The Geometry of Leptin Action in the Brain: More Complicated Than a Simple ARC
2009; Cell Press; Volume: 9; Issue: 2 Linguagem: Inglês
10.1016/j.cmet.2008.12.001
ISSN1932-7420
AutoresMartin G. Myers, Heike Münzberg, Gina M. Leinninger, Rebecca L. Leshan,
Tópico(s)Adipose Tissue and Metabolism
ResumoLeptin signals the repletion of fat stores, acting in the CNS to permit energy utilization by a host of autonomic and neuroendocrine processes and to decrease feeding. While much recent research has focused on the leptin-regulated circuitry of the hypothalamic arcuate nucleus (ARC), the majority of brain leptin receptor (LepRb)-expressing neurons lie outside the ARC in other CNS regions known to modulate energy balance. Each set of LepRb neurons throughout the brain presumably mediates unique aspects of leptin action, and understanding the function for LepRb-expressing neurons throughout the brain represents a crucial next step in the study of energy homeostasis. Leptin signals the repletion of fat stores, acting in the CNS to permit energy utilization by a host of autonomic and neuroendocrine processes and to decrease feeding. While much recent research has focused on the leptin-regulated circuitry of the hypothalamic arcuate nucleus (ARC), the majority of brain leptin receptor (LepRb)-expressing neurons lie outside the ARC in other CNS regions known to modulate energy balance. Each set of LepRb neurons throughout the brain presumably mediates unique aspects of leptin action, and understanding the function for LepRb-expressing neurons throughout the brain represents a crucial next step in the study of energy homeostasis. The naturalist Marston Bates famously observed that if evolution is a play, then ecology is the stage upon which it is performed (Bates, 1960Bates M. The Forest and the Sea: a Study of the Economy of Nature and the Ecology of Man. Random House, New York1960Google Scholar). Periodic inadequacy of food supplies likely represented an important component of this setting for mammalian evolution, selecting for the abilities to store energy for later use and to promote food seeking and conserve energy when food and energy stores are limiting. Presumably as a result of such selection, states of low or decreasing fat stores increase the drive to feed and attenuate energy utilization on a variety of endocrine and autonomic processes. Although a variety of signals convey information regarding energy stores and nutritional status, the adipocyte-derived hormone leptin plays a central role in mediating the response to energy sufficiency or deficit (Ahima et al., 2000Ahima R.S. Saper C.B. Flier J.S. Elmquist J.K. Leptin regulation of neuroendocrine systems.Front. Neuroendocrinol. 2000; 21: 263-307Crossref PubMed Scopus (612) Google Scholar). Circulating leptin levels mirror body fat stores, and leptin deficiency not only increases feeding, but (like fasting) decreases activity, sympathetic tone, and thyroid function; causes hypothalamic infertility; and impairs lactation (Elmquist et al., 1999Elmquist J.K. Elias C.F. Saper C.B. From lesions to leptin: hypothalamic control of food intake and body weight.Neuron. 1999; 22: 221-232Abstract Full Text Full Text PDF PubMed Scopus (956) Google Scholar, Ahima et al., 2000Ahima R.S. Saper C.B. Flier J.S. Elmquist J.K. Leptin regulation of neuroendocrine systems.Front. Neuroendocrinol. 2000; 21: 263-307Crossref PubMed Scopus (612) Google Scholar, Farooqi et al., 1999Farooqi I.S. Jebb S.A. Langmack G. Lawrence E. Cheetham C.H. Prentice A.M. Hughes I.A. McCamish M.A. O'Rahilly S. Effects of recombinant leptin therapy in a child with congenital leptin deficiency.N. Engl. J. Med. 1999; 341: 879-884Crossref PubMed Scopus (1441) Google Scholar, Oral et al., 2002Oral E.A. Simha V. Ruiz E. 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Numerous populations of LepRb-expressing neurons exist in the brain, and areas with particularly high LepRb expression include several regions of the hypothalamus, midbrain, and brainstem that play important roles in energy balance (Elmquist et al., 1998bElmquist J.K. Bjorbaek C. Ahima R.S. Flier J.S. Saper C.B. Distributions of leptin receptor mRNA isoforms in the rat brain.J. Comp. Neurol. 1998; 395: 535-547Crossref PubMed Scopus (852) Google Scholar, Leshan et al., 2006Leshan R.L. Bjornholm M. Munzberg H. Myers Jr., M.G. Leptin receptor signaling and action in the central nervous system.Obesity (Silver Spring). 2006; 14: 208S-212SCrossref PubMed Scopus (153) Google Scholar). For instance, LepRb is expressed in the lateral hypothalamic area (LHA), and ablation of the LHA attenuates food intake, suggesting an important role in the promotion of feeding (Kelley et al., 2005Kelley A.E. Baldo B.A. Pratt W.E. 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Electrolytic lesions of structures in the medial basal hypothalamus (MBH), including the arcuate nucleus (ARC) and ventromedial hypothalamic nucleus (VMH), result in hyperphagia and obesity, suggesting roles for these nuclei in limiting feeding (Elmquist et al., 1999Elmquist J.K. Elias C.F. Saper C.B. From lesions to leptin: hypothalamic control of food intake and body weight.Neuron. 1999; 22: 221-232Abstract Full Text Full Text PDF PubMed Scopus (956) Google Scholar). The more circumscribed chemical lesions produced by gold thioglucose (lateral ARC and VMH) and monosodium glutamate (medial basal ARC) also produce dramatic hyperphagia (Bergen et al., 1998Bergen H.T. Mizuno T.M. Taylor J. Mobbs C.V. Hyperphagia and weight gain after gold-thioglucose: relation to hypothalamic neuropeptide Y and proopiomelanocortin.Endocrinology. 1998; 139: 4483-4488Crossref PubMed Scopus (98) Google Scholar). The restoration of LepRb expression in the MBH of LepRb-null animals diminishes the hyperphagia, obesity, and hyperglycemia of these animals, consistent with an important role for MBH leptin action (Coppari et al., 2005Coppari R. Ichinose M. Lee C.E. Pullen A.E. Kenny C.D. McGovern R.A. Tang V. Liu S.M. Ludwig T. Chua Jr., S.C. et al.The hypothalamic arcuate nucleus: a key site for mediating leptin's effects on glucose homeostasis and locomotor activity.Cell Metab. 2005; 1: 63-72Abstract Full Text Full Text PDF PubMed Scopus (357) Google Scholar, Morton et al., 2003Morton G.J. Niswender K.D. Rhodes C.J. Myers Jr., M.G. Blevins J.T. Baskin D.G. Schwartz M.W. Arcuate nucleus-specific leptin receptor gene therapy attenuates the obesity phenotype of Koletsky (fak/fak) rats.Endocrinology. 2003; 144: 2016-2024Crossref PubMed Scopus (140) Google Scholar). While other brain regions have received less attention over the past decade, the study of ARC neuropeptidergic systems has become a major focus for energy balance research. At least two distinct populations of ARC neurons express LepRb: a leptin-activated set of neurons that expresses pro-opiomelanocortin (POMC) and an opposing, leptin-inhibited population that coexpresses neuropeptide Y (NPY) and agouti-related peptide (AgRP) (Elmquist et al., 2005Elmquist J.K. Coppari R. Balthasar N. Ichinose M. Lowell B.B. Identifying hypothalamic pathways controlling food intake, body weight, and glucose homeostasis.J. Comp. Neurol. 2005; 493: 63-71Crossref PubMed Scopus (323) Google Scholar, Morton et al., 2006Morton G.J. Cummings D.E. Baskin D.G. Barsh G.S. Schwartz M.W. Central nervous system control of food intake and body weight.Nature. 2006; 443: 289-295Crossref PubMed Scopus (1754) Google Scholar). Leptin action on this “ARC POMC/AgRP circuit” attenuates feeding (Elmquist et al., 2005Elmquist J.K. Coppari R. Balthasar N. Ichinose M. Lowell B.B. Identifying hypothalamic pathways controlling food intake, body weight, and glucose homeostasis.J. Comp. Neurol. 2005; 493: 63-71Crossref PubMed Scopus (323) Google Scholar, Morton et al., 2006Morton G.J. Cummings D.E. Baskin D.G. Barsh G.S. Schwartz M.W. Central nervous system control of food intake and body weight.Nature. 2006; 443: 289-295Crossref PubMed Scopus (1754) Google Scholar). Interference with POMC action in the brain (e.g., by deletion of POMC or the downstream melanocortin 4 receptor [MC4R]) or ablation of POMC neurons produces dramatic hyperphagia (albeit without many of the neuroendocrine sequelae of leptin deficiency, such as infertility and hypercortisolism) (Smart et al., 2006Smart J.L. Tolle V. Low M.J. Glucocorticoids exacerbate obesity and insulin resistance in neuron-specific proopiomelanocortin-deficient mice.J. 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NPY/AgRP neurons are essential for feeding in adult mice but can be ablated in neonates.Science. 2005; 310: 683-685Crossref PubMed Scopus (745) Google Scholar). The ARC POMC/AgRP circuit thus represents an important and well-understood circuit; it is also genetically tractable (e.g., by transgenic manipulation) due to the essentially ARC-restricted pattern of POMC and AgRP expression within the CNS (van de Wall et al., 2008van de Wall E. Leshan R. Xu A.W. Balthasar N. Coppari R. Liu S.M. Jo Y.H. MacKenzie R.G. Allison D.B. Dun N.J. et al.Collective and individual functions of leptin receptor modulated neurons controlling metabolism and ingestion.Endocrinology. 2008; 149: 1773-1785Crossref PubMed Scopus (249) Google Scholar, Butler and Cone, 2002Butler A.A. Cone R.D. The melanocortin receptors: lessons from knockout models.Neuropeptides. 2002; 36: 77-84Abstract Full Text PDF PubMed Scopus (179) Google Scholar, Elmquist et al., 2005Elmquist J.K. Coppari R. Balthasar N. Ichinose M. 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Furthermore, many factors other than leptin, such as the gut peptide ghrelin (which opposes leptin by activating AgRP/NPY neurons), also regulate these neurons (Morton et al., 2006Morton G.J. Cummings D.E. Baskin D.G. Barsh G.S. Schwartz M.W. Central nervous system control of food intake and body weight.Nature. 2006; 443: 289-295Crossref PubMed Scopus (1754) Google Scholar, Butler and Cone, 2002Butler A.A. Cone R.D. The melanocortin receptors: lessons from knockout models.Neuropeptides. 2002; 36: 77-84Abstract Full Text PDF PubMed Scopus (179) Google Scholar, Chen et al., 2004Chen H.Y. Trumbauer M.E. Chen A.S. Weingarth D.T. Adams J.R. Frazier E.G. Shen Z. Marsh D.J. Feighner S.D. Guan X.M. et al.Orexigenic action of peripheral ghrelin is mediated by neuropeptide Y and agouti-related protein.Endocrinology. 2004; 145: 2607-2612Crossref PubMed Scopus (535) Google Scholar, Tschop et al., 2006Tschop M.H. Castaneda T.R. Woods S.C. The brain is getting ready for dinner.Cell Metab. 2006; 4: 257-258Abstract Full Text Full Text PDF PubMed Scopus (9) Google Scholar). Also, insulin-mediated phosphatidylinositol 3′-kinase signaling (PI3K, which is also modulated by leptin) regulates the membrane potential of POMC and AgRP neurons, and PI3K in these neurons contributes importantly to the modulation of energy balance and glucose homeostasis (Niswender et al., 2004Niswender K.D. Baskin D.G. Schwartz M.W. Insulin and its evolving partnership with leptin in the hypothalamic control of energy homeostasis.Trends Endocrinol. Metab. 2004; 15: 362-369Abstract Full Text Full Text PDF PubMed Scopus (197) Google Scholar, Rother et al., 2008Rother E. Konner A.C. Bruning J.C. Neurocircuits integrating hormone and nutrient signaling in control of glucose metabolism.Am. J. Physiol. Endocrinol. Metab. 2008; 294: E810-E816Crossref PubMed Scopus (27) Google Scholar, Hill et al., 2008bHill J.W. Williams K.W. Ye C. Luo J. Balthasar N. 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McGovern R.A. Chua Jr., S.C. Elmquist J.K. Lowell B.B. Leptin receptor signaling in POMC neurons is required for normal body weight homeostasis.Neuron. 2004; 42: 983-991Abstract Full Text Full Text PDF PubMed Scopus (679) Google Scholar, van de Wall et al., 2008van de Wall E. Leshan R. Xu A.W. Balthasar N. Coppari R. Liu S.M. Jo Y.H. MacKenzie R.G. Allison D.B. Dun N.J. et al.Collective and individual functions of leptin receptor modulated neurons controlling metabolism and ingestion.Endocrinology. 2008; 149: 1773-1785Crossref PubMed Scopus (249) Google Scholar) and does not cause infertility or hypercortisolism, as is observed in Leprdb/db animals. Since ARC POMC and AgRP neurons account for only a portion of the overall leptin effect, other LepRb-expressing neurons must mediate crucial components of leptin action. Indeed, ARC LepRb neurons together comprise a minority of the total CNS LepRb neurons (Elmquist et al., 1998bElmquist J.K. Bjorbaek C. Ahima R.S. Flier J.S. Saper C.B. Distributions of leptin receptor mRNA isoforms in the rat brain.J. Comp. Neurol. 1998; 395: 535-547Crossref PubMed Scopus (852) Google Scholar, Leshan et al., 2006Leshan R.L. Bjornholm M. Munzberg H. Myers Jr., M.G. Leptin receptor signaling and action in the central nervous system.Obesity (Silver Spring). 2006; 14: 208S-212SCrossref PubMed Scopus (153) Google Scholar). Given the pleiotrophic effects of leptin, it is unreasonable to expect that a single neural circuit (such as the POMC/AgRP circuit) or a single nucleus (like the ARC) could mediate all or even the majority of leptin action. Each region and subregion of the brain contains neurons with specific functional properties that dictate the physiological outputs they control. For instance, while the ARC operates together with other medial hypothalamic and brainstem sites to regulate satiety (the perception of fullness that terminates feeding) (Woods et al., 2000Woods S.C. Schwartz M.W. Baskin D.G. Seeley R.J. Food intake and the regulation of body weight.Annu. Rev. Psychol. 2000; 51: 255-277Crossref PubMed Scopus (255) Google Scholar), the incentive (hedonic or rewarding) value of food is largely encoded by the ventral tegmental area (VTA) and striatum, which comprise the core of the mesolimbic dopamine (DA) system (Figlewicz et al., 2006Figlewicz D.P. Naleid A.M. Sipols A.J. Modulation of food reward by adiposity signals.Physiol. Behav. 2006; 91: 473-478Crossref PubMed Scopus (104) Google Scholar, Kelley et al., 2005Kelley A.E. Baldo B.A. Pratt W.E. A proposed hypothalamic-thalamic-striatal axis for the integration of energy balance, arousal, and food reward.J. Comp. Neurol. 2005; 493: 72-85Crossref PubMed Scopus (254) Google Scholar). Although ARC neurons project to a number of other regions in the hypothalamus, they densely innervate the paraventricular hypothalamic nucleus (PVH), which regulates autonomic and neuroendocrine (e.g., thyroid, adrenal) function to modulate energy expenditure, as well as contributing to satiety (Elmquist et al., 2005Elmquist J.K. Coppari R. Balthasar N. Ichinose M. Lowell B.B. Identifying hypothalamic pathways controlling food intake, body weight, and glucose homeostasis.J. Comp. Neurol. 2005; 493: 63-71Crossref PubMed Scopus (323) Google Scholar, Butler and Cone, 2002Butler A.A. Cone R.D. The melanocortin receptors: lessons from knockout models.Neuropeptides. 2002; 36: 77-84Abstract Full Text PDF PubMed Scopus (179) Google Scholar). PVH-specific reactivation of the MC4R (which mediates crucial responses to the ARC POMC neurons) attenuates the hyperphagia of MC4R-null animals (Balthasar et al., 2005Balthasar N. Dalgaard L.T. Lee C.E. Yu J. Funahashi H. Williams T. Ferreira M. Tang V. McGovern R.A. Kenny C.D. et al.Divergence of melanocortin pathways in the control of food intake and energy expenditure.Cell. 2005; 123: 493-505Abstract Full Text Full Text PDF PubMed Scopus (753) Google Scholar). Other MC4R-expressing neurons must contribute to the regulation of the autonomic nervous system, however, since PVH reactivation of MC4R fails to normalize autonomic control. Together with the known role for the PVH in autonomic regulation, these findings also hint that melanocortin-independent mechanisms likely contribute to the regulation of autonomic function via the PVH. Indeed, inputs from non-ARC areas that contain substantial populations of LepRb neurons (e.g., the VMH and the dorsomedial hypothalamic nucleus [DMH]) regulate the ARC and/or PVH, modifying the output of the circuit (Thompson and Swanson, 2003Thompson R.H. Swanson L.W. Structural characterization of a hypothalamic visceromotor pattern generator network.Brain Res. Brain Res. 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In addition to receiving copious projections from the ARC, the DMH densely innervates the PVH (as well as several other regions of the hypothalamus), and DMH lesions alter feeding (Thompson and Swanson, 2003Thompson R.H. Swanson L.W. Structural characterization of a hypothalamic visceromotor pattern generator network.Brain Res. Brain Res. Rev. 2003; 41: 153-202Crossref PubMed Scopus (159) Google Scholar, Zaretskaia et al., 2008Zaretskaia M.V. Zaretsky D.V. Sarkar S. Shekhar A. DiMicco J.A. Induction of Fos-immunoreactivity in the rat brain following disinhibition of the dorsomedial hypothalamus.Brain Res. 2008; 1200: 39-50Crossref PubMed Scopus (34) Google Scholar, Elmquist et al., 1999Elmquist J.K. Elias C.F. Saper C.B. From lesions to leptin: hypothalamic control of food intake and body weight.Neuron. 1999; 22: 221-232Abstract Full Text Full Text PDF PubMed Scopus (956) Google Scholar). The PVH and its surrounding circuitry present a reasonable (if simplified) model of the integrated leptin-responsive neural circuitry (Figure 1). Here, the VMH, DMH, and ARC function together with the PVH as an interconnected circuit, with leptin presumably acting via LepRb-expressing neurons in each region to modulate PVH output. Indeed, direct leptin action on SF-1-expressing VMH LepRb neurons contributes to the regulation of energy balance (Dhillon et al., 2006Dhillon H. Zigman J.M. Ye C. Lee C.E. McGovern R.A. Tang V. Kenny C.D. Christiansen L.M. White R.D. Edelstein E.A. et al.Leptin directly activates SF1 neurons in the VMH, and this action by leptin is required for normal body-weight homeostasis.Neuron. 2006; 49: 191-203Abstract Full Text Full Text PDF PubMed Scopus (560) Google Scholar, Bingham et al., 2008Bingham N.C. Anderson K.K. Reuter A.L. Stallings N.R. Parker K.L. Selective loss of leptin receptors in the ventromedial hypothalamic nucleus results in increased adiposity and a metabolic syndrome.Endocrinology. 2008; 149: 2138-2148Crossref PubMed Scopus (156) Google Scholar). The central nervous system controls each aspect of energy intake and expenditure in the context of overall homeostatic need and external conditions (not just energy status); the repletion of fat stores must therefore be integrated with other information that reflects the requirement for the activity of a particular system in order to respond appropriately to the aggregate conditions. For instance, in addition to the permissive effect of leptin, the PVH output to the sympathetic nervous system must take into account temperature, cardiovascular status, stress, activity, and so forth, and must then generate the appropriate tone via specific branches of the autonomic nervous system. Hence, in the face of low energy stores, core body temperature may be allowed to decrease slightly to conserve energy, but a larger decrease in core body temperature must still promote a robust thermogenic response (while at the same time not altering cardiovascular homeostasis). Each set of LepRb neurons within this ARC/VMH/DMH → PVH circuit presumably conveys specific information to the PVH. In this model of leptin action, each set of LepRb neurons (including those in the ARC) does not signal leptin levels alone, but rather transmits a signal that conveys information relevant to a specific set of inputs and outputs. For instance, the ARC senses rapid changes in insulin, ghrelin, and circulating nutrients, as well as leptin, to signal acute peripheral nutritional status. The DMH, in contrast, is shielded from acute alterations in peripheral nutritional status by the blood-brain barrier (BBB) (Faouzi et al., 2007Faouzi M. Leshan R. Bjornholm M. Hennessey T. Jones J. Munzberg H. Differential accessibility of circulating leptin to individual hypothalamic sites.Endocrinology. 2007; 148: 5414-5423Crossref PubMed Scopus (148) Google Scholar), but integrates (among other things) information about body temperature (from the preoptic area [POA], where another set of LepRb neurons lie) and stress, along with leptin-encoded information about long-term energy status (Thompson and Swanson, 2003Thompson R.H. Swanson L.W. Structural characterization of a hypothalamic visceromotor pattern generator network.Brain Res. Brain Res. Rev. 2003; 41: 153-202Crossref PubMed Scopus (159) Google Scholar). The VMH is rich in glucose-sensing neurons, and the LepRb neurons in this nucleus may also participate in the regulation of glucose homeostasis (Tong et al., 2007Tong Q. Ye C. McCrimmon R.J. Dhillon H. Choi B. Kramer M.D. Yu J. Yang Z. Christiansen L.M. Lee C.E. et al.Synaptic glutamate release by ventromedial hypothalamic neurons is part of the neurocircuitry that prevents hypoglycemia.Cell Metab. 2007; 5: 383-393Abstract Full Text Full Text PDF PubMed Scopus (266) Google Scholar, King, 2006King B.M. The rise, fall, and resurrection of the ventromedial hypothalamus in the regulation of feeding behavior and body weight.Physiol. Behav. 2006; 87: 221-244Crossref PubMed Scopus (331) Google Scholar). Thus, each set of LepRb neurons encodes a distinct type of information, and the presence of LepRb on these neurons allows the integration of information regarding long-term energy stores into the aggregate signal mediated by each population of neurons. Unfortunately, the current lack of markers (and thus neuron-specific Cre-expressing mice) for LepRb neurons in the DMH and elsewhere limits the functional analysis of many components of this integrated leptin-regulated circuit. In addition to the ARC LepRb neurons, it will thus be important to define the neurotransmitter content, neuronal targets, and physiologic function of each set of LepRb neurons in the VMH, DMH, and ARC, as well as to understand the stimuli and mechanisms that regulate their activity and gene expression. Satiety (the sensation of fullness that promotes meal termination) represents an important process by which leptin regulates feeding (Woods et al., 2000Woods S.C. Schwartz M.W. Baskin D.G. Seeley R.J. Food intake and the regulation of body weight.Annu. Rev. Psychol. 2000; 51: 255-277Crossref PubMed Scopus (255) Google Scholar). Brainstem neural circuits (including the nucleus of the solitary tract [NTS]) encode a major component of satiety (Morton et al., 2006Morton G.J. Cummings D.E. Baskin D.G. Barsh G.S. Schwartz M.W. Central nervous system control of food intake and body weight.Nature. 2006; 443: 289-295Crossref PubMed Scopus (1754) Google Scholar, Grill, 2006Grill H.J. 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