It is now well recognized that there are numerous peripheral and central signaling systems that regulate food intake and energy balance (1–5). Because food is ultimately the only source of energy, it follows that food intake must be carefully regulated: balancing hunger and the drive to eat with energy stores and metabolic demands to maintain adequate levels of energy to ensure survival. For most animals, the amount of available food is generally limited, and a long-term excess of stored energy is rarely observed. In the last 10 to 20 years in Western society, this has not been the case with regard to food supply. The availability of cheap, highly palatable, energy dense foods has led to an explosion in overconsumption. This, coupled with a general reduction in physical activity, has figured prominently in the rising prevalence of obesity, which has now reached “epidemic” proportions (6). In the final session of the symposium “The Neurobiology of Obesity,” the proceedings of which form this supplement of Obesity Research, four papers were presented that dealt with some of the regulatory systems that control food intake and energy balance. In this short overview, a perspective on these papers will be provided. In the first of these papers, Rexford Ahima outlines how adipose tissue—the primary energy store—is itself a regulatory system for energy balance. Adipose tissue responds to nutrients, neural, and hormonal signals with the release of hormones and paracrine signaling molecules, termed adipokines, that control food intake and energy metabolism, as well as immune and neuroendocrine function (1). Of the numerous adipokines now identified, leptin remains the principal signal of adiposity (7). Leptin is the product of the ob gene, and mice deficient in this gene display hyperphagia, massive obesity, and metabolic syndrome. If energy stores fall, for example, during fasting, leptin levels are reduced, and food intake is stimulated. In addition, a range of other energy-sparing metabolic and cellular processes are activated. The hypothalamus is probably the primary region where integration of leptin signaling occurs in the brain, but extrahypothalamic sites in the brainstem or midbrain that express leptin receptors may be important and, as pointed out by Ahima, have yet to be fully explored. The question of how peripherally released adipokines activate central neurons, remains to be fully elucidated. For leptin, the answer lies with transporters, not yet cloned and sequenced, located on the blood–brain barrier that allow it to enter the parenchyma intact (8). However, for many adipokines, transporters have been neither identified nor may even exist. Adiponectin is one such example. Adiponectin plays an important role in promoting insulin sensitivity, potentiates the effects of leptin, and when injected inside the brain, activates central neurons (1,9). However, there is no evidence that it crosses the blood–brain barrier (10,11). Currently, it is not resolved whether adiponectin acts in the brain under physiological conditions. However, resolution of this issue may lie in activation of neurons in circumventricular organs (12)—central structures that lie outside of the blood–brain barrier—which activate other central neurons. Alternatively, adipokines may activate endothelial cells of brain microvessels, which release secondary mediators to activate neurons inside the blood–brain barrier (11). Future work that is directed at how peripheral signals activate central neurons remains a high priority. As noted above, animals (and humans) lacking a functional copy of the leptin gene become severely obese (7). However, in common forms of obesity, leptin levels are not reduced, but, in fact, are elevated. Hyperleptinemia in common obesity is not associated with reduced food intake or increased energy expenditure, suggesting that neurons become resistant to its actions. Leptin resistance is discussed by Enriori et al., who highlight recent data that shows resistance to leptin in the hypothalamic nuclei that coordinate the regulation of energy expenditure and food intake. Hotchkiss Brain Institute and Institute of Infection, Immunity and Inflammation, Department of Physiology and Biophysics, University of Calgary, Calgary, Alberta, Canada. Address correspondence to Keith Sharkey, Department of Physiology and Biophysics, 3330 Hospital Drive NW, University of Calgary, Calgary, Alberta, Canada T2N 4N1. Email: ksharkey@ucalgary.ca Copyright © 2006 NAASO
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Dec 21, 2018
Anna Bakhman + 4
Open Access