Leptin: Primary Central Site of Action?

Abstract

The discovery of the fat hormone leptin 16 yr ago (1) heralded an explosion in obesity research that continues to this day. The original premise that this hormone acted simply as an adipostat directing appropriate energy balance regulatory output in the brain has comprehensively unfurled to reveal a far more complex picture. Inevitably perhaps, as the complexity increases so does the controversy. In keeping with this trend, the paper by Qi et al. (2) published in the current issue of Endocrinology calls into question the primacy of the hypothalamic arcuate nucleus in the central leptin signaling pathway. The widely accepted model is that adipocyte-derived leptin acts on first-order neurons in the hypothalamic arcuate nucleus, and the message is relayed to second-order neurons in other hypothalamic regions such as the dorsomedial nucleus, ventromedial nucleus, paraventricularnucleus, and lateral hypothalamic area (3–5). From a multitude of animal experiments, it is unequivocal that the central actions of leptin are anorexigenic. Thus, hypoleptinemia is a powerful orexigenic signal during fasting, and leptin administration decreases appetite and body weight (3–5). Early experiments also reported the pivotal importance of the arcuate nucleus to this response because the anorectic effects of peripherally and centrally administered leptin were abolished in rats following monosodium glutamate lesion of the arcuate nucleus (6, 7). In addition, it has been demonstrated that reactivation of the leptin receptor specifically in the arcuate nucleus leads to decreased food intake and body weight in leptin receptordeficient mice (8) and rats (9). Clearly, receptor distribution provides a good indication of sites of action, and there is fairly universal agreement on the distribution of the signaling (long) form of the leptin receptor in the brain. Thus, it is localized in the arcuate, dorsomedial, ventromedial and paraventricular nuclei, and the lateral hypothalamic area of the adult hypothalamus, regions known to be involved in energy balance and appetite control but with the highest density in the arcuate nucleus (10). Primary targets for leptin in the arcuate nucleus have long been identified as proopiomelanocortin and neuropeptide Y neurons, which coexpress the leptin receptor and in which leptin induces phosphorylation of the signal transducer and activator of transcription 3, a marker of leptin receptor activation (3–5, 10). It follows that deletion of the leptin receptor specifically in arcuate proopiomelanocortin and neuropeptide Y neurons of mice would result in a hyperphagic and obese phenotype; however, the effects on food intake and adiposity are less extreme compared with global leptin receptor deletion, indicating that other leptin-regulated pathways are also involved (11, 12). As mentioned above, the leptin receptor shows a wider hypothalamic distribution besides the arcuate nucleus and leptin receptor deletion specifically in the ventromedial nucleus also results in increased body weight and adiposity in mice (13). Indeed, neuronal activation in many hypothalamic sites is reported in response to leptin administration in rodents (10, 14). However, it remains equivocal whether the responses of different hypothalamic nuclei to leptin are independent or orchestrated by the arcuate nucleus. Now Qi et al. (2) report novel evidence for direct action of leptin on cells in the dorsal, ventromedial, and paraventricular hypothalamic nuclei in sheep, in the presence or absence of an arcuatenucleus.Thus, they found immunostaining for fos, a marker of neuronal activation, in the dorsal, ventromedial and paraventricular hypothalamic nuclei following peripheral leptin administration in their model of hypothalamo-pituitary disconnection in which the arcuate is