Central insulin and leptin-mediated autonomic control of glucose homeostasis

Abstract

Largely as a result of rising obesity rates, the incidence of type 2 diabetes is escalating rapidly. Type 2 diabetes results from multi-organ dysfunctional glucose metabolism. Recent publications have highlighted hypothalamic insulin- and adipokine-sensing as a major determinant of peripheral glucose and insulin responsiveness. The preponderance of evidence indicates that the brain is the master regulator of glucose homeostasis, and that hypothalamic insulin and leptin signaling in particular play a crucial role in the development of insulin resistance. This review discusses the neuronal crosstalk between the hypothalamus, autonomic nervous system, and tissues associated with the pathogenesis of type 2 diabetes, and how hypothalamic insulin and leptin signaling are integral to maintaining normal glucose homeostasis.

Figure 1. Key autonomic connections

Previously identified intra-hypothalamic and extra-hypothalamic connections that mediate sympathetic and parasympathetic signal transduction to peripheral organs. PVH, paraventricular hypothalamus; LH, lateral hypothalamus; ARC, arcuate nucleus; VMH, ventromedial hypothalamus; DMH, dorsomedial hypothalamus; DVN, dorsal vagal nucleus; NTS, nucleus of the tractus solitarii; IML, intermediolateral cell column of the spinal cord.

Figure 2. Autonomic regulation of key organs involved in peripheral glucose and insulin metabolism

This diagram depicts the reciprocal nature of the autonomic nervous system in the pancreas, liver, WAT, BAT, and skeletal muscle. Pancreatic hormone release is in constant flux according to the circulating glucose and insulin levels. Hypothalamic dysfunction during states of obesity and/or insulin resistance could reduce sympathetic tone, leading to hyperactive parasympathetic outflow and a subsequent increase in pancreatic hormones. The opposite control paradigm operates in the liver where parasympathetic activation reduces hepatic glucose production. Whether increased hepatic glucose production during hepatic vagotomy is due to parasympathetic ablation or sympathetic hyperactivity is uncertain. WAT lipolysis is impaired with sympathetic denervation, whereas activation of sympathetic outflow via central melanocortin signaling enhances WAT lipolysis. BAT thermogenesis is under similar control by the autonomic nervous system. The sympathetic branch is involved in enhancing the expression of genes that promote thermogenesis. For both WAT and BAT the mechanism of reciprocity of the parasympathetic branch could operate similarly to that in the liver and pancreas. Skeletal muscle is more often associated with somatic innervation because of the voluntary nature of skeletal movement. However, sympathetic nervous system pathways play an important part in insulin-independent glucose uptake, a function that could be mediated by the VMH.

Figure 3. Proposed mechanism of hypothalamus-mediated glucose and insulin resistance

With long-term exposure to a positive energy balance, WAT depots expand. Leptin levels increase in proportion to adipose expansion, resulting in central leptin resistance. Central leptin resistance alters the neuropeptide environment favoring orexigenic peptides such as NPY in the hypothalamus. The altered neuropeptide environment results in altered parasympathetic and sympathetic outflow: increased hepatic glucose production, increased insulin production, reduced insulin-independent glucose production and skeletal muscle insulin resistance, and reduced adipose lipolysis. As circulating insulin levels rise, adipose, liver, pancreas, and hypothalamus become insulin-resistant, and this exacerbates the state of metabolic dysfunction. PNS, parasympathetic nervous system; SNS, sympathetic nervous system; SOCS-3, suppressor of cytokine signaling-3; STAT-3, signal transducer and activator of transcription-3; NPY, neuropeptide Y; POMC, proopiomelanocortin.