Melanin Concentrating Hormone Is a Novel Regulator of Islet Function and Growth

Harvard University, Cambridge, Massachusetts, United States
Diabetes (Impact Factor: 8.1). 03/2007; 56(2):311-9. DOI: 10.2337/db06-0708
Source: PubMed


Melanin concentrating hormone (MCH) is a hypothalamic neuropeptide known to play a critical role in energy balance. We have previously reported that overexpression of MCH is associated with mild obesity. In addition, mice have substantial hyperinsulinemia and islet hyperplasia that is out of proportion with their degree of obesity. In this study, we further explored the role of MCH in the endocrine pancreas. Both MCH and MCHR1 are expressed in mouse and human islets and in clonal beta-cell lines as assessed using quantitative real-time PCR and immunohistochemistry. Mice lacking MCH (MCH-KO) on either a C57Bl/6 or 129Sv genetic background showed a significant reduction in beta-cell mass and complemented our earlier observation of increased beta-cell mass in MCH-overexpressing mice. Furthermore, the compensatory islet hyperplasia secondary to a high-fat diet, which was evident in wild-type controls, was attenuated in MCH-KO. Interestingly, MCH enhanced insulin secretion in human and mouse islets and rodent beta-cell lines in a dose-dependent manner. Real-time PCR analyses of islet RNA derived from MCH-KO revealed altered expression of islet-enriched genes such as glucagon, forkhead homeobox A2, hepatocyte nuclear factor (HNF)4alpha, and HNF1alpha. Together, these data provide novel evidence for an autocrine role for MCH in the regulation of beta-cell mass dynamics and in islet secretory function and suggest that MCH is part of a hypothalamic-islet (pancreatic) axis.

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Available from: Chong Wee Liew, Apr 10, 2014
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    • "Then, cDNAs were synthesized from 1 ␮g total RNA using oligo(dT), dNTP and MMLV Reverse Transcriptase (Fermentas). Real-time PCR was performed with gene specific primers for pMCH (Pissios et al., 2007). A 1 ␮L aliquot of cDNAs (diluted 1:10) was subjected to real-time RT-PCR using SyBR Green One step RT-PCR reagents (Applied Biosystems) and TaqMan R Universal Master Mix (Applied Biosystems). "
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    ABSTRACT: Alcohol consumption during pregnancy can cause a “fetal alcoholic syndrome” (FAS) in the progeny. This syndrome is characterized by important brain defects often associated to a decreased expression of the morphogenic protein Sonic Hedgehog (Shh). The goal of this study was to verify if a FAS could modify the differentiation of hypothalamic neurons producing MCH. Indeed, the expression of this peptide and neurons producing it are dependent of a Shh controlled genetic cascade in the embryo. To address this question, female rats received a 15% ethanol solution to drink during pregnancy and lactation. Higher abortion rate and smaller pups at birth confirmed that descendants were affected by this experimental condition. MCH expression was analyzed by RT-qPCR and immunohistochemistry in embryos taken at E11 and E13, or in pups and young adults born from control and alcoholic mothers. MCH expression level, number of MCH neurons or ratio of MCH sub-populations were not modified by our experimental conditions. However, Shh expression was significantly lover at E11 and we also observed that hindbrain serotonergic neurons were affected as reported in the literature. These findings as well as other data from the literature suggest that protective mechanisms are involved to maintain peptide expressions and differentiation of some specific neuron populations in the ventral diencephalon in surviving embryos exposed to ethanol during pregnancy.
    Brain Research Bulletin 08/2014; 107. DOI:10.1016/j.brainresbull.2014.07.006 · 2.72 Impact Factor
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    • "For example, although glucose tolerance worsens if MCH cells are made glucose-insensitive from birth (Kong et al. 2010), it actually improves if MCH cells are destroyed in the adult (Whiddon & Palmiter 2013). Furthermore, MCH overexpression leads to obesity and insulin resistance (Ludwig et al. 2001) and increases insulin levels (Pissios et al. 2007). It is possible that, like ORX neurones, MCH cells could have multiple, differentially modulated effects on glucose release and uptake. "
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    ABSTRACT: The brain can be viewed as a sophisticated control module for stabilizing blood glucose. A review of classical behavioural evidence indicates that central circuits add predictive (feedforward/anticipatory) control to the reactive (feedback/compensatory) control by peripheral organs. The brain/cephalic control is constructed and engaged, via associative learning, by sensory cues predicting energy intake or expenditure (e.g. sight, smell, taste, sound). This allows rapidly-measurable sensory information (rather than slowly generated internal feedback signals, e.g. digested nutrients) to control food selection, glucose supply for fight-or-flight responses, or preparedness for digestion/absorption. Predictive control is therefore useful for preventing large glucose fluctuations. We review emerging roles in predictive control of two classes of widely-projecting hypothalamic neurons, orexin/hypocretin (ORX) and melanin-concentrating hormone (MCH) cells. Evidence is cited that ORX neurons a) are activated by sensory cues (e.g. taste, sound); b) drive hepatic production, and muscle uptake, of glucose, via sympathetic nerves; c) stimulate wakefulness and exploration via global brain projections; d) are glucose-inhibited. MCH neurons are a) glucose-excited; b) innervate learning and reward centers to promote synaptic plasticity, learning, and memory, c) are critical for learning associations useful for predictive control (e.g. using taste to predict nutrient value of food). This evidence is unified into a model for predictive glucose control. During associative learning, inputs from some glucose-excited neurons may promote connections between the “fast” senses and reward circuits, constructing neural shortcuts for efficient action selection. In turn, glucose-inhibited neurons may engage locomotion/exploration, and coordinate the required fuel supply. Feedback inhibition of the latter neurons by glucose would ensure that glucose fluxes they stimulate (from liver, into muscle) are balanced. Estimating nutrient challenges from indirect sensory cues may become more difficult when the cues become complex and variable (e.g. like human foods today). Consequent errors of predictive glucose control may contribute to obesity and diabetes.This article is protected by copyright. All rights reserved.
    Acta Physiologica 08/2014; 213(1). DOI:10.1111/apha.12360 · 4.38 Impact Factor
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    • "However, a growing body of data indicates that MCH may also have non-neuronal function, especially by regulating the activity of more or less specialized peripheral blood mononuclear cells [PBMCs (42)]. The expression of ppMCH and/or MCHR1 genes in pancreatic islets or in adipocytes (43–45) may highlight a metabolism-related function of MCH at the periphery. Nevertheless, such action may not be totally independent of the intracerebral and/or spinal MCH pathway (46). "
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    ABSTRACT: The cyclic peptide Melanin Concentrating Hormone (MCH) is known to control a large number of brain functions in mammals such as food intake and metabolism, stress response, anxiety, sleep/wake cycle, memory, and reward. Based on neuro-anatomical and electrophysiological studies these functions were attributed to neuronal circuits expressing MCHR1, the single MCH receptor in rodents. In complement to our recently published work (1) we provided here new data regarding the action of MCH on ependymocytes in the mouse brain. First, we establish that MCHR1 mRNA is expressed in the ependymal cells of the third ventricle epithelium. Second, we demonstrated a tonic control of MCH-expressing neurons on ependymal cilia beat frequency using in vitro optogenics. Finally, we performed in vivo measurements of CSF flow using fluorescent micro-beads in wild-type and MCHR1-knockout mice. Collectively, our results demonstrated that MCH-expressing neurons modulate ciliary beating of ependymal cells at the third ventricle and could contribute to maintain cerebro-spinal fluid homeostasis.
    Frontiers in Endocrinology 11/2013; 4:182. DOI:10.3389/fendo.2013.00182
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