Hypothalamic sensing of ketone bodies after prolonged cerebral exposure leads to metabolic control dysregulation.

Lionel Carneiro,Xavier Fioramonti,Audrey Hébert,Corinne Leloup,Sarah Geller,Cendrine Repond,Luc Pellerin

doi:10.1038/srep34909

Abstract

Ketone bodies have been shown to transiently stimulate food intake and modify energy homeostasis regulatory systems following cerebral infusion for a moderate period of time (<6 hours). As ketone bodies are usually enhanced during episodes of fasting, this effect might correspond to a physiological regulation. In contrast, ketone bodies levels remain elevated for prolonged periods during obesity, and thus could play an important role in the development of this pathology. In order to understand this transition, ketone bodies were infused through a catheter inserted in the carotid to directly stimulate the brain for a period of 24 hours. Food ingested and blood circulating parameters involved in metabolic control as well as glucose homeostasis were determined. Results show that ketone bodies infusion for 24 hours increased food intake associated with a stimulation of hypothalamic orexigenic neuropeptides. Moreover, insulinemia was increased and caused a decrease in glucose production despite an increased resistance to insulin. The present study confirms that ketone bodies reaching the brain stimulates food intake. Moreover, we provide evidence that a prolonged hyperketonemia leads to a dysregulation of energy homeostasis control mechanisms. Finally, this study shows that brain exposure to ketone bodies alters insulin signaling and consequently glucose homeostasis.

Highlights

During fasting periods, obesity, or type 1 diabetes, their concentration increases and the brain starts to significantly use ketone bodies when their concentration rises above 4 mM, which corresponds to the Km of the ketone bodies transporter MCT1 expressed by the cerebral blood vessels[13,19,20,21]
The results presented by the authors support the idea that astrocytic ketogenesis in the hypothalamus induced by an increase in fatty acid metabolism is responsible for the food intake inhibition observed after 3 days of high fat diet[36,37]
Food intake and blood profile modifications induced by a 24h infusion of β-hydroxybutyrate (BHB) to the brain

Summary

Introduction

During fasting periods, obesity, or type 1 diabetes, their concentration increases and the brain starts to significantly use ketone bodies when their concentration rises above 4 mM, which corresponds to the Km of the ketone bodies transporter MCT1 expressed by the cerebral blood vessels[13,19,20,21]. The results presented by the authors support the idea that astrocytic ketogenesis in the hypothalamus induced by an increase in fatty acid metabolism is responsible for the food intake inhibition observed after 3 days of high fat diet[36,37] Such results are contradictory with our previous results[29], but the different strategies used (high fat diet vs carotidic infusion) associated with different time points (3 days vs 12 h) and in different animal models (rats vs mice) most likely explain such differences. A short-term infusion of 12 hours mimics a physiological increase in ketonemia and it activates the normal adaptive mechanism during a fast Notwithstanding, these previous studies concur to indicate that a modification of ketone bodies levels, whether on a short-term or a long-term basis, plays a particular and complex role in the control of energy homeostasis that is still far from being understood. Our hypothesis is that the physiological counterregulatory response previously unraveled after a 12-hour period might recede over a longer exposure time period, paving the way to pathophysiological alterations later on

Methods

Results

Conclusion