Figure 1. A schematic representation of the hypothalamic appetite-regulating circuitry in the rat. The arcuate nucleus (ARC) lies lateral to the ventral portion of the third ventricle (3V). Cells within the ARC produce proopiomelanocortin (POMC), the precursor gene for the satiety factor -melanocyte stimulating hormone (-MSH), or the orexigens neuropeptide Y (NPY) and agouti-related protein (AGRP). These cells have widespread projections to other appetite-regulating regions in the hypothalamus including the paraventricular nucleus (PVN), dorsomedial hypothalamus (DMH) and the lateral hypothalamic area (LHA); all three regions contain cells that express the Y1 and Y5 receptors (that bind NPY) or the melanocortin 3 and 4 receptors (MC3 R and MC4 R, that bind AGRP and -MSH). Arrows denote projection pathways extending between nuclei. In addition to the ARC, cells within the LHA also produce orexigenic peptides, orexin A and B and melanin-concentrating hormone (MCH), which exert their appetitive actions via the orexin 1 and 2 receptors (OX 1R and OX 2R) and the MCH 1 receptor (MCH 1R), distributed within the ARC, PVN, DMH and the ventromedial hypothalamus (VMH). This diagram illustrates the complex intra-hypothalamic circuitry implicated in the regulation of food intake and the maintenance of body weight and energy homeostasis.

Figure 2. A schematic diagram representing the different appetite-regulating pathways in the rodent compared to the sheep. In rodents, the efferent projections extending from the arcuate nucleus (ARC) to the paraventricular (PVN) have been largely implicated in the regulation of energy balance, in sheep however, few projections extend between these two nuclei indicating that this pathway is of less importance in the latter species (upper two panels). Conventional neuronal tracing techniques have failed to identify projections extending between the ARC and ventromedial hypothalamus (VMH) in rodents, albeit scanning photostimulation in brain slices suggests that cells within the VMH project to proopiomelanocortin (POMC)-containing cells of the ARC. This contrasts that in sheep, strong reciprocal projections between the neuropeptide Y (NPY) and POMC cells of the ARC and the VMH have been identified using anterograde and retrograde tracing techniques (middle panels). Furthermore, in rodents, the projection system extending from the ARC to the lateral hypothalamic area (LHA) has been well characterized. Orexin- and melanin-concentrating hormone (MCH)-positive cells of the LHA contain Y1 and Y5 as well as melanocortin (MC4) receptors (denoted by the purple and pink circles, respectively). It remains unknown as to whether orexin and MCH cells coexpress the NPY and melanocortin receptors. In spite of this, it is known that in sheep only a small number of NPY-positive cells project to the LHA (lower panels). This schematic figure demonstrates that various species-specific discrepancies exist in the topographical organization of appetite-regulating networks in the hypothalamus.

Figure 3. Illustration of the role of the peripheral hormones leptin, ghrelin and insulin in regulating energy homeostasis, particularly food intake and energy expenditure (thermogenesis). Leptin and insulin are synthesized and secreted by white fat and the pancreas, respectively, and act to inhibit feeding, whereas ghrelin is secreted by the stomach to increase feeding. In addition, leptin increases and ghrelin decreases thermogenic activity or energy expenditure.