Low resting metabolic rate and increased hunger due to ß-MSH and ß-endorphin deletion in a canine model.

Mutations that perturb leptin-melanocortin signaling are known to cause hyperphagia and obesity, but energy expenditure has not been well studied outside rodents. We report on a common canine mutation in pro-opiomelanocortin (POMC), which prevents production of ß-melanocyte-stimulating hormone (ß-MSH) and ß-endorphin but not α-MSH; humans, similar to dogs, produce α-MSH and ß-MSH from the POMC propeptide, but rodents produce only α-MSH. We show that energy expenditure is markedly lower in affected dogs, which also have increased motivational salience in response to a food cue, indicating increased wanting or hunger. There was no difference in satiety at a modified ad libitum meal or in their hedonic response to food, nor disruption of adrenocorticotropic hormone (ACTH) or thyroid axes. In vitro, we show that ß-MSH signals comparably to α-MSH at melanocortin receptors. These data implicate ß-MSH and ß-endorphin as important in determining hunger and moderating energy expenditure and suggest that this role is independent of the presence of α-MSH.

Obesity risk factors in British Labrador retrievers: Effect of sex, neuter status, age, chocolate coat colour and food motivation.

BACKGROUND: Canine obesity is a complex disease affected by genetic, endocrine and environmental factors. It is associated with reduced lifespan and many comorbidities. Prevalence differs by breed, with Labrador retrievers at high risk. Past data on how biological risk factors impact weight gain have been contradictory, possibly because they were obtained from genetically heterogeneous populations. METHODS: We investigated risk factors for canine obesity in a population of British Labrador retrievers (n = 521) with high-quality data on obesity, weight, owner-reported food motivation and related characteristics. We used linear regression to assess known and novel risk factors for obesity. RESULTS: We found that neutering increased obesity in males (p < 0.001) but not females (p = 0.37). Older age was associated with obesity in female Labradors (p = 0.013) but not males (p = 0.49). We identified two new risk factors for obesity in Labrador retrievers: chocolate coat colour (p < 0.001) and high food motivation (p < 0.001). LIMITATIONS: Strategic recruitment to collect both obese and lean dogs means this cohort is not suitable for assessing obesity prevalence in UK Labrador retrievers. CONCLUSION: Studying this genetically homogeneous population informs our knowledge of common risk factors for obesity and expands those relevant to Labrador retrievers.

The Genetic Basis of Obesity and Related Metabolic Diseases in Humans and Companion Animals.

Obesity is one of the most prevalent health conditions in humans and companion animals globally. It is associated with premature mortality, metabolic dysfunction, and multiple health conditions across species. Obesity is, therefore, of importance in the fields of medicine and veterinary medicine. The regulation of adiposity is a homeostatic process vulnerable to disruption by a multitude of genetic and environmental factors. It is well established that the heritability of obesity is high in humans and laboratory animals, with ample evidence that the same is true in companion animals. In this review, we provide an overview of how genes link to obesity in humans, drawing on a wealth of information from laboratory animal models, and summarise the mechanisms by which obesity causes related disease. Throughout, we focus on how large-scale human studies and niche investigations of rare mutations in severely affected patients have improved our understanding of obesity biology and can inform our ability to interpret results of animal studies. For dogs, cats, and horses, we compare the similarities in obesity pathophysiology to humans and review the genetic studies that have been previously reported in those species. Finally, we discuss how veterinary genetics may learn from humans about studying precise, nuanced phenotypes and implementing large-scale studies, but also how veterinary studies may be able to look past clinical findings to mechanistic ones and demonstrate translational benefits to human research.

Understanding obesity among companion dogs: New measures of owner's beliefs and behaviour and associations with body condition scores.

This research aimed to improve our understanding of how owners' beliefs and behaviour are associated with obesity in companion dogs. To do this, we employed new theoretical frameworks and integrated previously reported measures to curate a collection of brief, user-friendly self-report measures to assess owner factors. The reliability and validity of these was examined in two phases of empirical research, each with a cross-sectional questionnaire design that also examined the validity of assessing body condition score (BCS) from photographs submitted by owners. Phase 1 (n = 47 dog owners from France) found that the brief owner-report measures correlated with the long-form measures (all correlations except one exceeded r = 0.70). BCS as coded from photographs were highly correlated with a vet's assessment of the same dogs (r = 0.67). Phase 2 (n = 3339 dog owners from France, Germany, the UK, Italy, and Russia) investigated which measures are associated with obesity among companion dogs. Perceptions of the dog's vulnerability to the threat of obesity, perceived weight status, perceived costs associated with ownership, normative beliefs about feeding, social support from friends, and being in the precontemplation stage of change predicted BCS alongside demographic factors (e.g., dog's age, neutered status). Taken together, the findings provide a method for assessing a wide range of factors that may be associated with obesity among companion dogs and point to potential targets for interventions designed to reduce obesity.

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

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 ß-MSH and ß-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.

Development, factor structure and application of the Dog Obesity Risk and Appetite (DORA) questionnaire.

Background. Dogs are compelling models in which to study obesity since the condition shares many characteristics between humans and dogs. Differences in eating behaviour are recognised to contribute to obesity susceptibility in other species but this has not been systematically studied in dogs. Aim. To develop and validate an owner-reported measure of canine eating behaviour and owner or dog related factors which can alter the development of obesity. Further, to then test variation in food-motivation in dogs and its association with obesity and owner management. Methods. Owner interviews, a literature review and existing human appetite scales were used to identify relevant topics and generate items for the questionnaire. Following a pilot phase, a 75 item online questionnaire was distributed via social media. Responses from 302 dog/owner dyads were analysed and factor structure and descriptive statistics calculated. Results were compared with descriptions of dog behaviour and management from a subset of respondents during semi-structured interviews. The optimum questions were disseminated as a 34 item final questionnaire completed by 213 owners, with a subset of respondents repeating the questionnaire 3 weeks later to assess test-retest reliability. Results. Analysis of responses to the final questionnaire relating to 213 dog/owner dyads showed a coherent factor structure and good test-retest reliability. There were three dog factors (food responsiveness and satiety, lack of selectivity, Interest in food), four owner factors (owner motivation to control dog weight, owner intervention to control dog weight, restriction of human food, exercise taken) and two dog health factors (signs of gastrointestinal disease, current poor health). Eating behaviour differed between individuals and between breed groups. High scores on dog factors (high food-motivation) and low scores on owner factors (less rigorous control of diet/exercise) were associated with obesity. Owners of more highly food-motivated dogs exerted more control over their dogs' food intake than those of less food-motivated dogs. Conclusions. The DORA questionnaire is a reliable and informative owner-reported measure of canine eating behaviour and health and management factors which can be associated with obesity development. The tool will be applicable to study of the canine obesity model and to clinical veterinarians. Results revealed eating behaviour to be similarly associated with obesity as exercise and owners giving titbits.

Next generation sequencing--implications for clinical practice.

BACKGROUND: Genetic testing in inherited disease has traditionally relied upon recognition of the presenting clinical syndrome and targeted analysis of genes known to be linked to that syndrome. Consequently, many patients with genetic syndromes remain without a specific diagnosis. AREAS OF AGREEMENT: New 'next-generation' sequencing (NGS) techniques permit simultaneous sequencing of enormous amounts of DNA. A slew of research publications have recently demonstrated the tremendous power of these technologies in increasing understanding of human genetic disease. AREAS OF CONTROVERSY: These approaches are likely to be increasingly employed in routine diagnostic practice, but the scale of the genetic information yielded about individuals means that caution must be exercised to avoid net harm in this setting. AREAS TIMELY FOR DEVELOPING RESEARCH: Use of NGS in a research setting will increasingly have a major but indirect beneficial impact on clinical practice. However, important technical, ethical and social challenges need to be addressed through informed professional and public dialogue before it finds its mature niche as a direct tool in the clinical diagnostic armoury.

Early Diagnosis of Werner's Syndrome Using Exome-Wide Sequencing in a Single, Atypical Patient.

Genetic diagnosis of inherited metabolic disease is conventionally achieved through syndrome recognition and targeted gene sequencing, but many patients receive no specific diagnosis. Next-generation sequencing allied to capture of expressed sequences from genomic DNA now offers a powerful new diagnostic approach. Barriers to routine diagnostic use include cost, and the complexity of interpreting results arising from simultaneous identification of large numbers of variants. We applied exome-wide sequencing to an individual, 16-year-old daughter of consanguineous parents with a novel syndrome of short stature, severe insulin resistance, ptosis, and microcephaly. Pulldown of expressed sequences from genomic DNA followed by massively parallel sequencing was undertaken. Single nucleotide variants were called using SAMtools prior to filtering based on sequence quality and existence in control genomes and exomes. Of 485 genetic variants predicted to alter protein sequence and absent from control data, 24 were homozygous in the patient. One mutation - the p.Arg732X mutation in the WRN gene - has previously been reported in Werner's syndrome (WS). On re-evaluation of the patient several early features of WS were detected including loss of fat from the extremities and frontal hair thinning. Lymphoblastoid cells from the proband exhibited a defective decatenation checkpoint, consistent with loss of WRN activity. We have thus diagnosed WS some 15 years earlier than average, permitting aggressive prophylactic therapy and screening for WS complications, illustrating the potential of exome-wide sequencing to achieve early diagnosis and change management of rare autosomal recessive disease, even in individual patients of consanguineous parentage with apparently novel syndromes.

Prevalence of the group 1 Dermatophagoides allergens Der p 1 and Der f 1 in homes with no dogs, healthy dogs and Dermatophagoides-sensitized atopic dogs in Liverpool.

Dermatophagoides farinae is a frequent allergen in canine atopic dermatitis despite its reported scarcity in the UK, and the aim of this study was to determine whether dogs were uniquely exposed to this species. Der f 1 and Der p 1 in dust collected from living room carpets, bedroom carpets and dog beds of 13 houses with no dogs, 13 with healthy dogs, and 16 with Dermatophagoides-sensitized atopic dogs were quantified by ELISA. Der p 1 levels (microg g(-1) house dust) were significantly higher than Der f 1 in living rooms (Der p 1 median = 1.9, 95% CI = 2.05-6.32, n = 42; Der f 1 median = 0.07, 95% CI = 0.01-0.06, n = 42), bedrooms (Der p 1 median = 4.35, SD = 5.52; Der f 1 median = 0.01, 95% CI = 0.001-0.1, n = 42) and dog beds (Der p 1 median = 1.04, 95% CI = 1.4-8.1, n = 29; Der f 1 median = 0.008, 95% CI = 0.01-0.04, n = 29) (P < 0.0001). Living rooms in houses without dogs had significantly greater Der p 1 levels (median = 7.0, 95% CI = 3.53-15.8, n = 13) than houses with healthy (median = 1.19, 95% CI = 0.44-3.49, n = 13) or atopic dogs (median = 0.78, 95% CI = 0.63-2.42, n = 16) (P = 0.0004). Environmental flea control in living rooms and washing dog beds was associated with significantly reduced Der p 1 levels. This confirms that D. pteronyssinus is common but D. farinae is rare in the sampling area. Apparent sensitization to D. farinae is probably due to cross-reaction. A combination of environmental measures could reduce allergen exposure.