Energy Balance: A New Role for PPARα

The epidemic of obesity and its unfortunate sequelae — including, but not limited to, type 2 diabetes, cardiovascular disease and certain cancers — continues to grow. Fortunately, recent discoveries have inspired a veritable gold rush of scientific activity on energy balance in academic and industrial labs alike. As a consequence, we have learned more about the central and peripheral regulation of appetite, adiposity, energy expenditure and nutrient metabolism in the last decade than in the preceding 100 years. No area has drawn more attention than the control of food intake, a field that got a huge boost in 1994 with the discovery of the adipocyte-derived hormone leptin [1]. Following that seminal finding, a whole panoply of other endogenous peptides have been identified that also play important roles in regulating body weight, including the melanocortins, neuropeptide Y (NPY), ghrelin, melanin-concentrating hormone (MCH) and others [2,3]. An unusual fatty acid ethanolamide has recently been added to the list of molecules that affect food intake. This molecule, oleylethanolamide, has structural similarity to the endogenous cannabinoid anandamide [4]. Because cannabinoids can induce hunger — as is well known to marijuana smokers who get the ‘munchies’ — a group of researchers decided to test whether oleylethanolamide could also affect food intake in rodents. Interestingly, they found that oleylethanolamide suppresses food intake, an effect opposite to that of anandamide [5]. Subsequent experiments showed that oleylethanolamide does not interact with the cannabinoid receptor. These data indicated that fatty acid ethanolamides have a surprising range of functions in the control of appetite, and opened the door for the discovery of a new receptor involved in mediating this process. Many factors that regulate food intake, such as leptin and ghrelin, operate by directly stimulating receptors within the hypothalamus. These hormones interact with receptors on specific neurons in the arcuate nucleus, a region known to control appetite and body weight [2,3]. If small doses of leptin are injected directly into the central nervous system, for example, the effect is identical to that observed when the protein is administered peripherally. Other compounds affect appetite through both central and peripheral mechanisms. Cholecystokinin, for example, is a peptide secreted by the proximal small intestine in response to the ingestion of food, from whence it can act by direct stimulation of receptors in either the brain or the peripheral nervous system, specifically the vagus nerve [6]. If the vagus nerve is cut or damaged by a drug such as capsaicin, cholecystokinin’s ability to reduce food intake is reduced. Similar experiments have shown that peripheral afferent neurons are also important for the Dispatch Current Biology, Vol. 13, R961–R963, December 16, 2003, ©2003 Elsevier Science Ltd. All rights reserved. DOI 10.1016/j.cub.2003.11.043