From lesions to leptin: hypothalamic control of food intake and body weight.

By 1940, Hetherington and Ranson had laid to rest most doubts regarding the importance of the hypothalamus in regulating body weight. However, their electrolytic lesions were inherently crude and started debate about which specific hypothalamic cell groups are critical in the control of feeding and body weight. Despite intense activity, during the 45 years that followed the discovery of the ventromedial nucleus syndrome, we learned relatively little about the actual pathways in the hypothalamus that mediate feeding. Because of the similarity of the leptin deficiency syndrome to the ventromedial nucleus syndrome, the discovery of leptin and its receptors revitalized the field. In fact, the original observations of Hetherington and Ranson, implicating the “ventromedial nucleus, but also including the adjacent arcuate nucleus and parts of the dorsomedial and ventral premammillary nuclei” in the regulation of feeding, have proven to be both prescient and surprisingly accurate in identifying the hypothalamic cell groups with the highest levels of long-form leptin receptors.In the 4 years since the discovery of leptin, there has been remarkable progress in studying the effects of starvation, leptin deprivation, and leptin administration on the expression of genes for transcription factors (c-fos), signaling molecules (SOCS-3), and neurotransmitters (neuropeptide Y, agouti-related protein, α-melanocyte stimulating hormone, CART, MCH, and ORX) involved in feeding. The availability of these molecular tools, coupled with tract tracing, has resulted in striking progress in dissecting an extensive network of hypothalamic circuitry that regulates feeding (Figure 8Figure 8). Despite the fact that a number of pieces of this puzzle are still missing, the outline of the hypothalamic system for regulation of feeding is now more clear. In retrospect, the ventromedial nucleus itself is only a part of this network. It sits, however, at the epicenter of a web of pathways, running between the arcuate nucleus and the paraventricular nucleus and lateral hypothalamus, and this epicenter defines the mechanisms of neuronal regulation of feeding.‡To whom correspondence should be addressed (e-mail: csaper@caregroup.harvard.edu).Figure 8A Schematic Drawing Summarizing Some of the Major Pathways and Neurotransmitters that Have Been Implicated in the Regulation of FeedingPathways that are activated by leptin (and therefore presumably have an anorexic influence) are illustrated in red, whereas those that are inhibited by leptin (and are presumed to have a phagic influence) are in green. Circadian influences are illustrated by dashed blue pathways. Leptin is proposed to exert its effects on the hypothalamus by entering through the median eminence. Note that a lesion centered on the ventromedial nucleus (VMH) and arcuate nucleus (ARC), such as that shown in Figure 1Figure 1, would eliminate leptin influence, resulting in hyperphagia and obesity. A lesion in the lateral hypothalamus (as in Figure 1Figure 1) that destroys the MCH and ORX cells, which promote feeding, would result in aphagia and inanition. Other abbreviations are the same as in Figure 1, Figure 4, Figure 6, Figure 7.View Large Image | View Hi-Res Image | Download PowerPoint Slide