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.

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Although cholesterol plays various important roles in the body, when overconsumed, it causes atherosclerosis and results in ischemic heart disease. On the other hand, dietary fish oils contain n-3 fatty acids, such as eicosapentaenoic acid and docosahexaenoic acid, which prevent ischemic heart disease. This effect of n-3 fatty acids mainly results from the combined effects of inhibiting lipogenesis via a decrease of the mature form of sterol regulatory element-binding proteins (SREBPs) and stimulating fatty acid oxidation via peroxisome proliferator-activator receptor (PPAR) alpha activation in the liver. In this study, we examined the interactive effects on lipid metabolism of dietary 2% cholesterol (w/w) and 20% or 50% energy fish oil. In a safflower oil diet with 2% cholesterol, hepatic lipids accumulated. On the other hand, hepatic lipids did not accumulate in the fish oil diets with cholesterol. Furthermore, in the groups with fish oil energy ratios of 20%, the negative feedback control of cholesterol affected SREBP-2, and the actions of fish oil and cholesterol were equivalent, but this was not observed in the cases with fish oil energy ratios of 50%. The results of this study suggest that differences in lipid accumulation in the body are due to differences in lipid source and energy ratios which differentially impact the control of transcription factors by cholesterol.

Galanin-like peptide (GALP) has an anti-obesity effect in rats and mice. It has been reported that the uptake of GALP by the brain is higher after intranasal administration than with intravenous injection. This study therefore aimed to clarify the effect of intranasal administration of GALP on the feeding behavior of lean and obese mice. Autoradiography revealed the presence of 125I-GALP in the olfactory bulb and the brain microcirculation. The body weights of ob/ob mice gradually increased during vehicle treatment, but remained unchanged in response to repeated intranasal administration of GALP, with both ob/ob and diet-induced obese mice displaying significantly decreased food intake, water intake and locomotor activity when treated with GALP. These results suggest that intranasal administration is an effective route whereby GALP can exert its effect as an anti-obesity drug.