Investigating the physiological role of hypothalamic glucokinase in appetite and glucose homeostasis

Abstract

The brain relies on glucose as a source of energy. Mechanisms that promote the taste-independent intake of glucose have been proposed but not demonstrated. The arcuate nucleus (ARC) of the hypothalamus plays a critical role in regulating energy homoeostasis. It acts as a metabolic sensing unit responding to diverse signals, including glucose, to regulate appetite. Glucokinase is a glucose-sensing enzyme expressed in the ARC. The work in this thesis aims to investigate the physiological role of ARC glucokinase in energy homoeostasis. Recombinant adeno-associated virus (rAAV) expressing the pancreatic form of rat glucokinase mRNA (rAAV-GKS) was stereotactically delivered to the ARC of male Wistar rats (iARC-GKS). This approach specifically increased glucokinase activity in the ARC as compared to control rats (iARC-GFP). Pharmacological and genetic increase in ARC glucokinase activity resulted in a significant increase in food intake. Longitudinal experiments demonstrated that this food intake resulted in a significant increase in body weight and adiposity on normal chow and high-energy diets. Further work demonstrated that ARC glucokinase specifically promotes the intake of glucose, but not of fructose, and that the orexigenic effect of ARC glucokinase is driven by specific increase in appetite for glucose. Similar changes in glucose appetite and food intake were demonstrated to occur with alterations in ARC ATP-sensitive potassium (KATP) channel activation. Glucose-stimulated NPY release was increased with increased ARC glucokinase activity. This suggests that ARC glucokinase mediates its orexigenic glucose appetite promoting effects in part via altered KATP channel activation and NPY release, which is consistent with previous work. This work identifies ARC glucokinase as a regulator of glucose appetite and glucose appetite as an important driver of food intake. ARC glucokinase may represent the brain mechanism regulating the taste-independent intake of glucose and may underlie the phenomena of ‘sweet tooth’ and ‘carbohydrate craving’.