Leptin Differentially Regulates NPY and POMC Neurons Projecting to the Lateral Hypothalamic Area

Elias, Carol F.; Aschkenasi, Carl; Lee, Charlotte; Kelly, Joseph F.; Ahima, Rexford S.; Bjørbæk, Christian; Flier, Jeffrey S.; Saper, Clifford B.; Elmquist, Joel K.

doi:10.1016/s0896-6273(01)80035-0

Cited by 825 publications

(612 citation statements)

References 71 publications

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“…[57][58][59][60] The leptin receptor has also been identified in the human brain. 61 The arcuate nucleus: a site of leptin action Evidence indicates that leptin directly acts on the arcuate nucleus of the hypothalamus (Arc; Figure 1): (i) Radiolabeled leptin binds highly to the mediobasal hypothalamic region involving the Arc; 62 (ii) cells expressing Ob-Rb mRNA populate in the Arc and several other brain sites; [57][58][59][60][61] (iii) leptin induces the expression of an immediate early gene, c-fos (a marker of neuronal activation) [63][64][65][66] and suppressor of cytokine signaling-3 (SOCS-3, a cellular marker of direct leptin action) [65][66][67] in the Arc; (iv) Arc cells are directly hyperpolarized and depolarized by leptin. 68,69 The central melanocortin system mediates leptin action The term 'melanocortin' indicates a series of peptides that are cleaved from pro-opiomelanocortin (POMC).…”

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“…73 Leptin increases POMC mRNA in the Arc 74 and induces the expression of c-fos and SOCS-3 mRNA in Arc POMC neurons. 65,66 In addition, POMC mRNA in the Arc is markedly reduced in leptin-deficient ob/ob mice as well as in fasted rodents (when leptin levels rapidly fall). 75,76 The decrease in POMC expression is prevented by leptin administration.…”

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“…71,72 Notably, subsets of these neurons providing these inputs are leptin-responsive. 66 As noted, the LHA has long been considered to play an essential role in regulating food intake. Recently, two orexigenic peptides produced by discrete populations of LHA neurons in rodents and humans refocused attention on the LHA: melanin-concentrating hormone (MCH) [118][119][120] and the orexins (ORX, also called hypocretins).…”

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“…149,150 Importantly, NPY-producing Arc neurons coexpress AgRP and are inhibited by leptin. 66,68,69,97,98 Of NPY receptor subtypes, the Y1-, (Y1-R), Y2-, and Y5-receptors have been implicated in the regulation ), with permission). h: GFP-producing cell labeling the MC4-R. Bar ¼ 10 mm.…”

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“…200 MCH is, as stressed, an established regulator of energy balance [118][119][120]126,127 and is produced at the LHA that receives leptin and melanocortinergic signals. 66,71,72 Notably, a subset of MCH neurons coexpresses the M3 muscarinic acetylcholine receptor (M3Ach-R), and M3Ach-R À/À mice are hypophagic despite extremely low levels of serum leptin. 201 MCH accelerates feeding in M3Ach-R À/À mice when administered centrally, whereas an AgRP analogue does not.…”

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Body weight is regulated by the brain: a link between feeding and emotion

2005

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Regulated energy homeostasis is fundamental for maintaining life. Unfortunately, this critical process is affected in a high number of mentally ill patients. Eating disorders such as anorexia nervosa are prevalent in modern societies. Impaired appetite and weight loss are common in patients with depression. In addition, the use of neuroleptics frequently produces obesity and diabetes mellitus. However, the neural mechanisms underlying the pathophysiology of these behavioral and metabolic conditions are largely unknown. In this review, we first concentrate on the established brain machinery of food intake and body weight, especially on the melanocortin and neuropeptide Y (NPY) systems as illustration. These systems play a critical role in receiving and processing critical peripheral metabolic cues such as leptin and ghrelin. It is also notable that both systems modulate emotion and motivated behavior as well. Secondly, we discuss the significance and potential promise of multidisciplinary molecular and neuroanatomic techniques that will likely increase the understanding of brain circuitries coordinating energy homeostasis and emotion. Finally, we introduce several lines of evidence suggesting a link between the melanocortin/NPY systems and several neurotransmitter systems on which many of the psychotropic agents exert their influence. Maintaining energy homeostasis is fundamental for survival. However, obesity due to over-nutrition is an increasing worldwide public health problem. 1 In psychiatric practice, on the other hand, impaired appetite is one of the crucial issues. Anorexia and weight loss are common, for example, in patients suffering from depression. Eating disorders are medically intractable and life threatening. In addition, the so-called 'atypical' antipsychotic agents, currently and widely used to treat psychoses, often induce hyperphagia, obesity, and diabetes mellitus. [2][3][4] In the past decade, fortunately, there has been remarkable progress in understanding the molecular mechanisms of food intake and body weight. This is due in large part to increased research activity towards combating the rising incidences of obesity and associated metabolic disorders. As a result, it is now established that the central nervous system (CNS) senses and processes peripheral metabolic cues including leptin 5 and ghrelin, 6,7 resulting in coordinated energy homeostasis. However, the pathophysiology of the disequilibrium between energy intake and expenditure in psychiatric disorders remains largely unknown. Nevertheless, evidence suggests that several CNS systems regulating energy balance may be dysregulated in patients with mental illnesses, for example, eating disorders, and drug addiction. [8][9][10][11][12][13][14] In the current review, we will illustrate the neuroanatomic and molecular genetic aspects of the melanocortin and neuropeptide Y (NPY) systems residing in the CNS downstream of leptin and ghrelin, to discuss the neural bases of feeding, metabolism, and emotion. Additionally, we point the reader to...

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Body weight is regulated by the brain: a link between feeding and emotion

2005

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Chemical characterization of leptin-activated neurons in the rat brain

et al. 2000

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Leptin has profound effects on food intake, body weight, and neuroendocrine status. The lack of leptin results in hormonal and metabolic alterations and a dramatic increase in body weight. Leptin acts in the brain, especially in the hypothalamus; however, the central nervous system sites that respond to leptin have not been examined comprehensively. In this study, we explored systematically the distribution of leptin-activated neurons throughout the rat brain. Furthermore, we investigated the chemical identity of subsets of these leptin-activated cells. Fos-like immunoreactivity (Fos-IR) was investigated in the rat brain after two different doses of leptin (1.0 mg/kg and 5.0 mg/kg) at 2 hours and 6 hours after injections. The induction of Fos-IR was observed in hypothalamic nuclei, including the paraventricular nucleus (PVH), the retrochiasmatic area (RCA), the ventromedial nucleus (VMH), the dorsomedial nucleus (DMH), the arcuate nucleus (Arc), and the ventral premammillary nucleus (PMV). In addition, leptin-induced Fos-IR was found in several nuclei of the brainstem, including the superior lateral and external lateral subdivisions of the parabrachial nucleus (slPB and elPB, respectively), the supragenual nucleus, and the nucleus of the solitary tract (NTS). By using double-labeling immunohistochemistry or immunohistochemistry coupled with in situ hybridization, leptin-activated neurons were found that contained cocaine- and amphetamine-regulated transcript mRNA in several hypothalamic nuclei, including the RCA, Arc, DMH, and PMV. In the Arc and DMH, leptin-induced Fos-IR was observed in neurons that expressed neurotensin mRNA. Dynorphin neurons in the VMH and in the Arc also expressed Fos-IR. In the brainstem, we found that cholecystokinin neurons in the slPB and glucagon-like peptide-1 neurons in the NTS were activated by leptin. We also investigated the coexpression of Fos-IR and the long form of the leptin receptor (OBRb) mRNA. We found double-labeled neurons surrounding the median eminence and in the RCA, Arc, VMH, DMH, and PMV. However, in brainstem sites, very little OBRb mRNA was found; thus, there were very few double-labeled cells. These results suggest that leptin stimulates brain pathways containing neuropeptides that are involved in the regulation of energy balance, autonomic homeostasis, and neuroendocrine status.

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Relationship of EP1-4 prostaglandin receptors with rat hypothalamic cell groups involved in lipopolysaccharide fever responses

et al. 2000

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The action of prostaglandin E(2) (PGE(2)) in the preoptic area is thought to play an important role in producing fever. Pharmacologic evidence suggests that, among the four subtypes of E-series prostaglandin (EP) receptors, i.e., EP(1), EP(2), EP(3), and EP(4), the EP(1) receptor mediates fever responses. In contrast, evidence from mice with EP receptor gene deletions indicates that the EP(3) receptor is required for the initial (<1 hour) fever after intravenous (i.v.) lipopolysaccharide (LPS). To investigate which subtypes of EP receptors mediate systemic infection-induced fever, we assessed the coexpression of Fos-like immunoreactivity (Fos-IR) and EP(1-4) receptor mRNA in nuclei in the rat hypothalamus that have been shown to be involved in fever responses. Two hours after the administration of i.v. LPS (5 microg/kg), Fos-IR was observed in the ventromedial preoptic nucleus, the median preoptic nucleus, and the paraventricular hypothalamic nucleus. In these nuclei, EP(4) receptor mRNA was strongly expressed and the Fos-IR intensely colocalized with EP(4) receptor mRNA. Strong EP(3) receptor mRNA expression was only seen within the median preoptic nucleus but Fos-IR showed little coexpression with EP(3) receptor mRNA. EP(2) receptor mRNA was not seen in the PGE(2) sensitive parts of the preoptic area. Although approximately half of the Fos-immunoreactive neurons also expressed EP(1) receptor mRNA, EP(1) mRNA expression was weak and its distribution was so diffuse in the preoptic area that it did not represent a specific relationship. In the paraventricular nucleus, EP(4) mRNA was found in most Fos-immunoreactive neurons and levels of EP(4) receptor expression increased after i.v. LPS. Our findings indicate that neurons expressing EP(4) receptor are activated during LPS-induced fever and suggest the involvement of EP(4) receptors in the production of fever.

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Leptin Differentially Regulates NPY and POMC Neurons Projecting to the Lateral Hypothalamic Area

Cited by 825 publications

References 71 publications

Body weight is regulated by the brain: a link between feeding and emotion

Body weight is regulated by the brain: a link between feeding and emotion

Chemical characterization of leptin-activated neurons in the rat brain

Relationship of EP1-4 prostaglandin receptors with rat hypothalamic cell groups involved in lipopolysaccharide fever responses

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