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Roger D. Cone - One of the best experts on this subject based on the ideXlab platform.
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Loss of the Melanocortin-4 Receptor in mice causes dilated cardiomyopathy
eLife, 2017Co-Authors: Michael J. Litt, G Donald Okoye, Daniel S. Lark, Isin Cakir, Christy Moore, Mary C Barber, James B. Atkinson, Josh Fessel, Javid Moslehi, Roger D. ConeAbstract:Mutations in the gene that encodes a protein called the Melanocortin-4 Receptor are the most common genetic cause of early onset obesity in children. These mutations occur in about 1 in 1,500 people. The Melanocortin-4 Receptor is mostly found in the brain where it helps to balance how much a person eats with how many calories they burn. A mutation in just one of the two copies of the gene a person gets from their parents is enough to cause severe obesity. Mice that have been genetically engineered to lack this gene develop all the same symptoms as humans with the mutation. These symptoms include early onset obesity, a slower than normal heart rate, and reduced activity in the nerves that communicate with many body tissues including the gut. Patients with this syndrome are less likely to develop obesity-linked high blood pressure, which could be considered protective from some of the ill effects of excess weight. As a result, studying the animal model of the syndrome may help scientists better understand why mutations in the gene for the Melanocortin-4 Receptor cause obesity and how to better care for people with these mutations. Now, Litt et al. show that, contrary to expectations, mice lacking the gene for the Melanocortin-4 Receptor have a higher risk of heart failure than normal mice. An ultrasound scanner showed that the left side of the heart in the mice without the Melanocortin-4 Receptor becomes progressively larger and weaker. This reduces the heart’s ability to pump blood. Additionally, Litt et al. showed that the energy-producing structures within cells, called mitochondria, are defective in the heart cells of these mice. These defects cause the mitochondria to work harder and produce more harmful byproducts. The mitochondria in the animal’s muscles, however, appear normal. Further experiments showed that the genes active in the hearts of the mice lacking Melanocortin-4 Receptors are similar to genes active in heart cells treated with doxorubicin, a cancer drug that is toxic to the heart. This drug is known to cause heart failure in some people. The experiments suggest that physicians should watch for signs of heart failure in people who have mutations that affect their Melanocortin-4 Receptors. Mice with one good copy of the gene did not have signs of heart failure, but they appeared more sensitive to the toxic affects of doxorubicin. These findings suggest that clinical studies are needed to determine if there are potential heart problems or drug sensitivities in patients with mutations that affect the Melanocortin-4 Receptors.
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developmental control of the Melanocortin 4 Receptor by mrap2 proteins in zebrafish
Science, 2013Co-Authors: Julien A Sebag, Chao Zhang, Patricia M Hinkle, Amanda M Bradshaw, Roger D. ConeAbstract:The Melanocortin-4 Receptor (MC4R) is essential for control of energy homeostasis in vertebrates. MC4R interacts with Melanocortin Receptor accessory protein 2 (MRAP2) in vitro, but its functions in vivo are unknown. We found that MRAP2a, a larval form, stimulates growth of zebrafish by specifically blocking the action of MC4R. In cell culture, this protein binds MC4R and reduces the ability of the Receptor to bind its ligand, α–melanocyte-stimulating hormone (α-MSH). A paralog, MRAP2b, expressed later in development, also binds MC4R but increases ligand sensitivity. Thus, MRAP2 proteins allow for developmental control of MC4R activity, with MRAP2a blocking its function and stimulating growth during larval development, whereas MRAP2b enhances responsiveness to α-MSH once the zebrafish begins feeding, thus increasing the capacity for regulated feeding and growth.
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Melanocortin 4 Receptor mutations paradoxically reduce preference for palatable foods
Proceedings of the National Academy of Sciences of the United States of America, 2013Co-Authors: Brandon L Panaro, Roger D. ConeAbstract:Haploinsufficiency of the Melanocortin-4 Receptor (MC4R) results in Melanocortin obesity syndrome, the most common monogenic cause of severe early onset obesity in humans. The syndrome, which produces measurable hyperphagia, has focused attention on the role of MC4R in feeding behavior and macronutrient intake. Studies show that inhibition of MC4R signaling can acutely increase the consumption of high-fat foods. The current study examines the chronic feeding preferences of mice with deletion of one or both alleles of the MC4R to model the human syndrome. Using two-choice diet paradigms with high-fat or high-carbohydrate foods alongside normal chow, we show, paradoxically, that deletion of one allele has no effect, whereas deletion of both alleles of the MC4R actually decreases preference for palatable high-fat and high-sucrose foods, compared with wild-type mice. Nonetheless, we observed hyperphagic behavior from increased consumption of the low-fat standard chow when either heterozygous or homozygous mutant animals were presented with dietary variety. Thus, decreased MC4R signaling in Melanocortin obesity syndrome consistently yields hyperphagia irrespective of the foods provided, but the hyperphagia appears driven by variety and/or novelty, rather than by a preference for high-fat or high-carbohydrate foodstuffs.
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Melanocortin 4 Receptor signaling is required for weight loss after gastric bypass surgery
The Journal of Clinical Endocrinology and Metabolism, 2012Co-Authors: Ida J Hatoum, Roger D. Cone, Julia M Keogh, Nicholas Stylopoulos, Amanda M Vanhoose, Kelli L Boyd, Kate L J Ellacott, Lian Li, Kasia Blaszczyk, Sadaf I FarooqiAbstract:Context: Roux-en-Y gastric bypass (RYGB) is one of the most effective long-term therapies for the treatment of severe obesity. Recent evidence indicates that RYGB effects weight loss through multiple physiological mechanisms, including changes in energy expenditure, food intake, food preference, and reward pathways. Objective: Because central Melanocortin signaling plays an important role in the regulation of energy homeostasis, we investigated whether genetic disruption of the Melanocortin-4 Receptor (MC4R) in rodents and humans affects weight loss after RYGB. Methods and Results: Here we report that MC4R−/− mice lost substantially less weight after surgery than wild-type animals, indicating that MC4R signaling is necessary for the weight loss effects of RYGB in this model. Mice heterozygous for MC4R remain fully responsive to gastric bypass. To determine whether mutations affect surgically induced weight loss in humans, we sequenced the MC4R gene in 972 patients undergoing RYGB. Patients heterozygous fo...
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brain derived neurotrophic factor regulates energy balance downstream of Melanocortin 4 Receptor
Nature Neuroscience, 2003Co-Authors: Baoji Xu, Roger D. Cone, Evan H Goulding, Keling Zang, David Cepoi, Kevin R Jones, Laurence H Tecott, Louis F ReichardtAbstract:The Melanocortin-4 Receptor (MC4R) is critically involved in regulating energy balance, and obesity has been observed in mice with mutations in the gene for brain-derived neurotrophic factor (BDNF). Here we report that BDNF is expressed at high levels in the ventromedial hypothalamus (VMH) where its expression is regulated by nutritional state and by MC4R signaling. In addition, similar to MC4R mutants, mouse mutants that expresses the BDNF Receptor TrkB at a quarter of the normal amount showed hyperphagia and excessive weight gain on higher-fat diets. Furthermore, BDNF infusion into the brain suppressed the hyperphagia and excessive weight gain observed on higher-fat diets in mice with deficient MC4R signaling. These results show that MC4R signaling controls BDNF expression in the VMH and support the hypothesis that BDNF is an important effector through which MC4R signaling controls energy balance.
Alastair S Garfield - One of the best experts on this subject based on the ideXlab platform.
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Current Mechanistic and Pharmacodynamic Understanding of Melanocortin-4 Receptor Activation
Molecules, 2019Co-Authors: Shubh D. Sharma, Alastair S Garfield, Bhavik P. Shah, Patrick Kleyn, Ilia Ichetovkin, Ida Hatoum Moeller, William R. Mowrey, Lex H.t. Van Der PloegAbstract:In this work we summarize our understanding of Melanocortin 4 Receptor (MC4R) pathway activation, aiming to define a safe and effective therapeutic targeting strategy for the MC4R. Delineation of cellular MC4R pathways has provided evidence for distinct MC4R signaling events characterized by unique Receptor activation kinetics. While these studies remain narrow in scope, and have largely been explored with peptidic agonists, the results provide a possible correlation between distinct ligand groups and differential MC4R activation kinetics. In addition, when a set of small-molecule and peptide MC4R agonists are compared, evidence of biased signaling has been reported. The results of such mechanistic studies are discussed.
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Melanocortin-4 Receptor–regulated energy homeostasis
Nature Neuroscience, 2016Co-Authors: Michael J Krashes, Bradford B Lowell, Alastair S GarfieldAbstract:Central Melanocortinergic signaling via the Melanocortin-4 Receptor is both a culprit in and a target for obesity. The authors review our understanding of this evolutionarily conserved system in the regulation of mammalian energy homeostasis. The Melanocortin system provides a conceptual blueprint for the central control of energetic state. Defined by four principal molecular components—two antagonistically acting ligands and two cognate Receptors—this phylogenetically conserved system serves as a prototype for hierarchical energy balance regulation. Over the last decade the application of conditional genetic techniques has facilitated the neuroanatomical dissection of the Melanocortinergic network and identified the specific neural substrates and circuits that underscore the regulation of feeding behavior, energy expenditure, glucose homeostasis and autonomic outflow. In this regard, the Melanocortin-4 Receptor is a critical coordinator of mammalian energy homeostasis and body weight. Drawing on recent advances in neuroscience and genetic technologies, we consider the structure and function of the Melanocortin-4 Receptor circuitry and its role in energy homeostasis.
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Melanocortin 4 Receptor regulated energy homeostasis
Nature Neuroscience, 2016Co-Authors: Michael J Krashes, Bradford B Lowell, Alastair S GarfieldAbstract:Central Melanocortinergic signaling via the Melanocortin-4 Receptor is both a culprit in and a target for obesity. The authors review our understanding of this evolutionarily conserved system in the regulation of mammalian energy homeostasis. The Melanocortin system provides a conceptual blueprint for the central control of energetic state. Defined by four principal molecular components—two antagonistically acting ligands and two cognate Receptors—this phylogenetically conserved system serves as a prototype for hierarchical energy balance regulation. Over the last decade the application of conditional genetic techniques has facilitated the neuroanatomical dissection of the Melanocortinergic network and identified the specific neural substrates and circuits that underscore the regulation of feeding behavior, energy expenditure, glucose homeostasis and autonomic outflow. In this regard, the Melanocortin-4 Receptor is a critical coordinator of mammalian energy homeostasis and body weight. Drawing on recent advances in neuroscience and genetic technologies, we consider the structure and function of the Melanocortin-4 Receptor circuitry and its role in energy homeostasis.
Sadaf I Farooqi - One of the best experts on this subject based on the ideXlab platform.
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Melanocortin 4 Receptor signaling is required for weight loss after gastric bypass surgery
The Journal of Clinical Endocrinology and Metabolism, 2012Co-Authors: Ida J Hatoum, Roger D. Cone, Julia M Keogh, Nicholas Stylopoulos, Amanda M Vanhoose, Kelli L Boyd, Kate L J Ellacott, Lian Li, Kasia Blaszczyk, Sadaf I FarooqiAbstract:Context: Roux-en-Y gastric bypass (RYGB) is one of the most effective long-term therapies for the treatment of severe obesity. Recent evidence indicates that RYGB effects weight loss through multiple physiological mechanisms, including changes in energy expenditure, food intake, food preference, and reward pathways. Objective: Because central Melanocortin signaling plays an important role in the regulation of energy homeostasis, we investigated whether genetic disruption of the Melanocortin-4 Receptor (MC4R) in rodents and humans affects weight loss after RYGB. Methods and Results: Here we report that MC4R−/− mice lost substantially less weight after surgery than wild-type animals, indicating that MC4R signaling is necessary for the weight loss effects of RYGB in this model. Mice heterozygous for MC4R remain fully responsive to gastric bypass. To determine whether mutations affect surgically induced weight loss in humans, we sequenced the MC4R gene in 972 patients undergoing RYGB. Patients heterozygous fo...
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clinical spectrum of obesity and mutations in the Melanocortin 4 Receptor gene
The New England Journal of Medicine, 2003Co-Authors: Sadaf I Farooqi, Julia M Keogh, Emma Lank, Tim Cheetham, Stephen OrahillyAbstract:Background Melanocortin 4 Receptor (MC4R) deficiency is the commonest monogenic form of obesity. However, the clinical spectrum and mode of inheritance have not been defined, pathophysiological mechanisms leading to obesity are poorly understood, and there is little information regarding genotype–phenotype correlations. Methods We determined the nucleotide sequence of the MC4R gene in 500 probands with severe childhood obesity. Family studies were undertaken to examine cosegregation of identified mutations with obesity. Subjects with MC4R deficiency underwent metabolic and endocrine evaluation; the results were correlated with the signaling properties of mutant Receptors. Results Twenty-nine probands (5.8 percent) had mutations in MC4R; 23 were heterozygous, and 6 were homozygous. Mutation carriers had severe obesity, increased lean mass, increased linear growth, hyperphagia, and severe hyperinsulinemia; homozygotes were more severely affected than heterozygotes. Subjects with mutations retaining residual...
Ja-hyun Baik - One of the best experts on this subject based on the ideXlab platform.
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Glucose-regulated protein 78 binds to and regulates the Melanocortin-4 Receptor
Experimental and Molecular Medicine, 2018Co-Authors: Ye Ran Yoon, Mi Hyun Choi, Seung Woo Shin, Im Joo Rhyu, Je Kyung Seong, Young-gyu Ko, Ja-hyun BaikAbstract:The Melanocortin-4 Receptor (MC4R) belongs to the G protein-coupled Receptor (GPCR) family and plays an essential role in the control of energy homeostasis. Here, we identified a novel MC4R-interacting protein, glucose-regulated protein 78 (GRP78), from a pulldown assay using hypothalamic protein extracts and the third intracellular loop of MC4R. We found that MC4R interacted with GRP78 in both the cytosol and at the cell surface and that this interaction increased when MC4R was internalized in the presence of the agonist melanotan-II (MTII). Downregulation of GRP78 using a short interfering RNA approach attenuated MTII-mediated Receptor internalization. Reduction in GRP78 expression during tunicamycin-induced endoplasmic reticulum stress also suppressed MTII-mediated internalization of MC4R and cAMP-mediated transcriptional activity. Furthermore, lentiviral-mediated short hairpin RNA knockdown of endogenous GRP78 in the paraventricular nucleus (PVN) of the hypothalamus resulted in an increase in body weight in mice fed a high-fat diet. These results suggest that GRP78 in the PVN binds to MC4R and may have a chaperone-like role in the regulation of MC4R trafficking and signaling.
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Glucose-regulated protein 78 binds to and regulates the Melanocortin-4 Receptor
Experimental & Molecular Medicine, 2018Co-Authors: Ye Ran Yoon, Mi Hyun Choi, Seung Woo Shin, Im Joo Rhyu, Je Kyung Seong, Young-gyu Ko, Ja-hyun BaikAbstract:The Melanocortin-4 Receptor (MC4R) belongs to the G protein-coupled Receptor (GPCR) family and plays an essential role in the control of energy homeostasis. Here, we identified a novel MC4R-interacting protein, glucose-regulated protein 78 (GRP78), from a pulldown assay using hypothalamic protein extracts and the third intracellular loop of MC4R. We found that MC4R interacted with GRP78 in both the cytosol and at the cell surface and that this interaction increased when MC4R was internalized in the presence of the agonist melanotan-II (MTII). Downregulation of GRP78 using a short interfering RNA approach attenuated MTII-mediated Receptor internalization. Reduction in GRP78 expression during tunicamycin-induced endoplasmic reticulum stress also suppressed MTII-mediated internalization of MC4R and cAMP-mediated transcriptional activity. Furthermore, lentiviral-mediated short hairpin RNA knockdown of endogenous GRP78 in the paraventricular nucleus (PVN) of the hypothalamus resulted in an increase in body weight in mice fed a high-fat diet. These results suggest that GRP78 in the PVN binds to MC4R and may have a chaperone-like role in the regulation of MC4R trafficking and signaling. A molecular ‘chaperone’ helps regulate an essential metabolic signaling protein by ensuring that the protein is in the right place at the right time. The Melanocortin-4 Receptor (MC4R) controls food intake and energy burning. Abnormal MC4R activity is strongly linked with obesity. Little is known about how this protein is regulated, but researchers led by Ja-Hyun Baik at Korea University, Seoul, South Korea, have identified a potentially important partner for MC4R. They determined that MC4R binds a so-called ‘chaperone’ protein, GRP78, which facilitates trafficking of this Receptor from the cell membrane, where it can engage in active signaling, to the cell interior. The researchers showed that GRP78 helps cells cope with cellular stress associated with metabolic disease. Absence of this protein increases sensitivity to diet-induced obesity in mice, indicating a possible target for drug development.
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Melanocortin 4 Receptor and dopamine D2 Receptor expression in brain areas involved in food intake
Endocrinology and Metabolism, 2015Co-Authors: Ye Ran Yoon, Ja-hyun BaikAbstract:Background The Melanocortin 4 Receptor (MC4R) is involved in the regulation of homeostatic energy balance by the hypothalamus. Recent reports showed that MC4R can also control the motivation for food in association with a brain reward system, such as dopamine. We investigated the expression levels of MC4R and the dopamine D2 Receptor (D2R), which is known to be related to food rewards, in both the hypothalamus and brain regions involved in food rewards.
Julia M Keogh - One of the best experts on this subject based on the ideXlab platform.
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evaluation of a Melanocortin 4 Receptor mc4r agonist setmelanotide in mc4r deficiency
Molecular metabolism, 2017Co-Authors: Tinhhai Collet, Beatrice Dubern, Jacek Mokrosinski, Hillori Connors, Julia M Keogh, Edson Mendes De Oliveira, Elana Henning, Christine PoitoubernertAbstract:Objective Pro-opioMelanocortin (POMC)-derived peptides act on neurons expressing the Melanocortin 4 Receptor (MC4R) to reduce body weight. Setmelanotide is a highly potent MC4R agonist that leads to weight loss in diet-induced obese animals and in obese individuals with complete POMC deficiency. While POMC deficiency is very rare, 1–5% of severely obese individuals harbor heterozygous mutations in MC4R. We sought to assess the efficacy of Setmelanotide in human MC4R deficiency.
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Melanocortin 4 Receptor signaling is required for weight loss after gastric bypass surgery
The Journal of Clinical Endocrinology and Metabolism, 2012Co-Authors: Ida J Hatoum, Roger D. Cone, Julia M Keogh, Nicholas Stylopoulos, Amanda M Vanhoose, Kelli L Boyd, Kate L J Ellacott, Lian Li, Kasia Blaszczyk, Sadaf I FarooqiAbstract:Context: Roux-en-Y gastric bypass (RYGB) is one of the most effective long-term therapies for the treatment of severe obesity. Recent evidence indicates that RYGB effects weight loss through multiple physiological mechanisms, including changes in energy expenditure, food intake, food preference, and reward pathways. Objective: Because central Melanocortin signaling plays an important role in the regulation of energy homeostasis, we investigated whether genetic disruption of the Melanocortin-4 Receptor (MC4R) in rodents and humans affects weight loss after RYGB. Methods and Results: Here we report that MC4R−/− mice lost substantially less weight after surgery than wild-type animals, indicating that MC4R signaling is necessary for the weight loss effects of RYGB in this model. Mice heterozygous for MC4R remain fully responsive to gastric bypass. To determine whether mutations affect surgically induced weight loss in humans, we sequenced the MC4R gene in 972 patients undergoing RYGB. Patients heterozygous fo...
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clinical spectrum of obesity and mutations in the Melanocortin 4 Receptor gene
The New England Journal of Medicine, 2003Co-Authors: Sadaf I Farooqi, Julia M Keogh, Emma Lank, Tim Cheetham, Stephen OrahillyAbstract:Background Melanocortin 4 Receptor (MC4R) deficiency is the commonest monogenic form of obesity. However, the clinical spectrum and mode of inheritance have not been defined, pathophysiological mechanisms leading to obesity are poorly understood, and there is little information regarding genotype–phenotype correlations. Methods We determined the nucleotide sequence of the MC4R gene in 500 probands with severe childhood obesity. Family studies were undertaken to examine cosegregation of identified mutations with obesity. Subjects with MC4R deficiency underwent metabolic and endocrine evaluation; the results were correlated with the signaling properties of mutant Receptors. Results Twenty-nine probands (5.8 percent) had mutations in MC4R; 23 were heterozygous, and 6 were homozygous. Mutation carriers had severe obesity, increased lean mass, increased linear growth, hyperphagia, and severe hyperinsulinemia; homozygotes were more severely affected than heterozygotes. Subjects with mutations retaining residual...