Autonomic Nervous System in Obesity and Insulin-Resistance-The Complex Interplay between Leptin and Central Nervous System

Abstract

The role of the autonomic nervous system in obesity and insulin-resistant conditions has been largely explored. However, the exact mechanisms involved in this relation have not been completely elucidated yet, since most of these mechanisms display a bi-directional effect. Insulin-resistance, for instance, can be caused by sympathetic activation, but, in turn, the associated hyperinsulinemia can activate the sympathetic branch of the autonomic nervous system. The picture is made even more complex by the implicated neural, hormonal and nutritional mechanisms. Among them, leptin plays a pivotal role, being involved not only in appetite regulation and glucose homeostasis but also in energy expenditure. The purpose of this review is to offer a comprehensive view of the complex interplay between leptin and the central nervous system, providing further insights on the impact of autonomic nervous system balance on adipose tissue and insulin-resistance. Furthermore, the link between the circadian clock and leptin and its effect on metabolism and energy balance will be evaluated.

Keywords: autonomic nervous system (ANS); central nervous system (CNS); insulin-resistance; leptin.

Figure 1

Peripheral signals of sense of satiety, after gastric distension, reach the nucleus of the solitary tract/area prostrema complex (NTS/AP) via afferent vagal nerves (green line). The NTS projects to the dorsal motor nucleus (DMN). This pathway modulates glucose production, gastrointestinal motility and hormone release (cholecystokinin, CCK; peptide YY, PYY; glucagon-like peptide-1, GLP-1), and pancreatic secretion via efferent vagal nerves (light blue line). The suggested site of action of vagal nerve stimulation (VNS) is indicated by the dotted purple lines, while the mechanism of weight loss hypothesized vagal nerve blockade (VBLOC) includes a decrease in gastric emptying and inhibition of pancreatic exocrine secretion (dotted red lines) [5].

Figure 2

Relationship between obesity and blood pressure (BP). Insulin-mediated sympathetic stimulation is a mechanism recruited in the obese to restore energy balance by increasing metabolic rate. The increased BP is related to the increased levels of insulin and sympathetic nervous system (SNS) activity [3].

Figure 3

The concept of selective leptin resistance. The sympatho-excitatory effects of leptin on the cardiovascular system are maintained through its action in the brain region of the DMH, while its metabolic effects result ineffective, suggesting that some form of obesity may be characterized by a “selective leptin resistance” [36]. DMH, dorsomedial hypothalamus.

Figure 4

Cold exposure- or food intake-stimulated sympathetic activation through leptin action results in lipolysis in white adipose tissue (WAT) and thermogenesis in brown adipose tissue (BAT) and beige fat (Beige AT). Sympathetic nervous system (SNS) activated by leptin results in mobilization from WAT of free fatty acids (FFA), which are then used by BAT inducing heat production. Sympathetic activation also induces the formation of Beige AT through the browning of WAT, which contributes to adaptive thermogenesis [5].

Figure 5

Leptin has an effect on appetite and insulin-glucose axis. In the hypothalamus, leptin activates pro-piomelacortin/cocaine-and-amphetamine responsive transcript (POMC/CART) neurons and inhibits neuropeptide Y/agouti-related peptide (NPY/AgRP) neurons, leading to anorexia. (A) In leptin-sensitive individuals, leptin inhibits insulin production and secretion from pancreatic beta cells while insulin stimulates leptin secretion from adipose tissue. Leptin increases glucose uptake in skeletal muscle tissue and stimulates liver insulin sensitivity via the sympathetic nervous system (SNS). (B)The leptin-resistant overweight individuals are resistant to the anorectic and weight-reducing effects of leptin, despite the increase in plasma leptin levels. Leptin resistance leads to hyperinsulinemia which, in turn, increases plasma leptin [45]. ARC, arcuate nucleus; LHA lateral hypothalamic area; NTS nucleus of the solitary tract; PVN, periventricular nucleus.

Figure 6

The leptin endocrine feedback loop to maintain the homeostasis of energy balance. In the CNS, the SCN clock rhythmically transmits the signal to the peripheral adipose tissue clock and potentiates the response of ARC neurons to circulating leptin. In white adipocytes, the BMAL1/CLOCK heterodimer that received signals from SCN directly controls leptin expression by regulating the activity of C/EBPα. Leptin stimulates SNS activity via the ARC of the hypothalamus to maintain energy homeostasis [54]. CNS, central nervous system; SCN, suprachiasmatic nucleus; ARC, arcuate nucleus; C/EBPα, CCAATenhancer-binding protein alpha; SNS, sympathetic nervous system.