Obesity and the central nervous system

Abstract

The past decade has witnessed an explosion of information regarding the role of the central nervous system in the development of obesity and the influence of peripheral, hormonal signals that modulate CNS regulation of energy homeostasis. A Journal of Physiology Symposium held in Washington, DC in association with the 2007 Experimental Biology meeting focused on recent work defining central neural mechanisms that mediate ingestive behaviour and the central effects of peripheral hormonal signals that modulate feeding. A crowd estimated at 500 was treated to a series of talks by leaders in the field who discussed state-of-the-art data and models regarding the brain as an initiator of obesity and as a target organ of peripheral feedback signals that regulate feeding behaviour. The opening speaker, Dr Barry Levin, provided a very informative and entertaining overview of his work that some obesity-prone individuals have an inborn reduction in their ability to sense and respond to inhibitory signals from adipose stores and other organs which ordinarily limit their intake of energy when in excess of metabolic needs (see Levin, 2007). Furthermore, the physiological processes which drive all of us to seek and ingest food and limit energy expenditure during periods of negative energy balance provide an irresistible drive to regain lost adipose stores in weight-reduced obese individuals. This provides a potential basis for the well-recognized difficulty of maintaining weight loss. For this reason, prevention of obesity and the identification of factors that promote the development of neural pathways which enhance the sensitivity to negative feedback signals from the periphery should be a major focus of research. Dr Mary Dallman spoke next and presented a very interesting and compelling case for peripheral signals, specifically glucocorticoids and insulin, as modulators of the central pathways that regulate ingestive behaviour (see Dallman et al. 2007). Glucocorticoids act primarily in a feed-forward fashion on brain to activate CNS pathways that implement wanting appropriate to physiological needs. Thus, depending on the available conditions, elevated glucocorticoids may augment the behavioural desire to run, fight or feed. Although glucocorticoids stimulate intake of chow, fat and sucrose, insulin appears to sculpt calorie-associated desires toward foods high in fat, acting through hepatic branch afferents of the vagus nerve. Conditions of reduced food allowance and chronic stress excite glucocorticoid-augmented central neural networks that may ultimately lead toward ultimate abdominal obesity. This provides a potential link between stress and obesity. Dr Gregory Morton presented a creative use of gene targeting and viral gene therapy to rescue leptin-receptors in the arcuate nucleus of Koletsky rats that lack leptin receptor protein (see Morton, 2007). Growing evidence suggests that hypothalamic areas that respond to a variety of peripheral signals regulate food intake, energy expenditure and endogenous glucose production. 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. Finally, Dr Steven Heymsfield reviewed the development program for MK-0557, a highly selective and potent antagonist of the NPY5 receptor by the Merck Research Laboratories. About one decade ago it became clear that the neuropeptide Y-5 receptor is involved in food intake regulation, with agonism increasing intake. Merck launched an intensive programme leading to the discovery of MK-0557 (an NPY5R antagonist). The successful preclinical work was followed by PET and pharmacokinetic studies in humans that supported safety and receptor occupancy. A short-term positive proof of concept weight loss study then led to a large long-term series of clinical trials which ultimately demonstrated that the antagonist resulted in minimal weight loss. Many lessons in neurobiology and drug development can be learned from this progression of studies. The overall goal is that the understanding of how and why certain individuals gain weight and the central mechanisms that make it difficult to sustain weight loss might lead to therapeutic potential to prevent the process, rather than deal with its consequences in already obese individuals. Insights into the central neural networks that regulate food intake and how these networks are modulated provide a very promising avenue towards achieving these goals.