Cosponsoring associations The European Society of Endocrinology and the Pediatric Endocrine Society. This guideline was funded by the Endocrine Society. Objective To formulate clinical practice guidelines for the assessment, treatment, and prevention of pediatric obesity. Participants The participants include an Endocrine Society-appointed Task Force of 6 experts, a methodologist, and a medical writer. Evidence This evidence-based guideline was developed using the Grading of Recommendations, Assessment, Development, and Evaluation approach to describe the strength of recommendations and the quality of evidence. The Task Force commissioned 2 systematic reviews and used the best available evidence from other published systematic reviews and individual studies. Consensus process One group meeting, several conference calls, and e-mail communications enabled consensus. Endocrine Society committees and members and co-sponsoring organizations reviewed and commented on preliminary drafts of this guideline. Conclusion Pediatric obesity remains an ongoing serious international health concern affecting ∼17% of US children and adolescents, threatening their adult health and longevity. Pediatric obesity has its basis in genetic susceptibilities influenced by a permissive environment starting in utero and extending through childhood and adolescence. Endocrine etiologies for obesity are rare and usually are accompanied by attenuated growth patterns. Pediatric comorbidities are common and long-term health complications often result; screening for comorbidities of obesity should be applied in a hierarchal, logical manner for early identification before more serious complications result. Genetic screening for rare syndromes is indicated only in the presence of specific historical or physical features. The psychological toll of pediatric obesity on the individual and family necessitates screening for mental health issues and counseling as indicated. The prevention of pediatric obesity by promoting healthful diet, activity, and environment should be a primary goal, as achieving effective, long-lasting results with lifestyle modification once obesity occurs is difficult. Although some behavioral and pharmacotherapy studies report modest success, additional research into accessible and effective methods for preventing and treating pediatric obesity is needed. The use of weight loss medications during childhood and adolescence should be restricted to clinical trials. Increasing evidence demonstrates the effectiveness of bariatric surgery in the most seriously affected mature teenagers who have failed lifestyle modification, but the use of surgery requires experienced teams with resources for long-term follow-up. Adolescents undergoing lifestyle therapy, medication regimens, or bariatric surgery for obesity will need cohesive planning to help them effectively transition to adult care, with continued necessary monitoring, support, and intervention. Transition programs for obesity are an uncharted area requiring further research for efficacy. Despite a significant increase in research on pediatric obesity since the initial publication of these guidelines 8 years ago, further study is needed of the genetic and biological factors that increase the risk of weight gain and influence the response to therapeutic interventions. Also needed are more studies to better understand the genetic and biological factors that cause an obese individual to manifest one comorbidity vs another or to be free of comorbidities. Furthermore, continued investigation into the most effective methods of preventing and treating obesity and into methods for changing environmental and economic factors that will lead to worldwide cultural changes in diet and activity should be priorities. Particular attention to determining ways to effect systemic changes in food environments and total daily mobility, as well as methods for sustaining healthy body mass index changes, is of importance.

Pediatric Obesity-Assessment, Treatment, and Prevention: An Endocrine Society Clinical Practice Guideline.

We have reviewed the distinctive features of excess weight, its causes, and related prevention and management efforts, as well as data gaps and recommendations for future research in low- and middle-income countries (LMICs). Obesity is rising in every region of the world, and no country has been successful at reversing the epidemic once it has begun. In LMICs, overweight is higher in women compared with men, in urban compared with rural settings, and in older compared with younger individuals; however, the urban–rural overweight differential is shrinking in many countries. Overweight occurs alongside persistent burdens of underweight in LMICs, especially in young women. Changes in the global diet and physical activity are among the hypothesized leading contributors to obesity. Emerging risk factors include environmental contaminants, chronic psychosocial stress, neuroendocrine dysregulation, and genetic/epigenetic mechanisms. Data on effective strategies to prevent the onset of obesity in LMICs or elsewhe...

Obesity in Low- and Middle-Income Countries: Burden, Drivers, and Emerging Challenges

In high-, middle- and low-income countries, the rising prevalence of obesity is the underlying cause of numerous health complications and increased mortality. Being a complex and heritable disorder, obesity results from the interplay between genetic susceptibility, epigenetics, metagenomics and the environment. Attempts at understanding the genetic basis of obesity have identified numerous genes associated with syndromic monogenic, non-syndromic monogenic, oligogenic and polygenic obesity. The genetics of leanness are also considered relevant as it mirrors some of obesity's aetiologies. In this report, we summarize ten genetically elucidated obesity syndromes, some of which are involved in ciliary functioning. We comprehensively review 11 monogenic obesity genes identified to date and their role in energy maintenance as part of the leptin-melanocortin pathway. With the emergence of genome-wide association studies over the last decade, 227 genetic variants involved in different biological pathways (central nervous system, food sensing and digestion, adipocyte differentiation, insulin signalling, lipid metabolism, muscle and liver biology, gut microbiota) have been associated with polygenic obesity. Advances in obligatory and facilitated epigenetic variation, and gene-environment interaction studies have partly accounted for the missing heritability of obesity and provided additional insight into its aetiology. The role of gut microbiota in obesity pathophysiology, as well as the 12 genes associated with lipodystrophies is discussed. Furthermore, in an attempt to improve future studies and merge the gap between research and clinical practice, we provide suggestions on how high-throughput '-omic' data can be integrated in order to get closer to the new age of personalized medicine.

Recent progress in genetics, epigenetics and metagenomics unveils the pathophysiology of human obesity

https://www.cell.com/cell/pdf/S0092-8674(15)00261-5.pdf

The Hunger Genes: Pathways to Obesity

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.

Melanocortin-4 receptor-regulated energy homeostasis.

Melanocortin receptor accessory proteins (MRAPs) modulate signaling of melanocortin receptors in vitro. To investigate the physiological role of brain-expressed melanocortin 2 receptor accessory protein 2 (MRAP2), we characterized mice with whole-body and brain-specific targeted deletion of Mrap2, both of which develop severe obesity at a young age. Mrap2 interacts directly with melanocortin 4 receptor (Mc4r), a protein previously implicated in mammalian obesity, and it enhances Mc4r-mediated generation of the second messenger cyclic adenosine monophosphate, suggesting that alterations in Mc4r signaling may be one mechanism underlying the association between Mrap2 disruption and obesity. In a study of humans with severe, early-onset obesity, we found four rare, potentially pathogenic genetic variants in MRAP2, suggesting that the gene may also contribute to body weight regulation in humans.

/pdf/loss-of-function-of-the-melanocortin-2-receptor-accessory-2g8hac6lnv.pdf

Caroline Ho

Papers

Loss of function of the melanocortin 2 receptor accessory protein 2 is associated with mammalian obesity.