Emerging role of the brain in the homeostatic regulation of energy and glucose metabolism

Abstract

Accumulated evidence from genetic animal models suggests that the brain, particularly the hypothalamus, has a key role in the homeostatic regulation of energy and glucose metabolism. The brain integrates multiple metabolic inputs from the periphery through nutrients, gut-derived satiety signals and adiposity-related hormones. The brain modulates various aspects of metabolism, such as food intake, energy expenditure, insulin secretion, hepatic glucose production and glucose/fatty acid metabolism in adipose tissue and skeletal muscle. Highly coordinated interactions between the brain and peripheral metabolic organs are critical for the maintenance of energy and glucose homeostasis. Defective crosstalk between the brain and peripheral organs contributes to the development of obesity and type 2 diabetes. Here we comprehensively review the above topics, discussing the main findings related to the role of the brain in the homeostatic regulation of energy and glucose metabolism.

Figure 1

Integration of peripheral metabolic signals andthe central nervous system maintains energy homeostasis. The brain integrates metabolic signals from peripheral tissues such as the liver, pancreas, adipose tissue, gut and muscle. Specialized neuronal networks in the brain coordinate adaptive changes in food intake and energy expenditure in response to altered metabolic conditions. Neuropeptide Y/agouti-related protein- and proopiomelanocortin-producing neurons in the hypothalamic arcuate nucleus primarily sense the body energy state. These neurons project to other hypothalamic nuclei and to the nucleus of the solitary tract in the brain stem to control multiple aspects of the homeostatic regulation of energy balance. ARC, arcuate nucleus; CCK, cholecystokinin; GLP-1, glucagon-like peptide-1; IL-6, interleukin-6; PP, pancreatic polypeptide; PVN, paraventricular nucleus; PYY, peptide YY.

Figure 2

Brain regulation of glucose homeostasis. The brain senses peripheral metabolic signals through hormones (insulin, leptin and so on) and nutrients (glucose, free fatty acids and so on) to regulate glucose metabolism. The sites of the convergence of these metabolic signals are the hypothalamus and brain stem. The autonomic nervous system intervenes in the brain and peripheral metabolic organs to modulate pancreatic insulin/glucagon secretion, hepatic glucose production and skeletal muscle glucose uptake. AP, area postrema; ARC, arcuate nucleus; BLM, basolateral medulla; DMN, dorsomedial nucleus; DMNX, dorsal motor nucleus of the vagus; FFA, free fatty acids; LH, lateral hypothalamus; NTS, nucleus of the solitary tract; PNS, parasympathetic nervous system; PVN, paraventricular nucleus; SNS, sympathetic nervous system; VMH, ventromedial hypothalamus.

Figure 3

Pathogenesis of obesity and type 2 diabetes due to defective central regulation of energy and glucose homeostasis. Reduced nutrient sensing and impaired insulin and leptin signaling in the hypothalamus may result in a positive energy balance and predispose weight gain, causing insulin resistance in peripheral metabolic organs. Obesity-associated insulin resistance may lead to type 2 diabetes when it is combined with β-cell dysfunction. IRS, insulin receptor substrate; PI3K, phosphatidylinositol 3 kinase; STAT3, signal transducer and activator of transcription 3.