Of Mice and MEN What Transgenic Models Tell Us about Hypothalamic Control of Energy Balance

POMC mutations can cause obesity, adrenal insuffiThe hypothalamus plays a key role in the regulation ciency, and alterations in hair pigmentation in mice (Yasof food intake and energy expenditure, demonstrated wen et al., 1999) and humans (Krude et al., 1998) and through the effects that discrete lesions within this reseveral reports that MC4-R mutations are associated gion of the brain have on appetite and body weight. with dominantly inherited human obesity (Barsh, 1999). Lesions in the lateral hypothalamus (LHA) or “feeding Despite overwhelming genetic evidence in mice and hucenter” lead to decreased food intake and weight loss, mans that a-MSH is a critical satiety-inducing peptide, primarily by eliminating the neurons that promote feedthe response to central injection of a-MSH itself is not ing through their projections elsewhere in the CNS (i.e., particularly robust, highlighting a subtle difference beorexigenic pathways; Elmquist et al., 1999). Lesions of tween pharmacological and genetic findings. the ventromedial and arcuate nuclei or “satiety center” Further characterization of the melanocortin pathway produce hyperphagia and obesity, most likely by dehas been accomplished through the analysis of genes stroying the leptin-responsive neurons that decrease that suppress the agouti phenotype. Mutations at the feeding via anorexigenic projections to the LHA, paramahogany locus, when homozygous, can suppress the ventricular nucleus (PVN), and central autonomic sites. effects of Ay on coat color and body weight. Recent Over the past 5 years, analysis of a diverse group of positional cloning reveals that the mahogany gene entransgenic and naturally occurring mouse mutants has codes a single transmembrane-spanning protein that is substantially increased our understanding of the pathostructurally similar to cell surface proteoglycans. Since physiology of obesity, a relatively common disturbance the mahogany mutation does not suppress the obese of energy balance. A picture of intricate signaling within phenotype of the MC4-R mutant, nor that of several the brain as well as complex hormonal communication other obese mouse models such as db/db, tub, and between metabolically active peripheral tissues and the Cpe, it would appear that the mahogany protein funcnervous system is emerging, but in the process, seemtions in the pathway downstream of a-MSH but upingly contradictory genetic and pharmacological data stream of MC4-R, perhaps as a signaling or low-affinity are mounting (compare Figures 1A and 1B). What do receptor for the agouti protein (Figure 1A; Gunn et al., transgenic models really tell us about the brain and the 1999; Nagle et al., 1999). regulation of energy homeostasis, and can these studies Products of the ob and db genes—leptin and its rebe reconciled with pharmacological and physiological ceptor, respectively—are cornerstones of the other maanalyses? jor pathway that suppresses appetite in mammals by Gene Targeting of Anorexigenic Pathways: relaying the metabolic state of peripheral adipose tisMutated and Not Satiated sues, the primary site of leptin synthesis, to the hypothalPharmacological and genetic studies indicate that the amus. Pharmacological and genetic studies are in genmelanocortin system makes a critical contribution to the eral agreement that leptin pathways play a critical role regulation of many of the central responses to satiety in the regulation of energy balance (Figure 1). Mice that signals (Figure 1). Identification of the agouti signaling fail to synthesize leptin (ob/ob) or those that express protein, ectopically overexpressed in one of the most abnormal hypothalamic leptin receptors (db/db) deextensively studied obese mouse models, Ay/a agouti, velop early onset obesity, increased food intake, reprovided the impetus for future biochemical and genetic duced metabolic rate, and infertility (Elmquist et al., investigation of energy balance (Barsh, 1999). The agouti 1999). Peripheral or central administration of the 16 kDa product antagonizes the action of a-MSH, a satietyleptin protein to ob/ob mice rescues reproductive funcinducing neuropeptide that is cleaved from the proopiotion and results in weight loss through an increase in melanocortin (POMC) precursor, by competing for its metabolic rate and locomotor activity and a decrease in binding to the G protein–coupled melanocortin 4 recepfeeding. The specific neuronal pathways that transduce tor (MC4-R). The result is a maturity onset obesity synthe leptin signal, initiated by binding to receptors in drome that is associated with hyperphagia, hyperinsuthe hypothalamic nuclei that cluster around the median linemia, and hyperglycemia. The finding that agouti eminence, have been functionally mapped by analyzing functions in the hypothalamus, a tissue in which it is not ob/ob mice that are additionally mutated in other neuronormally synthesized, stimulated the search for closely peptide-encoding genes and through the use of probes related proteins, culminating in the identification of the to rapidly activated components of the leptin signaling