Hypothalamic Responses to Fasting Indicate Metabolic Reprogramming Away from Glycolysis Toward Lipid Oxidation

Abstract

Nutrient-sensitive hypothalamic neurons regulate energy balance and glucose homeostasis, but the molecular mechanisms mediating hypothalamic responses to nutritional state remain incompletely characterized. To address these mechanisms, the present studies used quantitative PCR to characterize the expression of a panel of genes the hypothalamic expression by nutritional status of which had been suggested by DNA microarray studies. Although these genes regulate a variety of function, the most prominent set regulate intermediary metabolism, and the overall pattern clearly indicated that a 48-h fast produced a metabolic reprogramming away from glucose metabolism and toward the utilization of alternative fuels, particularly lipid metabolism. This general reprogramming of intermediary metabolism by fasting was observed both in cortex and hypothalamus but most prominently in hypothalamus. The effect of fasting on the expression of these genes may be mediated by reduction in plasma glucose or glucose metabolism, rather than leptin, because they were generally recapitulated by hypoglycemia even in the presence of elevated insulin and in vitro by low glucose but were not recapitulated in ob/ob mice. These studies suggest that fasting reduces glucose metabolism and thus minimizes the production of hypothalamic malonyl-coenzyme A. However, because the reprogramming of glucose metabolism by fasting was also observed in cortex, this apparent substrate competition may mediate more general responses to nutritional deprivation, including those responsible for the protective effects of dietary restriction. The present studies also provide a large panel of novel glucose-regulated genes that can be used as markers of glucose action to address mechanisms mediating hypothalamic responses to nutritional state.

Metabolic mystery: aging, obesity, diabetes, and the ventromedial hypothalamus

“…Furthermore, fasting induces the mobilization and metabolism of lipids in the hypothalamus that are required for molecular responses to fasting [46]. Consistent with these observations, Cpt1a in the VMH is induced by fasting in the VMH but not the cortex, rapidly reversed 4 hours after feeding [47]. FFAs are normally elevated by fasting, leading to the activation of the nuclear receptor peroxisome proliferator-activated receptor (Ppar)-alpha, which then induces Cpt1a (stimulating metabolism of FFAs) as well as genes that inhibit glucose metabolism, such as pyruvate dehydrogenase kinase, isozyme 4Pdk4 (PDK4) [48].…”

Hypothalamic Fkbp51 is induced by fasting, and elevated hypothalamic expression promotes obese phenotypes

“…Our initial screen assessed gene expression in a hypothalamic dissection that includes the VMN and the ARC, a portion of the PVN, but relatively little lateral hypothalamus (18). Extending these studies to microdissected nuclei, we observed that fasting induced Fkbp51 in all of these hypothalamic nuclei in both mice and rats (although not significantly in mouse PVN).…”

Mechanisms by Which the Ketogenic Diet Reverses Obesity and Diabetes

“…This was associated with a shift away from hypothalamic glucose metabolism and toward metabolism of alternative substrates, as we had previously observed during fasting, and which would be expected to cause obese phenotypes [52], as well as a reduction of hypothalamic POMC, which we had previously demonstrated is causally associated with obese and diabetic phenotypes [51][52][53]. We went on to demonstrate that experimental manipulation toward hypothalamic lipid metabolism (by over-expressing Cpt1a) also promoted obese phenotypes, including reduction of hypothalamic POMC, although not as robustly as inhibiting Cbp [51].…”