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Query: UMLS:C0028754 (obesity)
 124,988 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Genetics and environment contribute to the development of obesity, in both humans and rodents. However, the potential interaction between genes important in energy balance, strain background, and dietary environment has been only minimally explored. We investigated the effects of genetic ablation of melanin-concentrating hormone (MCH), a neuropeptide with a key role in energy balance, with chow and a high-fat diet (HFD) in two different mouse strains, one obesity-prone (C57BL/6) and the other obesity-resistant (129). Substantial differences were seen in wild-type (WT) animals of different strains. 129 animals had significantly lower levels of spontaneous locomotor activity than C57BL/6; however, 129 mice gained less weight on both chow and HFD. In both strains, deletion of MCH led to attenuated weight gain compared with WT counterparts, an effect secondary to increased energy expenditure. In both strains, feeding a HFD led to further increases in energy expenditure in both WT and MCH-KO mice; however, this increase was more pronounced in 129 mice. In addition, mice lacking MCH have a phenotype of increased locomotor activity, an effect also seen in both strains. The relative increase in activity in MCH(-/-) mice is modest in animals fed chow but increases substantially when animals are placed on HFD. These studies reinforce the important role of MCH in energy homeostasis and indicate that MCH is a plausible target for antiobesity therapy.
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PMID:Mice with MCH ablation resist diet-induced obesity through strain-specific mechanisms. 1573 2

Melanin-concentrating hormone (MCH) is a cyclic orexigenic peptide expressed in the lateral hypothalamus, which plays an important role in regulating energy balance. To elucidate the physiological role of MCH in obesity development, the present study examined the effect of a selective MCH1 receptor (MCH1R) antagonist in the diet-induced obesity mouse model. The MCH1R antagonist has high affinity and selectivity for MCH-1R and potently inhibits intracerebroventricularly injected MCH-induced food intake in Sprague Dawley rats. Chronic intracerebroventricular infusion of the MCH1R antagonist (7.5 microg/d) completely suppressed body weight gain in diet-induced obese mice during the treatment periods and significantly decreased cumulative food intake, by 14%. Carcass analysis showed that the MCH1R antagonist resulted in a selective decrease of body fat in the diet-induced obese mice. In addition, the MCH1R antagonist ameliorated the obesity-related hypercholesterolemia, hyperinsulinemia, hyperglycemia, and hyperleptinemia. These results indicate that MCH has a major role in the development of diet-induced obesity in mice and that a MCH1R antagonist might be a useful candidate as an antiobesity agent.
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PMID:Antiobesity effect of a melanin-concentrating hormone 1 receptor antagonist in diet-induced obese mice. 1581 71

Appetite regulation is part of a feedback system that controls the energy balance, involving a complex interplay of hunger and satiety signals, produced in the hypothalamus as well as in peripheral organs. Hunger signals may be generated in peripheral organs (e.g. ghrelin) but most of them are expressed in the hypothalamus (neuropeptide Y, orexins, agouti-related peptide, melanin concentrating hormone, endogenous opiates and dopamine) and are expressed during situations of energy deficiency. Some satiety signals, such as cholecystokinin, glucagon-like peptide 1, peptide YY and enterostatin are released from the digestive tract in response to food intake. Others, such as leptin and insulin, are mobilized in response to perturbations in the nutritional state. Still others are generated in neurones of the hypothalamus (alpha-melanocyte-stimulating hormone and serotonin). Satiety signals act by inhibiting the expression of hunger signals and/or by blunting their effect. Palatable food, i.e. food rich in fat and sugar, up-regulates the expression of hunger signals and satiety signals, at the same time blunting the response to satiety signals and activating the reward system. Hence, palatable food offsets normal appetite regulation, which may explain the increasing problem of obesity worldwide.
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PMID:How palatable food disrupts appetite regulation. 1599 51

Transgenic hyperexpression of melanin-concentrating hormone (MCH) produces a phenotype of obesity and glucose intolerance. However, it is not known whether under this specific condition, glucose intolerance develops as a direct consequence of hyperexpressed MCH or is secondary to increased adiposity. Here, rats were treated i.c.v. with MCH or with an antisense oligonucleotide to MCH (MCH-ASO). MCH promoted an increase in blood glucose and a decrease in blood insulin levels during a glucose tolerance test. MCH also caused a decrease in the constant of glucose disappearance during an insulin tolerance test. All these effects of MCH were independent of body weight variation and were accompanied by reduced insulin receptor substrate (IRS)-1 engagement of phosphatidylinositol-3 kinase (PI3-kinase) in white and brown adipose tissues, skeletal muscle and liver and by reduced Akt activation in skeletal muscle. MCH also led to a significant reduction in ERK activation in white adipose tissue. Finally, inhibition of hypothalamic MCH expression promoted a significant increase in ERK activation in brown adipose tissue. We conclude that hypothalamic MCH controls glucose homeostasis through mechanisms that are, at least in part, independent of adiposity.
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PMID:Melanin-concentrating hormone induces insulin resistance through a mechanism independent of body weight gain. 2825 9

The observation that loss of orexin (hypocretin) neurons causes human narcolepsy raises the possibility that other acquired disorders might also result from loss of hypothalamic neurons. To test this possibility for body weight, mice with selective loss of melanin concentrating hormone (MCH) neurons were generated. MCH was chosen to test because induced mutations of the MCH gene in mice cause hypophagia and leanness. Mice with ablation of MCH neurons were generated using toxin (ataxin-3)-mediated ablation strategy. The mice appeared normal but, after 7 weeks, developed reduced body weight, body length, fat mass, lean mass, and leptin levels. Leanness was characterized by hypophagia and increased energy expenditure. To study the role of MCH neurons on obesity secondary to leptin deficiency, we generated mice deficient in both ob gene product (leptin) and MCH neurons. Absence of MCH neurons in ob/ob mice improved obesity, diabetes, and hepatic steatosis, suggesting that MCH neurons are important mediators of the response to leptin deficiency. These data show that loss of MCH neurons can lead to an acquired leanness. This has implications for the pathogenesis of acquired changes of body weight and might be considered in clinical settings characterized by substantial weight changes later in life.
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PMID:Late-onset leanness in mice with targeted ablation of melanin concentrating hormone neurons. 1640 34

Ablation of the hypothalamic peptide, melanin-concentrating hormone (MCH), leads to a lean phenotype and resistance to diet-induced obesity. Observation of MCH(-/-) mice at older ages suggested that these effects persist in mice >1 year old. Leanness secondary to caloric restriction is known to be associated with improved glucose tolerance as well as an overall increase in life span. Because the MCH(-/-) model represents leanness secondary to increased energy expenditure rather than caloric restriction, we were interested in determining whether this model of leanness would be associated with beneficial metabolic effects at older ages. To assess the effects of MCH ablation over a more prolonged period, we monitored male and female MCH(-/-) mice up to 19 months. The lean phenotype of MCH(-/-) mice persisted over the duration of the study. At 19 months, MCH(-/-) male and female mice weighed 23.4 and 30.8% less than their wild-type counterparts, a result of reduced fat mass in MCH(-/-) mice. Aged MCH(-/-) mice exhibited better glucose tolerance and were more insulin sensitive compared with wild-type controls. Aging-associated decreases in locomotor activity were also attenuated in MCH(-/-) mice. We also evaluated two molecules implicated in the pathophysiology of aging, p53 and silent inflammatory regulator 2 (Sir2). We found that expression of the tumor suppressor protein p53 was higher in MCH(-/-) mice at 9 and 19 months of age. In contrast, expression of Sir2 was unchanged. In aggregate, these findings suggest that MCH ablation improves the long-term outcome for several indicators of the aging process.
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PMID:MCH-/- mice are resistant to aging-associated increases in body weight and insulin resistance. 1644 77

The hypothalamic peptide melanin-concentrating hormone (MCH) plays important roles in energy homeostasis. Animals overexpressing MCH develop hyperphagia, obesity, and insulin resistance. In this study, mice lacking both the MCH receptor-1 (MCHr1 knockout) and leptin (ob/ob) double-null mice (MCHr1 knockout ob/ob) were generated to investigate whether the obesity and/or the insulin resistance linked to the obese phenotype of ob/ob mice was attenuated by ablation of the MCHr1 gene. In MCHr1 knockout ob/ob mice an oral glucose load resulted in a lower blood glucose response and markedly lower insulin levels compared with the ob/ob mice despite no differences in body weight, food intake, or energy expenditure. In addition, MCHr1 knockout ob/ob mice had higher locomotor activity and lean body mass, lower body fat mass, and altered body temperature regulation compared with ob/ob mice. In conclusion, MCHr1 is important for insulin sensitivity and/or secretion via a mechanism not dependent on decreased body weight.
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PMID:Melanin-concentrating hormone receptor 1 deficiency increases insulin sensitivity in obese leptin-deficient mice without affecting body weight. 1650 36

Melanin-concentrating hormone (MCH), an orexigenic neuropeptide in mammals, activates a G-protein coupled receptor, MCHR1. It is expected that antagonists of MCHR1 function will prove therapeutically useful as anti-obesity agents. Intracellular signaling by MCHR1 has been investigated primarily using non-neural cell lines expressing the recombinant receptor, in which MCHR1 has been shown to couple to G alpha(i/o) and G alpha(q) G-proteins. While these cell lines have been widely utilized to discover and optimize small molecule antagonists, it is unknown whether the intracellular signaling pathways in these cells accurately reflect those in neurons. Thus, we sought to develop a neurally derived cell line endogenously expressing MCHR1. IMR32, a human neuroblastoma cell line, has been shown to express MCHR1 mRNA; however, we were unable to detect either MCH-binding or MCH-stimulated Ca++-mobilization in these cells. Following transfection of IMR32 cells with a plasmid encoding human G alpha(16) G-protein, we isolated a cell line, I3.4.2, which responded to MCH in Ca++-mobilization assays. We found that the expression level of MCHR1 mRNA in I3.4.2 cells was 2000-fold higher than in the parent cell line. Using [125I]MCH saturation-binding to I3.4.2 cell membranes, we estimated the Bmax as 0.72 pmol/mg protein and the Kd as 0.35 nM. We report that Ca++-mobilization in I3.4.2 cells was insensitive to pertussis toxin (Ptx) treatment, indicating that signaling was via G alpha(q) G-proteins. Furthermore, negative results in cAMP accumulation assays confirmed the lack of signaling via the G alpha(i/o) G-proteins. Our results suggest that the I3.4.2 cell line may be useful for characterization of MCHR1 activity in a neural-derived cell line.
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PMID:Characterization of a neuronal cell line expressing native human melanin-concentrating hormone receptor 1 (MCHR1). 1652 57

Melanin-concentrating hormone (MCH) is a critical hypothalamic anabolic neuropeptide, with key central and peripheral actions on energy balance regulation. The actions of MCH are, so far, known to be transduced through two seven-transmembrane-like receptor paralogues, named MCH1R and MCH2R. MCH2R is not functional in rodents. MCH1R is an important receptor involved in mediating feeding behaviour modulation by MCH in rodents. Pharmacological antagonism at MCH1R in rodents diminishes food intake and results in significant and sustained weight loss in fat tissues, particularly in obese animals. Additionally, MCH1R antagonists have been shown to have anxiolytic and antidepressant properties. The purpose of this review is to highlight the recent numerous pieces of evidence showing that pharmacological blockade at MCH1R could be a potential treatment for obesity and its related metabolic syndrome, as well as for various psychiatric disorders.
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PMID:Further insights into the neurobiology of melanin-concentrating hormone in energy and mood balances. 1654 71

Melanin-concentrating hormone (MCH) is a cyclic, nonadecapeptide expressed in the CNS of all vertebrates that regulates feeding behavior and energy homeostasis via interaction with the central melanocortin system. Regulation of this interaction results in modulation of food intake and body weight gain, demonstrating significant therapeutic potential for the treatment of obesity. The MCH-1 receptor (MCH-R1) has been identified as a key target in MCH regulation, as small molecule antagonists of MCH-R1 have demonstrated activity in vivo. Herein, we document our research in a bicyclo[3.1.0]hexyl urea series with particular emphasis on structure-activity relationships and optimization of receptor occupancy, measured both in vitro and via an ex vivo binding assay following an oral dosing regimen. Several compounds have been tested in vivo and exhibit oral efficacy in relevant acute rodent feeding models. In particular, 24u has proven efficacious in chronic rodent models of obesity, showing a statistically significant reduction in food intake and body weight over a 28 day study.
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PMID:Discovery of orally efficacious melanin-concentrating hormone receptor-1 antagonists as antiobesity agents. Synthesis, SAR, and biological evaluation of bicyclo[3.1.0]hexyl ureas. 1657 Sep 26


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