (8:45 or 20:45).</p

Neurotensinergic fibers appose orexin neurons.

<p><b>A</b>, Double immunofluorescence study shows that many varicose terminals with neurotensin-like immunoreactivity (green) make appositions to orexin neurons (red) in the LHA (Left panels). Right panel, high power view of rectangular region in left panel. <b>B</b>, Photomicrograph showing distribution of Fos (black nuclear label) and orexin (brown label) expression in LHA. Scale bar indicates 40 µm. Upper panels, left panel, control (saline injection); right panel, SR142948 injection at 20:45. Animals were sacrificed at 21:45 and subjected to immunostaining. Lower panels, left panel, control (saline injection); right panel, SR142948 injection at 8:45. Animals were sacrificed at 9:45 and subjected to immunostaining. <b>C</b>, SR142948 administration decreased Fos immunoreactivity of orexin neurons, but not in MCH neurons.</p