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      A Deletion in the Canine POMC Gene Is Associated with Weight and Appetite in Obesity-Prone Labrador Retriever Dogs

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          Summary

          Sequencing of candidate genes for obesity in Labrador retriever dogs identified a 14 bp deletion in pro-opiomelanocortin ( POMC) with an allele frequency of 12%. The deletion disrupts the β-MSH and β-endorphin coding sequences and is associated with body weight (per allele effect of 0.33 SD), adiposity, and greater food motivation. Among other dog breeds, the deletion was only found in the closely related flat-coat retriever (FCR), where it is similarly associated with body weight and food motivation. The mutation is significantly more common in Labrador retrievers selected to become assistance dogs than pets. In conclusion, the deletion in POMC is a significant modifier of weight and appetite in Labrador retrievers and FCRs and may influence other behavioral traits.

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          Highlights

          • A POMC mutation is common in the obesity-prone Labrador retriever breed of dog

          • It disrupts β-MSH and β-endorphin production, both implicated in energy homeostasis

          • Mutation is absent from other breeds except related flat-coat retrievers

          • The mutation is associated with weight, adiposity, and food motivation in both breeds

          Abstract

          Companion dogs from the obesity-prone Labrador retriever breed were found to carry a mutation in POMC in this study by Raffan et al. The mutation is predicted to disrupt production of the neuroactive peptides β-MSH and β-endorphin and was associated with greater weight, adiposity, and food motivation in affected dogs.

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          Most cited references23

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          Prevalence of obesity in dogs examined by Australian veterinary practices and the risk factors involved.

          A study was undertaken to determine the prevalence of obesity in dogs examined by veterinary practices across Australia, and to determine the risk factors involved; 1700 practices were asked to complete a veterinarian opinion survey, and of the 428 practices that responded, 178 were selected to complete an RSPCA Australia Pet Obesity Questionnaire, together with additional practices selected by Australian State and Territory RSPCA societies. This questionnaire was sent to a total of 209 practices which were asked to record details of eligible dogs, and the reason why they had been examined during the previous month. Fifty-two (24.9 per cent) of the practices responded and provided data on 2661 dogs, of which 892 (33.5 per cent) were overweight and 201 (7.6 per cent) were obese. A further 112 dogs (4.2 per cent) were classified as thin or very thin, but these were excluded from subsequent analyses. Of the remaining 2549 dogs, approximately half were female and 1905 (74.7 per cent) were neutered. The dogs' weight category was influenced by several factors. Breed influenced the importance of sex and neutering as risk factors. The prevalence of overweight and obese dogs combined was 41 per cent; the prevalence increased with age up to about 10 years old, and then declined. Rural and semirural dogs were more at risk of obesity than urban and suburban dogs.
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            Unraveling the brain regulation of appetite: lessons from genetics.

            Over the past 20 years, genetic studies have illuminated critical pathways in the hypothalamus and brainstem mediating energy homeostasis, such as the melanocortin, leptin, 5-hydroxytryptamine and brain-derived neurotrophic factor signaling axes. The identification of these pathways necessary for appropriate appetitive responses to energy state has yielded insight into normal homeostatic processes. Although monogenic alterations in each of these axes result in severe obesity, such cases remain rare. The major burden of disease is carried by those with common obesity, which has so far resisted yielding meaningful biological insights. Recent progress into the etiology of common obesity has been made with genome-wide association studies. Such studies now reveal more than 32 different candidate obesity genes, most of which are highly expressed or known to act in the CNS, emphasizing, as in rare monogenic forms of obesity, the role of the brain in predisposition to obesity.
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              A metabolic defect promotes obesity in mice lacking melanocortin-4 receptors.

              Melanocortin-4 receptor (Mc4r)-null mice exhibit late-onset obesity. To determine whether aberrant metabolism contributes to the obesity, food consumption by Mc4r-null mice was restricted to (pair-fed to) that consumed by wild-type (WT) mice. Pair-fed Mc4r-null females maintained body weights intermediate to that of WT and nonpair-fed Mc4r-null females, whereas pairfeeding normalized the body weights of Mc4r-null male mice. Fat pad and circulating leptin levels were elevated in both male and female pair-fed Mc4r-null mice compared with WT mice. Oxygen consumption of Mc4r-null mice with similar body weights as WT controls was reduced by 20%. Locomotor activity of young nonobese Mc4r-null males was significantly lower than that of WT males; however, locomotion of young nonobese females was normal. Core body temperature of Mc4r-null mice was normal, and they responded normally to cold exposure. Young nonobese Mc4r-null females were unable to induce uncoupling protein 1 (UCP1) in brown adipose tissue in response to peripheral leptin administration, whereas UCP1 mRNA was increased by 60% in the WT females. These results indicate that Mc4r deficiency enhances caloric efficiency, similar to that seen in the agouti obesity syndrome and in melanocortin-3 receptor-null mice.
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                Author and article information

                Contributors
                Journal
                Cell Metab
                Cell Metab
                Cell Metabolism
                Cell Press
                1550-4131
                1932-7420
                10 May 2016
                10 May 2016
                : 23
                : 5
                : 893-900
                Affiliations
                [1 ]University of Cambridge Metabolic Research Laboratories, WT-MRC Institute of Metabolic Science, University of Cambridge, Cambridge CB2 0QQ, UK
                [2 ]MRC Epidemiology Unit, WT-MRC Institute of Metabolic Science, University of Cambridge, Cambridge CB2 0QQ, UK
                [3 ]School of Clinical Medicine, University of Cambridge, Cambridge CB2 0SP, UK
                [4 ]The Roslin Institute, University of Edinburgh, Easter Bush, Midlothian EH25 9RG, UK
                [5 ]The Royal (Dick) School of Veterinary Studies, University of Edinburgh, Easter Bush, Midlothian EH25 9RG, UK
                [6 ]Institute of Ageing and Chronic Disease, University of Liverpool, Neston, Cheshire CH64 7TE, UK
                [7 ]Department of Canine Genetics, Animal Health Trust, Newmarket, Suffolk CB8 7UU, UK
                [8 ]IMBIM, Uppsala University, Uppsala 75123, Sweden
                [9 ]Department of Anatomy, Physiology, and Biochemistry, Swedish University of Agricultural Sciences, Uppsala 75007, Sweden
                [10 ]Department of Animal Breeding and Genetics, Swedish University of Agricultural Sciences, Uppsala 75007, Sweden
                [11 ]Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA
                [12 ]Science for Life Laboratory, Uppsala 75123, Sweden
                Author notes
                []Corresponding author er311@ 123456cam.ac.uk
                [∗∗ ]Corresponding author so104@ 123456medschl.cam.ac.uk
                [13]

                Co-senior author

                [14]

                Twitter: @GOdogsProject

                Article
                S1550-4131(16)30163-2
                10.1016/j.cmet.2016.04.012
                4873617
                27157046
                874c7477-75fd-4701-9eea-64b2a917e522
                © 2016 The Authors

                This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

                History
                : 19 January 2016
                : 16 March 2016
                : 13 April 2016
                Categories
                Short Article

                Cell biology
                Cell biology

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