Fuel sensing and the central nervous system (CNS): implications for the regulation of energy balance and the treatment for obesity

Abstract

This review describes the product of the 3-day International Association for the Study of Obesity (IASO) Stock Conference held in March 2004 and sponsored by Abbott Laboratories. The conference was focused on how the mechanisms by which individual cells sense their own fuel status might influence the energy balance of the entire organism. Whether you are a single-celled organism or a sophisticated mammal with a large cerebral cortex, it is critical that cellular activity be matched to the available fuel necessary for that activity. Rapid progress has been made in the last decade in our understanding of the critical metabolic events that cells monitor to accomplish this critical task. More recent developments have begun to apply this understanding to how critical populations of neurones may monitor similar events to control both food intake and energy expenditure. The picture that emerges is that numerous peripheral fuel sensors communicate to the central nervous system (CNS) via neural and humoral routes. Moreover, it has been known for decades that specific populations of neurones sense changes in ambient glucose levels and adjust their firing rate in response and changes in neuronal glucose metabolism can influence energy balance. The CNS, however, does not just sense glucose but rather appears to be sensitive to a wide range of metabolic perturbations associated with fuel availability. This information is used to adjust both caloric intake and the disposition of fuels in the periphery. Increased understanding of these CNS fuel-sensing mechanisms may lead to novel therapeutic targets for obesity.

A role for sweet taste: Calorie predictive relations in energy regulation by rats.

“…However, rather than exhibiting less weight gain and adiposity, the rats in the nonpredictive groups that ate the lower calorie, saccharin-sweetened yogurt gained more weight and body fat than did rats in the predictive groups that ate the higher calorie yogurt sweetened with glucose. The finding that consuming a lower calorie food yielded more weight gain and body adiposity than did consuming an equal amount of a higher calorie version of the same food appears to pose difficulties for views that emphasize the homeostatic aspects of energy regulation (Cummings & Overduin, 2007;Murphy & Bloom, 2006;Seeley & York, 2005).…”

Biology's response to dieting: the impetus for weight regain

“…3A). Levels of glucose are detected by nutrientsensing systems in both the periphery (15,41,56,130,212) and brain (111,130), with consequences to energy balance and fuel utilization in the periphery. TGs may even be sensed via their putative effects on leptin and insulin transport across the blood-brain barrier (13,108,232).…”

Neuronal control of energy homeostasis

“…This promoted a new flourish of gene discoveries, which identified novel neuropeptides, their receptors and transcription factors that mediate leptin function in the hypothalamus and subsequently, led to the discovery of the hypothalamic melanocortin system, the key neuronal system in the control of energy balance by leptin signaling. Other metabolic signals, such as insulin, ghrelin, estrogen, prolactin, glucocorticoids, resistin and interleukins, etc., as well as nutrients such as glucose and free fatty acids [21][22][23], which, to a certain extent, modify energy balance and body weight, also target the hypothalamic melanocortin system [16,5,[24][25][26], presumably in coordination with leptin function.…”