Hypothalamic leptin regulation of energy homeostasis and glucose metabolism

Abstract

Growing evidence suggests that food intake, energy expenditure and endogenous glucose production are regulated by hypothalamic areas that respond to a variety of peripheral signals. Therefore, in response to a reduction in energy stores or circulating nutrients, the brain initiates responses in order to promote positive energy balance to restore and maintain energy and glucose homeostasis. In contrast, in times of nutrient abundance and excess energy storage, key hypothalamic areas activate responses to promote negative energy balance (i.e. reduced food intake and increased energy expenditure) and decreased nutrient availability (reduced endogenous glucose production). Accordingly, impaired responses or 'resistance' to afferent input from these hormonal or nutrient-related signals would be predicted to favour weight gain and insulin resistance and may contribute to the development of obesity and type 2 diabetes.

Figure 1. Model depicting the central control of energy homeostasis and glucose metabolism

Neuronal systems sense input from adiposity signals (e.g. insulin and leptin) and nutrient-related signals (FFAs) and activate responses to regulate food intake, energy expenditure and hepatic glucose production (adapted from Schwartz & Porte, 2005).

Figure 2. Model of the hypothalamic regulation of hepatic glucose production

Both insulin activation of the IRS-PI3K pathway and increased concentration of LCFA-CoA levels in the ARC are proposed to activate second-order neurons that project to hindbrain areas. In response to this input, output of motor neurons of the vagus nerve that supply the liver is increased (adapted from Pocai et al. 2005b). ARC, arcuate nucleus; NTS, nucleus of the solitary tract; FFA, free fatty acids.

Figure 3. Model of the hypothalamic neurocircuits involved in glucose metabolism

Insulin and leptin act in the arcuate nucleus (ARC) to inhibit NPY/AgRP neurons and activate pro-opiomelanocortin (POMC) neurons. Both neuronal subsets project to other hypothalamic areas including the paraventricular nucleus (PVN) and lateral hypothalamic area (LHA). Activation of neuronal projections from these hypothalamic neurons to hindbrain areas, such as the nucleus of the solitary tract (NTS), generates a vagal signal to the liver to regulate hepatic glucose production. 3V, third ventricle.