Molecular Psychiatry (1999) 4, 8–12  1999 Stockton Press All rights reserved 1359–4184/99 $12.00

NEWS & VIEWS Leptin and the hypothalamus: neuroendocrine regulation of food intake

The mechanisms and pathways for the control of food intake and body weight represent one of the most active areas of contemporary biomedical research, and might indicate new patho- physiological and pharmacological targets for eating disorders.

Obesity, bulimia, and anorexia nervosa are prevalent tain hypothalamic centers. Food intake, neuroendo- disorders in Western countries that are associated with crine function, and energy expenditure, including significant morbidity and mortality.1 Thus, prevention motor activity and thermogenesis, are all altered by the and treatment of these disease states would have binding of leptin in the hypothalamus.8 Leptin is cur- important public health implications. However, efforts rently viewed as an important regulator of energy bal- towards prevention and treatment of these conditions ance which acts to keep energy stores stable. Falling require a better understanding of the mechanisms leptin in response to fasting results in adaptive neuro- responsible for energy homeostasis and body weight endocrine and metabolic responses, including regulation. It is well known that despite frequent and decreased thyroid hormone levels that conserve sometimes marked fluctuations in energy intake and energy, increased corticosteroid levels that result in expenditure, body weight and adipose stores remain mobilization of energy stores away from fat, and dimin- remarkably stable over prolonged periods of time, indi- ished reproductive capacity. All of these neuroendo- cating that body adiposity is regulated by a controlled crine changes are teleologically appropriate responses feedback system. It is also well known that hypothal- to increase survival and limit procreation in periods of amic centers play a central role in the regulation of starvation.9 In contrast, leptin levels are increased in energy homeostasis, a fact originally proven based on most cases of human obesity,7 indicating an underlying data derived from experimental disruption of certain leptin resistance. Although a defect in the blood–brain hypothalamic areas and later from intracerebroventric- barrier transport system has been considered respon- ular injection of orexigenic or anorexigenic neuro- sible for this leptin resistance,10 defects in the sites of transmitters.2 Our understanding of this physiological leptin action in the central nervous system (CNS) have fact was recently greatly advanced by the discovery also been proposed.2,4 Finally, mutations in either the and further study of leptin, the product of the ob gene3 leptin or the leptin receptor gene result in morbid obes- which serves as the signal responsible for linking adi- ity and neuroendocrine dysfunction not only in rod- pose stores with hypothalamic centers in this feedback ents but also in humans.4,11 Since leptin has important loop that regulates energy homeostasis and body physiological roles in both starvation and obesity, the weight. Study of the peripheral and hypothalamic molecular targets of leptin action in the brain and lep- actions of leptin has revealed several exciting aspects tin’s complex network of interactions are currently the of this complex neuroendocrine control system. focus of intensive research efforts.

Leptin secretion and action Leptin and hypothalamic neuropeptides Leptin is secreted by the adiopose tissue and the pla- Leptin receptors have been found in several regions of centa,4 displays significant circadian and ultradian the brain. These include the cerebellum, cortex, hippo- rhythmicity, 5 and circulates bound to specific binding campus, thalamus, choroid plexus and brain capillary proteins.6 Leptin conveys information to the brain on endothelium in addition to the hypothalamus.2,4 The the amount of energy stored as fat7 and acts by binding long and active receptor isoform, however, is mainly to its receptor in the hypothalamus and, thus, activat- expressed in the arcuate, dorsomedial, ventromedial ing the JAK-STAT signal transduction pathway in cer- and paraventricular nuclei of the hypothalamus, where leptin’s actions are exerted most rapidly and intensely.2,12 In these nuclei leptin alters the Correspondence: C Mantzoros, MD, DSc, Division of Endocrin- ology, RN 324, Beth Israel Deaconess Medical Center, 99 Brook- expression of several classical neuropeptides such as line Ave, Boston, MA 02215, USA. E-mail: cmantzorȰbih. NPY, TRH and CRH as well as novel neuropeptides harvard.edu including urocortin, agouti-related peptide (AGRP) and News & Views 9 melanin-concentrating-hormone (MCH) (see Image that leptin and the POMC-a-MSH/AGRP system is section). The best studied neuropeptides are NPY in important for body weight and energy homeostasis. the arcuate nucleus2,11,13,14 and TRH and CRH in the Thus, leptin couples changes in energy balance paraventricular nucleus.2,15–17 However, important and/or adipose stores to the appropriate hypothalamic new data on the interactions between leptin and sev- response by altering the expression of hypothalamic eral other neuropeptides accumulate rapidly18 and will neuropeptides. Indeed, leptin receptors are expressed briefly be reviewed below. by both POMC and NPY neurons in the arcuate The orexigenic neuropeptide NPY has been impli- nucleus.19 Moreover, recent experimental evidence cated in a wide range of actions including regulation indicates that NPY and POMC are expressed in adjac- of food intake and energy expenditure, cardiovascular ent but distinct subpopulations of arcuate nucleus neu- and neuropsychological function as well as activation rons, while certain NPY neurons coexpress the of several neuroendocrine axes.14 NPY is considered to endogenous melanocortin antagonist AGRP.19 Thus, it be the major mediator of leptin’s actions in the arcuate has been suggested that a unique cell type of hypothal- nucleus. Recent experimental evidence suggests that amic neurons releases NPY and AGRP simultaneously NPY is increased in low leptin states, ie starvation,9,19 in response to falling leptin levels. This, coupled with whereas leptin administration down-regulates NPY in decreased release of anorexigenic neuropeptides elicits the arcuate nucleus. This, in turn, results in a a robust compensatory response to fasting that results reduction of food intake, increase in the activity of the in increased food intake, maintenance of energy sympathetic nervous system and increase in energy homeostasis and stability of adipose stores. expenditure as well as alteration of the peripheral Targets of leptin in the hypothalamus other than metabolic milieu.2,9,18 Injection of NPY centrally melanocyte-stimulating hormone (a-MSH), its competi- results in hyperphagia, decreased thermogenesis, and tive antagonist agouti-related protein (AGRP), and pro- insulin resistance, ie characteristics of leptin-deficient opiomelanocortin (POMC) include the newly disco- conditions.18–21 Importantly, the severe obesity of lep- vered anorectic neuropeptide cocaine and amphetam- 26 tin-deficient mice (ob/ob mice) is attenuated, but not ine-related peptide (CART) and melanin concentrat- completely corrected, by NPY deficiency.18–21 In ing hormone (MCH). CART is a leptin-dependent addition, experiments using NPY knockout as well as hypothalamic neuropeptide that inhibits food intake, NPY receptors Y1 and Y5-deficient mice, reveal that has been implicated in the psychological reward path- way and may be responsible for the markedly these mice do not develop significant disturbances in decreased appetite in drug addicts.26 MCH acts on the daily food intake and body weight, indicating that melanosomes to regulate skin color and antagonizes hypothalamic control of feeding is redundant. Since the effect of a-MSH on skin pigment. Similar to their NPY is by no means the only mediator of leptin’s opposing actions in the skin, MCH and a-MSH are also actions in the brain, other potential targets of leptin in functional antagonists in the hypothalamus, but in con- the hypothalamus have been agressively sought. trast to a-MSH and AGRP which are antagonists acting Recent data indicate that in addition to NPY, pro- on the same receptor, MCH acts via an as-yet-unidenti- opiomelanocortin (POMC) is also downstream of leptin fied receptor to increase food intake.2 Although leptin in the pathway regulating energy homeostasis, as may 2,14,18,22 appears to regulate CART and MCH expression, the be the products of the fat tub and Ay genes. physiological significance of this action is not clear and Arcuate nucleus neurons containing POMC express Y1 much work is needed to elucidate the role of CART NPY receptors and project to the PVN where they exert and MCH and their interactions with other neuropep- a net inhibitory effect on food intake. Leptin positively tides. For example, physiological characterization of regulates POMC mRNA expression in the arcuate knock out or transgenic mice overexpressing MCH and nucleus and upregulation of POMC results in increased CART may provide important information and is production of a-MSH. This anorexigenic peptide pro- expected with great interest. duced by POMC is an agonist to the melanocortin 4 Another neuropeptide that has recently attracted the 2 receptors (MC3 and 4). attention of investigators is CRH. Both CRH and the Interestingly, leptin downregulates expression of CRH-like neuropeptide urocortin inhibit food intake another peptide in the arcuate nucleus; the agouti- and CRH has been found to stimulate energy expendi- related peptide (AGRP).23 AGRP acts as an antagonist ture and sympathetic nervous system activity.27 Leptin to a-MSH at the MC3, MC4 melanocortin receptor level receptors are expressed in CRH-containing neurons leading to obesity.14,18,23,24 Leptin-deficient ob/ob mice and leptin induces expression of CRH in the PVN.28,29 have decreased hypothalamic NPY and AGRP levels. Recent evidence also indicates that leptin may affect Decreased leptin levels in response to fasting have food intake via CRH-receptor mediated pathways.28 recently been associated with similar changes of hypo- However, although CRH and/or urocortin are thalamic neuropeptides that are reversed by exogenous important for the effect of leptin on food intake, it leptin administration.9,18,23,24 These findings from ani- appears that these neuropeptides act in conjunction mal experiments were recently confirmed by studies on with other neuropeptides implicated in appetite regu- the first family of humans with a mutation of the POMC lation.28 molecules. This mutation causes obesity, adrenal All the above mentioned neuropeptides are mainly insufficiency and red hair pigmentation,25 indicating expressed in the arcuate nucleus, the DMH and PVN. News & Views 10 In contrast, a recently discovered family of neuropep- leading to obesity have adrenal insufficiency also.11 tides, the orexins, were found to be expressed in the Based on these converging lines of evidence, it appears dorsolateral hypothalamus,18,23 a hypothalamic area that leptin influences not only energy homeostasis but long suspected to play an important role in appetite also neuroendocrine function by altering the regulation. Like hypothalamic NPY, orexin mRNA lev- expression of CRH, a neuropeptide that regulates appe- els appear to increase with fasting and acute adminis- tite, behavioral arousal and the hypothalamic-pitu- tration of orexin markedly stimulates food intake, but itary-adrenal axis. these findings need to be replicated. Although the effect of long-term administration of orexins has not yet been studied and their interactions with other neur- Leptin and the TRH-thyroid axis opeptides remain to be elucidated, it is likely that orex- Similar to its effect on CRH, leptin appears to regulate ins are a major family of appetite-regulating neuropep- TRH levels in PVN. Falling leptin levels in response to tides. The relationship between leptin and other starvation have been associated with decreased TSH hypothalamic neuropeptides, such as the tubby tran- and triiodothyronine levels, while exogeneous admin- script, neurotensin and CCK has only now begun to be istration of leptin to starving mice blunts the thyroid deciphered. The exact expression loci of all of these axis abnormalities associated with falling leptin lev- neuropeptides, the projections of cells expressing these els.9 Further experiments have indicated that this neuropeptides throughout the brain and the potential action of leptin is probably exerted at the level of the functional interaction between these molecules are the hypothalamus, since leptin administration prevents focus of much scientific attention. the fasting-induced suppression of TRH expression in Elucidation of this complex network of interactions rodent hypothalamus.32 Importantly, in patients with provides not only a working model for understanding leptin deficiency due to a homozygous mutation of the the feedback system that regulates energy homeostasis leptin receptor, thyrotropin secretion is reduced.11 but may also explain several genetic models of obesity Thus, it appears that leptin, by signaling the status of in rodents. Thus, the obesity of leptin-deficient ob/ob energy stores to the brain, is a major mediator of the and leptin-resistant db/db mice is likely to occur due thyroid axis response to food deprivation which has to increased NPY and AGRP as well as decreased teleologic implications since falling thyroid hormone POMC and melanocortin signaling. In contrast, in the levels may decrease metabolic requirements. yellow obese or agouti mouse model of obesity the lep- tin system is not defective. However, ectopic pro- duction of agouti protein antagonizes the melanocortin Leptin and the reproductive axis receptors and results in obesity. Knock out of the mel- In addition to its effect on CRH and TRH, leptin anocortin receptors results in a phenotype similar to appears to affect the GnRH-gonadal axis. More specifi- that of the agouti mouse or mice with transgenic over- cally, it has been shown that leptin may alter the func- expression of the agouti-related protein.30 Deletion and tion of hypothalamic explants and influence LH overexpression of other neuropeptides is now being secretion by pituitary cells.8,15 In vivo experiments performed and the results of these experiments are awaited with great interest. have shown that leptin mediates the LH-gonadal changes in response to starvation in mice.9 Leptin administration accelerates the onset of puberty in pre- Leptin and neuroendocrine function pubertal mice and restores the fertility of infertile lep- 33 Leptin and the CRH-ACTH-adrenal axis tin-deficient ob/ob mice. Increasing leptin levels may 34 In addition to its direct effect on the expression of the also be the factor that triggers puberty in humans, and above orexigenic/anorexigenic neuropeptides, patients with leptin deficiency due to a homozygous accumulating evidence suggests that leptin also affects mutation of the leptin receptor have no pubertal devel- 11 energy homeostasis by regulating neuroendocrine opment. We found that leptin may regulate the function. More specifically, leptin regulates the minute-to-minute oscillations in the levels of LH and expression of TRH and CRH in the paraventricular estradiol and that the nocturnal rise of leptin may nucleus, thus influencing the hypothalamic-pituitary- determine the changes in nocturnal LH profile in nor- thyroid and adrenal axes. Initially, animal experiments mal women.35 This can explain the disruption of hypo- demonstrated that leptin inhibits the starvation- thalami-pituitary-gonadal function which is character- induced activation of the ACTH-adrenal axis in vivo,9 istic of low leptin states, such as cachexia and anorexia and later, in vitro studies indicated that leptin inhibits nervosa.35 Indeed, the low leptin levels observed in the hypoglycemia-induced CRH secretion by perifused anorexia nervosa36,37 are responsible for the abnormal hypothalami.31 These observations in animals linking menstrual function in these women8 and increasing leptin with the CRH-ACTH-adrenal axis were conse- leptin levels in response to treatment are associated quently extended to humans. First, studies in healthy with increasing gonadotropin levels.38 Thus low leptin adults demonstrated that leptin’s circadian and ultrad- levels convey to the brain information about inad- ian rhythmicity is significantly and inversely related to equate energy reserves and result in a teleologically that of cortisol and ACTH.5 In addition, it was recently appropriate suppression of the LH-gonadal axis that shown that patients with leptin receptor mutations would limit procreation. News & Views 11 Leptin and the growth hormone axis Center and the Harvard Medical School) and the Bos- Experimental data suggest that leptin is a metabolic ton Obesity Nutrition Research Council Award. signal that regulates growth hormone secretion. Although leptin administration to fed rodents does not CS Mantzoros alter growth hormone secretion, administration to Division of Endocrinology, Department of Internal fasted rodents restores the fasting-induced abnormal Medicine growth hormone secretion.39 The role of leptin in reg- Beth Israel Deaconess Medical Center ulating the secretion of growth hormone was recently Harward Medical School confirmed in humans since patients with leptin Boston, MA 02215, USA deficiency due to a homozygous mutation of the leptin receptor have reduced growth hormone secretion in References addition to early onset obesity.11 However, the associ- ation between leptin and the growth hormone system 1 Manson JA, Faich GA. Pharmacotherapy for obesity—do the bene- fits outweigh the risks? New Engl J Med 1996; 29: 659–660. in humans is complex and needs further study. 2 Flier JS, Maratos-Flier E. Obesity and the hypothalamus: novel pep- tides for new pathways. 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