Melanin-concentrating hormone 1 receptor-deficient mice are lean, hyperactive, and hyperphagic and have altered metabolism

Marsh, Donald J.; Weingarth, Drew T.; Novi, Dawn E.; Chen, Howard Y.; Trumbauer, Myrna E.; Chen, Airu S.; Guan, Xiao-Ming; Jiang, Michael; Feng, Yue; Camacho, Ramon; Shen, Zhu; Frazier, Easter G.; Yu, Hong; Metzger, Joseph M.; Kuca, Stephanie J.; Shearman, Lauren P.; Gopal-Truter, Shobhna; MacNeil, Douglas J.; Strack, Alison M.; MacIntyre, D. Euan; Ploeg, Lex H.T. Van der; Su, Qian

doi:10.1073/pnas.052706899

Cited by 536 publications

(415 citation statements)

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“…This indicates that physical activity does not contribute to the lean phenotype of Pmch-deficient rats and supports the idea that loss of Pmch primarily results in a decrease of caloric intake. Interestingly, the Mchr1 knockout E485 mice show hyperphagia and an increased physical activity (8,38). Although loss of Pmch or Mchr1 both produce a lean phenotype, the aberrant behavior resulting in leanness is different (i.e., normal activity vs. hyperactivity, and hypophagia vs. hyperphagia), and no explaining mechanisms have been proposed to date.…”

Section: E483mentioning

confidence: 99%

Pmchexpression during early development is critical for normal energy homeostasis

Mul

Berg³

et al. 2010

American Journal of Physiology-Endocrinology and Metabolism

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Mul JD, Yi CX, van den Berg SAA, Ruiter M, Toonen PW, van der Elst MCJ, Voshol PJ, Ellenbroek BA, Kalsbeek A, la Fleur SE, Cuppen E. Pmch expression during early development is critical for normal energy homeostasis. Am J Physiol Endocrinol Metab 298: E477-E488, 2010. First published November 24, 2009 doi:10.1152/ajpendo.00154.2009.-Postnatal development and puberty are times of strong physical maturation and require large quantities of energy. The hypothalamic neuropeptide melanin-concentrating hormone (MCH) regulates nutrient intake and energy homeostasis, but the underlying mechanisms are not completely understood. Here we use a novel rat knockout model in which the MCH precursor Pmch has been inactivated to study the effects of loss of MCH on energy regulation in more detail. Pmch Ϫ/Ϫ rats are lean, hypophagic, osteoporotic, and although endocrine parameters were changed in pmch Ϫ/Ϫ rats, endocrine dynamics were normal, indicating an adaptation to new homeostatic levels rather than disturbed metabolic mechanisms. Detailed body weight growth and feeding behavior analysis revealed that Pmch expression is particularly important during early rat development and puberty, i.e., the first 8 postnatal weeks. Loss of Pmch resulted in a 20% lower set point for body weight that was determined solely during this period and remained unchanged during adulthood. Although the final body weight is diet dependent, the Pmch-deficiency effect was similar for all diets tested in this study. Loss of Pmch affected energy expenditure in both young and adult rats, although these effects seem secondary to the observed hypophagia. Our findings show an important role for Pmch in energy homeostasis determination during early development and indicate that the MCH receptor 1 system is a plausible target for childhood obesity treatment, currently a major health issue in first world countries. melanin-concentrating hormone; hypothalamus; childhood obesity; rat knockout model CHILDHOOD OBESITY IS NOW WIDELY recognized as a severe public health issue (43). Treatment with drugs aimed at neural systems involved in the determination of the energy balance could potentially result in a lower energy balance during puberty as well as later in adulthood. Therefore, neuropeptides involved in body weight regulation during early development and puberty are attractive targets for anti-childhood obesity drugs.The neuronal metabolic systems in humans and primates develop prenatally, while in rodents these systems develop during the first 3 postnatal weeks (5, 21). This results in the activation and optimization of neuronal systems during early rodent development. A second important metabolic period is puberty, a period of major growth, hormonal changes, and sexual maturation. In the rat, puberty is characterized by different responses of young-adolescent [postnatal day (PND) 40] and young-adult (PND 60) male rats to environmental cues like stress and cold (17,18). In addition to these age-dependent behavioral differences, the amount of food consumed durin...

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Section: E483mentioning

confidence: 99%

Pmchexpression during early development is critical for normal energy homeostasis

Mul

Berg³

et al. 2010

American Journal of Physiology-Endocrinology and Metabolism

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“…PMHC is proteolytically processed into the orexigenic hormone melanin-concentrating hormone (MCH), as well as into neuropeptide EI (NEI) and neuropeptide GE (NGE). The PMHC gene is involved in the regulation of energy homoeostasis as PMCH-deficient mice have high metabolic rate, are hypophagic and lean whereas mice that over-express the gene are hyperphagic and mildly obese (Marsh et al, 2002). The relative high level of PMHC gene expression in cows that tend to poorly express oestrus behaviour may be explained, for example, as a defence mechanism against energy deficit or as a route to establish different energy allocation strategies.…”

Section: The Study Ran From September 2006 To April 2007 and Was Apprmentioning

confidence: 99%

Expression profiles of genes regulating dairy cow fertility: recent findings, ongoing activities and future possibilities

Beerda

Wyszyńska-Koko

Pas

et al. 2008

Animal

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Subfertility has negative effects for dairy farm profitability, animal welfare and sustainability of animal production. Increasing herd sizes and economic pressures restrict the amount of time that farmers can spend on counteractive management. Genetic improvement will become increasingly important to restore reproductive performance. Complementary to traditional breeding value estimation procedures, genomic selection based on genome-wide information will become more widely applied. Functional genomics, including transcriptomics (gene expression profiling), produces the information to understand the consequences of selection as it helps to unravel physiological mechanisms underlying female fertility traits. Insight into the latter is needed to develop new effective management strategies to combat subfertility. Here, the importance of functional genomics for dairy cow reproduction so far and in the near future is evaluated. Recent gene profiling studies in the field of dairy cow fertility are reviewed and new data are presented on genes that are expressed in the brains of dairy cows and that are involved in dairy cow oestrus (behaviour). Fast-developing new research areas in the field of functional genomics, such as epigenetics, RNA interference, variable copy numbers and nutrigenomics, are discussed including their promising future value for dairy cow fertility.

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“…The MCH1-R is expressed in numerous areas of the brain [3], and mediates the orexigenic actions of MCH in rodents. MCH1-R knock out mice are lean, hyperphagic, hyperactive, have an increased metabolism and are resistant to diet induced obesity (DIO) [7,17].…”

Section: Introductionmentioning

confidence: 99%

Effects of MCH and a MCH1-receptor antagonist on (palatable) food and water intake

Morens

Nørregaard²,

Receveur³

et al. 2005

Brain Research

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Receveur, J-M. (2005). Effects of MCH and a MCH1-receptor antagonist on (palatable) food and water intake. Brain-research, 1062(1-2), 32-38. DOI: 10.1016DOI: 10. /j.brainres.2005 Copyright Other than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons).Take-down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim.Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons the number of authors shown on this cover page is limited to 10 maximum. AbstractMelanin concentrating hormone (MCH) is a regulator of ingestive behavior, but several issues regarding its effects on specific components of ingestive behavior remain to be elucidated. Therefore, we injected, in the 3rd ventricle of male Wistar rats, saline, MCH (5 Ag), MCH (5 Ag) together with a MCH1-R antagonist (A, 10 Ag) and the antagonist alone (A, 10 Ag). Our results show that (1) central administration of MCH stimulates food intake (lab chow and medium high fat diet) and this can be blocked by a MCH1-R antagonist; (2) the MCH-induced increase in food intake is mediated through increased meal number, meal duration and meal size; (3) the MCH1-R antagonist is able to significantly reduce the intake of a highly palatable food (condensed sweet milk) and is more effective in blocking MCH-induced food intake when rats are fed a palatable medium high fat food; and (4) MCH stimulated water intake independently from and disproportionately to food intake. In conclusion, our results point to an involvement of endogenous MCH in the enhanced intake of palatable food. Furthermore, they confirm that MCH stimulates not only food intake but also water intake. D

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Melanin-concentrating hormone 1 receptor-deficient mice are lean, hyperactive, and hyperphagic and have altered metabolism

Cited by 536 publications

References 28 publications

Pmchexpression during early development is critical for normal energy homeostasis

Pmchexpression during early development is critical for normal energy homeostasis

Expression profiles of genes regulating dairy cow fertility: recent findings, ongoing activities and future possibilities

Effects of MCH and a MCH1-receptor antagonist on (palatable) food and water intake

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