The Role of Melanin-Concentrating Hormone in Energy Homeostasis and Mood Disorders

Antal‐Zimanyi, Ildiko; Khawaja, Xavier

doi:10.1007/s12031-009-9207-6

Cited by 32 publications

(27 citation statements)

References 102 publications

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“…The increase in the time spent in REMS and the decrease in the REMS latency during the rebound following sleep deprivation are both changes similar to those described in depression. Furthermore, the antidepressant-like profile of MCH-R1 antagonists suggest the role of MCH in the regulation of mood (Antal-Zimanyi and Khawaja 2009;Borowsky et al 2002;Chung et al 2011;Lagos et al 2011a;Millan et al 2008).…”

Section: Introductionmentioning

confidence: 99%

Acute escitalopram treatment inhibits REM sleep rebound and activation of MCH-expressing neurons in the lateral hypothalamus after long term selective REM sleep deprivation

et al. 2013

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Rationale Selective rapid eye movement sleep (REMS) deprivation using the platform-on-water ("flower pot") method causes sleep rebound with increased REMS, decreased REMS latency, and activation of the melaninconcentrating hormone (MCH) expressing neurons in the hypothalamus. MCH is implicated in the pathomechanism of depression regarding its influence on mood, feeding behavior, and REMS. Objectives We investigated the effects of the most selective serotonin reuptake inhibitor escitalopram on sleep rebound following REMS deprivation and, in parallel, on the activation of MCH-containing neurons.Methods Escitalopram or vehicle (10 mg/kg, intraperitoneally) was administered to REMS-deprived (72 h) or home cage male Wistar rats. During the 3-h-long "rebound sleep", electroencephalography was recorded, followed by an MCH/Fos double immunohistochemistry. Results During REMS rebound, the time spent in REMS and the number of MCH/Fos double-labeled neurons in the lateral hypothalamus increased markedly, and REMS latency showed a significant decrease. All these effects of REMS deprivation were significantly attenuated by escitalopram treatment. Besides the REMS-suppressing effects, escitalopram caused an increase in amount of and decrease in latency of slow wave sleep during the rebound. Conclusions These results show that despite the high REMS pressure caused by REMS deprivation procedure, escitalopram has the ability to suppress REMS rebound, as well as to diminish the activation of MCH-containing neurons, in parallel. Escitalopram caused a shift from REMS to slow wave sleep during the rebound. Furthermore, these data point to the potential connection between the serotonergic system and MCH in sleep regulation, which can be relevant in depression and in other mood disorders.

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Section: Introductionmentioning

confidence: 99%

Acute escitalopram treatment inhibits REM sleep rebound and activation of MCH-expressing neurons in the lateral hypothalamus after long term selective REM sleep deprivation

et al. 2013

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“…Based on rodent studies, it is anticipated that either loss or gain of MCHR1 function will predispose to selected phenotypes in humans (e.g., a lean or obese phenotype, respectively) (Antal-Zimanyi and Khawaja, 2009;Pissios, 2009;Chung et al, 2010). As a candidate obesity susceptibility gene, the MCHR1 locus has therefore been screened for mutations (Gibson et al, 2004;Wermter et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

“…As a candidate obesity susceptibility gene, the MCHR1 locus has therefore been screened for mutations (Gibson et al, 2004;Wermter et al, 2005). The variants that have been identified to date are not associated with standard indices of obesity (including body mass index, waist circumference, and glucose tolerance) (Antal-Zimanyi and Khawaja, 2009). However, it is of note that the two major loss-of-function variants described in our work (H210R and P377S) were, respectively, identified in two markedly underweight students, but not in an obese cohort that was studied in parallel (Wermter et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

“…Stimulation with MCH, the receptor's endogenous ligand, triggers G␣ i -mediated inhibition of cAMP formation and consequent downstream signaling (Saito et al, 1999;Shimomura et al, 1999). In contrast to the wide tissue distribution of the receptor, expression of MCH in the brain is restricted to the hypothalamus and zona incerta (Pissios and Maratos-Flier, 2003;Antal-Zimanyi and Khawaja, 2009). …”

Section: Introductionmentioning

confidence: 99%

“…Since these initial observations, an increasing number of small-molecule MCHR1 antagonists have been studied in rodents and shown to reduce body weight. In addition, several of these antagonists, including SNAP-7941, show anxiolytic and/or antidepressant properties when assessed in murine models (Antal-Zimanyi and Khawaja, 2009;Chung et al, 2010). The development of MCHR1 antagonists is therefore being actively pursued as a potential therapeutic for obesity and/or mood disorders in humans.…”

Section: Introductionmentioning

confidence: 99%

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Two Naturally Occurring Mutations in the Type 1 Melanin-Concentrating Hormone Receptor Abolish Agonist-Induced Signaling

Goldstein¹,

Schroeder²,

Fortin³

et al. 2010

J Pharmacol Exp Ther

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The melanin-concentrating hormone (MCH) receptor type 1 (MCHR1) is a seven-transmembrane domain protein that modulates orexigenic activity of MCH, the corresponding endogenous peptide agonist. MCH antagonists are being explored as a potential treatment for obesity. In the current study, we examined the pharmacological impact of 11 naturally occurring mutations in the human MCHR1. Wild-type and mutant receptors were transiently expressed in human embryonic kidney 293 cells. MCHR1-mediated, G␣ i -dependent signaling was monitored by using luciferase reporter gene assays. Two mutants, R210H and P377S, failed to respond to MCH. Five other variants showed significant alterations in MCH efficacy, ranging from 44 to 142% of the wild-type value. At each of the MCH-responsive mutants, agonist potency and inhibition by (S)-methyl 3-((3-(4-(3-acetamidophenyl) piperidin-1-yl)propyl)carbamoyl)-4-(3,4-difluorophenyl)-6-(methoxymethyl)-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (SNAP-7941), an established MCHR1 small-molecule antagonist, were similar to wild type. To explore the basis for inactivity of the R210H and P377S mutants, we examined expression levels of these receptors. Assessment by enzyme-linked immunosorbent assay revealed that cell surface expression of both nonfunctional receptors was comparable with wild type. Overnight treatment with SNAP-7941, followed by washout of antagonist, enhanced MCH induced signaling by the wild-type receptor and restored MCH responsiveness of the P377S but not the R210H variant. It is of note that the two loss-of-function mutants were identified in markedly underweight individuals, raising the possibility that a lean phenotype may be linked to deficient MCHR1 signaling. Formal association studies with larger cohorts are needed to explore the extent to which signaling-deficient MCHR1 variants influence the maintenance of body weight.

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Targeting MCH Neuroendocrine Circuit in Lateral Hypothalamus to Protect Against Skeletal Senescence

Guo,

Zhu,

et al. 2024

Advanced Science

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Neuroendocrine regulation is essential for maintaining metabolic homeostasis. However, whether neuroendocrine pathway influence bone metabolism and skeletal senescence is unelucidated. Here, a central neuroendocrine circuit is identified that directly controls osteogenesis. Using virus based tracing, this study is identified that melanin concentrating hormone (MCH) expressing neurons in the lateral hypothalamus (LH) are connected to the bone. Chemogenetic activation of MCH neurons in the LH induces osteogenesis, whereas inhibiting these neurons reduces osteogenesis. Meanwhile, MCH is released into the circulation upon chemogenetic activation of these neurons. Single cell sequencing reveals that blocking MCH neurons in the LH diminishes osteogenic differentiation of bone marrow stromal cells (BMSCs) and induces senescence. Mechanistically, MCH promotes BMSC differentiation by activating MCHR1 via PKA signaling, and activating MCHR1 by MCH agonists attenuate skeletal senescence in mice. By elucidating a brain‐bone connection that autonomously enhances osteogenesis, these findings uncover the neuroendocrinological mechanisms governing bone mass regulation and protect against skeletal senescence.

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The Role of Melanin-Concentrating Hormone in Energy Homeostasis and Mood Disorders

Cited by 32 publications

References 102 publications

Acute escitalopram treatment inhibits REM sleep rebound and activation of MCH-expressing neurons in the lateral hypothalamus after long term selective REM sleep deprivation

Acute escitalopram treatment inhibits REM sleep rebound and activation of MCH-expressing neurons in the lateral hypothalamus after long term selective REM sleep deprivation

Two Naturally Occurring Mutations in the Type 1 Melanin-Concentrating Hormone Receptor Abolish Agonist-Induced Signaling

Targeting MCH Neuroendocrine Circuit in Lateral Hypothalamus to Protect Against Skeletal Senescence

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