Role of the Autonomic Nervous System and Neuropeptides in the Development of Obesity in Humans: Targets for Therapy?

Jerry   R.   Greenfield; Lesley   V.   Campbell

Abstract

Obesity and type 2 diabetes have reached epidemic proportions worldwide. These metabolic disorders, particularly obesity, are characterised by increased basal sympathetic nervous system (SNS) activity but an impaired sympathetic response to certain stimuli, such as insulin. Although targeting the SNS may seem an attractive avenue for the pharmacological prevention and treatment of obesity and related metabolic disorders, it remains unknown whether changes in SNS tone are primary and contribute to the development of these metabolic conditions or whether they develop secondary to the obese state. This question can be answered by the study of insulinresistant individuals prior to the development of obesity and type 2 diabetes. Using this model, it has been shown that early insulin resistance is associated with increased SNS activity in genetically-predisposed humans. It has been suggested that in insulin-resistant states, hyperinsulinaemia is the initiating factor that increases sympathetic neural activity. Over time, adrenoreceptor down-regulation and/or reduced sensitivity are likely to develop, resulting in reduced sympathetic responsiveness. In the postprandial state, this will lead to impaired diet-induced thermogenesis and post-prandial fat oxidation, promoting the accumulation of body fat. More recent evidence demonstrates that stress-induced SNS overactivity up-regulates Neuropeptide Y, an orexigenic hormone, and its Y2 receptor, in visceral adipose tissue, the fat depot most strongly linked to insulin resistance and type 2 diabetes. There is evidence that SNS overactivity specifically contributes to the development of abdominal obesity via this pathway, which could represent a novel target for the prevention and treatment of abdominal obesity and related metabolic consequences.

Keywords: Autonomic nervous system, sympathetic nervous system, insulin resistance, overweight, obesity, neuropeptide Y, Y2 receptor

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