0013-7227/04/$15.00/0 Endocrinology 145(6):2621–2626 Printed in U.S.A. Copyright © 2004 by The Endocrine Society doi: 10.1210/en.2004-0231 Minireview: Leptin and Development of Hypothalamic Feeding Circuits SEBASTIEN G. BOURET AND RICHARD B. SIMERLY Oregon National Primate Research Center, Division of Neuroscience and Oregon Health and Science University, Beaverton, Oregon 97006 The arcuate nucleus of the hypothalamus (ARH) is a critical gest that leptin is required for normal development of ARH component of the forebrain pathways that regulate energy pathways and that this developmental activity of leptin is homeostasis, and it plays a particularly important role in re- restricted to a neonatal window of maximum sensitivity that laying leptin signal to other part of the hypothalamus. How- corresponds to a period of elevated leptin secretion. Thus, ever, until recently, little was known about the development leptin may function to organize formation of hypothalamic of these critical pathways. Recent work investigating the de- circuitry in much the same way that sex steroids act on sex- velopment of leptin-sensitive hypothalamic pathways sug- ually dimorphic circuits. Perturbations in perinatal nutrition gests possible developmental mechanisms that may contrib- that alter leptin levels may, therefore, have enduring conse- ute to obesity later in life. Anatomic findings indicate that quences for the formation and function of circuits regulating ARH circuits are structurally and functionally immature until food intake and body weight. (Endocrinology 145: 2621–2626, the third week of postnatal life in mice. Recent data also sug- 2004) URING THE PAST 30 yr, we have witnessed a 7-fold review will focus on the development of hypothalamic cir- D increase in the incidence of childhood obesity with cuits regulating feeding, paying particular attention to the accompanying increases in type II diabetes and other patho- development of projection pathways from the arcuate nu- logical conditions associated with obesity (1). In addition to cleus of the hypothalamus, a key region regulating neuroen- adversely affecting quality of life for affected patients, epi- docrine function that also plays a critical role in mediating demiological studies indicate that such rates of obesity will the actions of leptin on food intake and body weight. have a dramatic impact on life expectancy (2). Although there are some obvious sociological factors that contribute to this The Arcuate Nucleus of the Hypothalamus (ARH) as alarming rise in obesity, we know relatively little about bi- a Major Site of Leptin’s Actions ological processes that promote obesity in children. There It has been accepted for decades that the hypothalamus appears to be a genetic basis for a small percentage of obese plays a critical role in the regulation of feeding, and recent patients, and in nearly all these cases symptoms arise during work has defined a core circuitry in the hypothalamus that childhood. However, alterations in prenatal nutrition have appears to mediate many of the effects of leptin on feeding also been implicated in the development of obesity (see Refs. and energy balance. The effectiveness of the adipocyte- 3–6). Children born with low birth weights tend to become derived hormone leptin in regulating energy stores is due to obese later in life with an increased risk of developing type its direct access to hypothalamic neurons that control feeding II diabetes (7, 8). Similarly, mice born to obese dams display behavior and other aspects of energy metabolism (see Refs. a propensity for obesity in adulthood and give birth to off- 10–14 for reviews). Distinct subsets of hypothalamic neurons spring that also tend to become obese (9). At least one de- may respond to leptin by virtue of their location in regions terminant for these patterns of obesity appears to be maternal where the blood-brain barrier is compromised, or through diet because dams raised on a high-fat diet develop diet- neural connections with circumventricular organs. The ARH induced obesity and have greater numbers of offspring that meets both of these requirements because it resides above the become obese (9). Circulating hormones that act on the brain median eminence and shares connections with regions such represent important signals that reflect peripheral energy as the subfornical organ (15). The ARH has long been asso- status and may, therefore, influence development of central ciated with obesity (16). Its cells express leptin receptors mechanisms that regulate food intake and body weight. This (17–19) and exhibit signal transducer and activator of tran- scription 3 phosphorylation in response to central and pe- Abbreviations: AgRP, Agouti-related protein; ARH, arcuate nucleus ripheral injections of leptin, which is generally viewed as a of the hypothalamus; BSTp, principal nucleus of the bed nuclei of the molecular signature of leptin signaling (20–22). Moreover stria terminalis; DMH, dorsomedial nucleus of the hypothalamus; ob ob the projections of the ARH to other hypothalamic sites im- Lep /Lep , leptin-deficient mice; LHA, lateral hypothalamic area; plicated in the control of feeding such as the periventricular NPY, neuropeptide Y; POMC, proopiomelanocortin; PVH, paraven- tricular nucleus of the hypothalamus; WT, wild-type. (PVH) and dorsomedial (DMH) hypothalamic nuclei, as well Endocrinology is published monthly by The Endocrine Society (http:// as to the lateral hypothalamic area (LHA) (23), suggest that www.endo-society.org), the foremost professional society serving the the ARH is a principal monitor of leptin signaling in the brain endocrine community. (Fig. 1). Importantly, the distribution of ARH projections 2621 Downloaded from endo.endojournals.org by on November 24, 2008 2622 Endocrinology, June 2004, 145(6):2621–2626 Bouret and Simerly • Minireview overlapping projections to other key parts of the hypothal- amus (23–27) and appear to exert opposing regulatory func- tions: NPY and AgRP are orexigenic, whereas melanocortins are anorexigenic (for reviews see Refs. 10, 12, and 28). Developmental Aspects of Leptin Signaling Accumulating evidence suggests that there are physiolog- ical differences in the regulation of energy balance between adults and neonates. In sharp contrast to the effects of leptin on adults, several groups reported that exogenous leptin does not significantly inhibit growth, food intake, or energy expenditure during the first 2–3 postnatal weeks (29–32). More specifically, Mistry and colleagues (31) have shown that leptin does not alter significantly oxygen consumption (a marker of energy expenditure) or food intake in normal lean or obese leptin-deficient (Lepob/Lepob) mice until post- natal d 17 (P17) (31). Consistent with these data, neonatal Lepob/Lepob mice do not differ in body weight from wild- type (WT) littermates, but begin to diverge in weight during the second postnatal week (Ref. 31 and our unpublished data). The general thinking has been that the neonatal brain is relatively insensitive to leptin and may present leptin resistance (31). However, leptin receptors are expressed in the ARH of rats (33) and mice (Ref. 34 and our unpublished data) before development of ARH pathways, and recent find- ings suggest that this receptor can initiate cellular responses to leptin. For example, Proulx et al. (30) reported that acute peripheral leptin treatment modifies NPY and POMC mRNA expression in the ARH of postnatal rats. They also demon- strated an increase in suppressors-of-cytokine-signaling 3 gene expression (a marker of leptin receptor activity) in the ARH after leptin administration. In addition, leptin admin- istration between P6 and P16 in mice resulted in elevated expression of the proto-oncogene c-Fos in arcuate POMC neurons as it does in adults (35). Collectively these results provide convincing evidence that leptin receptors are present FIG. 1. Pathways for integration of feeding. Schematic representa- tion (horizontal section) of the organization of major projections from and functional in the ARH during the postnatal period and the ARH. The relative size of each pathway is roughly proportional to suggest that the leptin insensitivity observed during this the thickness of the lines associated with it. Inputs from the ARH that period may be due to a failure of these cells to relay leptin contain AgRP/NPY and ␣MSH and that project to the PVH, DMH, and signals to other parts of the hypothalamus. LHA represent major routes for regulation of body weight and food intake by leptin. AVPV, Anteroventral periventricular nucleus; BST, bed nuclei of the stria terminalis; LC, locus coeruleus; LSv, ventral Development of Projection Pathways from the ARH part of the lateral septum; MEA, medial nucleus of the amygdala; MPN, medial preoptic nucleus; NTS, nucleus of the solitary tract; Methods for visualizing neuronal pathways during de- Ob-Rb, long form of the leptin receptor; PAG, periaqueductal gray; velopment have been available for some time yet have only PBI, parabrachial nucleus; PVa, anterior periventricular nucleus of the hypothalamus; PVpo, preoptic periventricular nucleus. recently been applied in the hypothalamus. In part because of its importance for the regulation of feeding, the first sys- tematic study using axonal labeling defined the ontogeny of appears virtually identical in both rats and mice, and the projection pathways from the ARH (35). The results indicate organization of these pathways is quite similar in males and that ARH projections are immature at birth and develop females (23). mainly during the second week of life in mice. Interestingly, The ARH contains two populations of neurons that play ARH projections to key sites known to mediate food intake a particularly important role in distributing leptin signals and energy balance develop within distinct temporal do- centrally. Neuropeptide Y (NPY) and agouti-related protein mains with innervation of the DMH occurring first on P6, (AgRP) are coexpressed within a subpopulation of arcuate followed by innervation of the PVH on P8–P10 and inner- neurons. A separate subpopulation of neurons in the ARH vation of the LHA on P12 (Fig.