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Journal of the American Association of... Jul 2020Genetics is now known to play a substantial role in the predisposition to obesity and may contribute up to 70% risk for the disease. Over a hundred genes and gene...
Genetics is now known to play a substantial role in the predisposition to obesity and may contribute up to 70% risk for the disease. Over a hundred genes and gene variants related to excess weight have been discovered. Yet, genetic obesity risk does not always translate into actual obesity development, suggesting complex interactions between genetic, behavioral, and environmental influences and resulting epigenetic changes. Rare but serious forms of monogenic obesity typically appear in early childhood. Polygenic obesity is most common and demonstrates strong interplay between genes and the obesogenic environment. This review provides an overview of genetic causes of obesity, potential mechanisms of epigenetic changes, and environmental influences that should diminish obesity bias and offer hope for more effective obesity prevention and intervention strategies.
Topics: Alpha-Ketoglutarate-Dependent Dioxygenase FTO; Humans; Multifactorial Inheritance; Obesity; United States
PubMed: 32658169
DOI: 10.1097/JXX.0000000000000447 -
The Lancet. Diabetes & Endocrinology Aug 2014Plasma triglyceride concentration is a biomarker for circulating triglyceride-rich lipoproteins and their metabolic remnants. Common mild-to-moderate... (Review)
Review
Plasma triglyceride concentration is a biomarker for circulating triglyceride-rich lipoproteins and their metabolic remnants. Common mild-to-moderate hypertriglyceridaemia is typically multigenic, and results from the cumulative burden of common and rare variants in more than 30 genes, as quantified by genetic risk scores. Rare autosomal recessive monogenic hypertriglyceridaemia can result from large-effect mutations in six different genes. Hypertriglyceridaemia is exacerbated by non-genetic factors. On the basis of recent genetic data, we redefine the disorder into two states: severe (triglyceride concentration >10 mmol/L), which is more likely to have a monogenic cause; and mild-to-moderate (triglyceride concentration 2-10 mmol/L). Because of clustering of susceptibility alleles and secondary factors in families, biochemical screening and counselling for family members is essential, but routine genetic testing is not warranted. Treatment includes management of lifestyle and secondary factors, and pharmacotherapy. In severe hypertriglyceridaemia, intervention is indicated because of pancreatitis risk; in mild-to-moderate hypertriglyceridaemia, intervention can be indicated to prevent cardiovascular disease, dependent on triglyceride concentration, concomitant lipoprotein disturbances, and overall cardiovascular risk.
Topics: Animals; Biomarkers; Combined Modality Therapy; Genetic Predisposition to Disease; Health Promotion; Humans; Hypertriglyceridemia; Life Style; Multifactorial Inheritance; Practice Guidelines as Topic; Triglycerides
PubMed: 24731657
DOI: 10.1016/S2213-8587(13)70191-8 -
Gastroenterology Clinics of North... Jun 2023Genetic forms of obesity contribute to ∼7% of severe obesity in children and adolescents. The exact global prevalence of monogenic and syndromic forms of obesity is... (Review)
Review
Genetic forms of obesity contribute to ∼7% of severe obesity in children and adolescents. The exact global prevalence of monogenic and syndromic forms of obesity is not well established, most likely due to missed or delayed diagnosis. The challenge in determining the prevalence can be attributed to the lack of consensus on identifying and evaluating symptoms of genetic defects in a timely manner and hence a vastly undertested patient population. Further large-scale and long-term studies are needed to advance the understanding of this unique phenotype of obesity and effective treatment options."
Topics: Humans; Pediatric Obesity; Phenotype; Prevalence
PubMed: 37197876
DOI: 10.1016/j.gtc.2023.03.005 -
Hormone Research in Paediatrics 2022The increasing number of obese children and adolescence is a major problem in health-care systems. Currently, the gold standard for the treatment of these patients with... (Review)
Review
BACKGROUND
The increasing number of obese children and adolescence is a major problem in health-care systems. Currently, the gold standard for the treatment of these patients with obesity is a multicomponent lifestyle intervention. Unfortunately, this strategy is not leading to a substantial and long-lasting weight loss in the majority of patients. This is the reason why there is an urgent need to establish new treatment strategies for children and adolescents with obesity to reduce the risk for the development of any comorbidities like cardiovascular diseases or diabetes mellitus type 2.
SUMMARY
In this review, we outline available pharmacological therapeutic options for children and compare the available study data with the outcome of conservative treatment approaches.
KEY MESSAGES
We discussed, in detail, how knowledge about underlying molecular mechanisms might support the identification of effective antiobesity drugs in the future and in which way this might modulate current treatment strategies to support children and adolescence with obesity to lose body weight.
Topics: Adolescent; Anti-Obesity Agents; Body Weight; Child; Diabetes Mellitus, Type 2; Humans; Life Style; Pediatric Obesity
PubMed: 34351307
DOI: 10.1159/000518432 -
Handbook of Clinical Neurology 2021Neural circuits in the hypothalamus play a key role in the regulation of human energy homeostasis. A critical circuit involves leptin-responsive neurons in the... (Review)
Review
Neural circuits in the hypothalamus play a key role in the regulation of human energy homeostasis. A critical circuit involves leptin-responsive neurons in the hypothalamic arcuate nucleus (the infundibular nucleus in humans) expressing the appetite-suppressing neuropeptide proopiomelanocortin (POMC) and the appetite-stimulating Agouti-related peptide. In the fed state, the POMC-derived melanocortin peptide α-melanocyte-stimulating hormone stimulates melanocortin-4 receptors (MC4Rs) expressed on second-order neurons in the paraventricular nucleus of the hypothalamus (PVN). Agonism of MC4R leads to reduced food intake and increased energy expenditure. Disruption of this hypothalamic circuit by inherited mutations in the genes encoding leptin, the leptin receptor, POMC, and MC4R can lead to severe obesity in humans. The characterization of these and closely related genetic obesity syndromes has informed our understanding of the neural pathways by which leptin regulates energy balance, neuroendocrine function, and the autonomic nervous system. A broader understanding of these neural and molecular mechanisms has paved the way for effective mechanism-based therapies for patients whose severe obesity is driven by disruption of these pathways.
Topics: Energy Metabolism; Humans; Hypothalamus; Leptin; Obesity; Pro-Opiomelanocortin; Receptor, Melanocortin, Type 4; Receptors, Leptin; Syndrome
PubMed: 34238466
DOI: 10.1016/B978-0-12-820683-6.00022-1 -
Progress in Molecular Biology and... 2016Obesity is a metabolic disease, which is becoming an epidemic health problem: it has been recently defined in terms of Global Pandemic. Over the years, the approaches... (Review)
Review
Obesity is a metabolic disease, which is becoming an epidemic health problem: it has been recently defined in terms of Global Pandemic. Over the years, the approaches through family, twins and adoption studies led to the identification of some causal genes in monogenic forms of obesity but the origins of the pandemic of obesity cannot be considered essentially due to genetic factors, because human genome is not likely to change in just a few years. Epigenetic studies have offered in recent years valuable tools for the understanding of the worldwide spread of the pandemic of obesity. The involvement of epigenetic modifications-DNA methylation, histone tails, and miRNAs modifications-in the development of obesity is more and more evident. In the epigenetic literature, there are evidences that the entire embryo-fetal and perinatal period of development plays a key role in the programming of all human organs and tissues. Therefore, the molecular mechanisms involved in the epigenetic programming require a new and general pathogenic paradigm, the Developmental Origins of Health and Disease theory, to explain the current epidemiological transition, that is, the worldwide increase of chronic, degenerative, and inflammatory diseases such as obesity, diabetes, cardiovascular diseases, neurodegenerative diseases, and cancer. Obesity and its related complications are more and more associated with environmental pollutants (obesogens), gut microbiota modifications and unbalanced food intake, which can induce, through epigenetic mechanisms, weight gain, and altered metabolic consequences.
Topics: DNA Methylation; Epigenesis, Genetic; Humans; Obesity
PubMed: 27288829
DOI: 10.1016/bs.pmbts.2016.02.002 -
Current Diabetes Reports Aug 2018This review aims to present current information on genes underlying severe obesity, with the main emphasis on the three genes LEP, LEPR and MC4R. (Review)
Review
PURPOSE OF REVIEW
This review aims to present current information on genes underlying severe obesity, with the main emphasis on the three genes LEP, LEPR and MC4R.
RECENT FINDINGS
There is a substantial amount of evidence that variants in at least ten different genes are the cause of severe monogenic obesity. The majority of these are involved in the leptin-melanocortin signalling pathway. Due to the frequency of some of the identified variants, it is clear that monogenic variants also make a significant contribution to common obesity. The artificial distinction between rare monogenic obesity and common polygenic obesity is now obsolete with the identification of MC4R variants of strong effect in the general population.
Topics: Body Mass Index; Genetic Predisposition to Disease; Humans; Leptin; Obesity; Receptor, Melanocortin, Type 4; Receptors, Leptin
PubMed: 30121879
DOI: 10.1007/s11892-018-1053-x -
The Lancet. Child & Adolescent Health Apr 2023Severe obesity in adolescents has a profound impact on current and future health. Metabolic and bariatric surgery (MBS) is increasingly used in adolescents... (Randomized Controlled Trial)
Randomized Controlled Trial
Metabolic and bariatric surgery versus intensive non-surgical treatment for adolescents with severe obesity (AMOS2): a multicentre, randomised, controlled trial in Sweden.
BACKGROUND
Severe obesity in adolescents has a profound impact on current and future health. Metabolic and bariatric surgery (MBS) is increasingly used in adolescents internationally. However, to our knowledge, there are no randomised trials examining the currently most used surgical techniques. Our aim was to evaluate changes in BMI and secondary health and safety outcomes after MBS.
METHODS
The Adolescent Morbid Obesity Surgery 2 (AMOS2) study is a randomised, open-label, multicentre trial done at three university hospitals in Sweden (located in Stockholm, Gothenburg, and Malmö). Adolescents aged 13-16 years with a BMI of at least 35 kg/m, who had attended treatment for obesity for at least 1 year, passed assessments from a paediatric psychologist and a paediatrician, and had a Tanner pubertal stage of at least 3, were randomly assigned (1:1) to MBS or intensive non-surgical treatment. Exclusion criteria included monogenic or syndromic obesity, major psychiatric illness, and regular self-induced vomiting. Computerised randomisation was stratified for sex and recruitment site. Allocation was concealed for both staff and participants until the end of the inclusion day, and then all participants were unmasked to treatment intervention. One group underwent MBS (primarily gastric bypass), while the other group received intensive non-surgical treatment starting with 8 weeks of low-calorie diet. The primary outcome was 2-year change in BMI, analysed as intention-to-treat. The trial is registered at ClinicalTrials.gov, NCT02378259.
FINDINGS
500 people were assessed for eligibility between Aug 27, 2014, and June 7, 2017. 450 participants were excluded (397 did not meet inclusion criteria, 39 declined to participate, and 14 were excluded for various other reasons). Of the 50 remaining participants, 25 (19 females and six males) were randomly assigned to receive MBS and 25 (18 females and seven males) were assigned to intensive non-surgical treatment. Three participants (6%; one in the MBS group and two in the intensive non-surgical treatment group) did not participate in the 2-year follow-up, and in total 47 (94%) participants were assessed for the primary endpoint. Mean age of participants was 15·8 years (SD 0·9) and mean BMI at baseline was 42·6 kg/m (SD 5·2). After 2 years, BMI change was -12·6 kg/m (-35·9 kg; n=24) among adolescents undergoing MBS (Roux-en-Y gastric bypass [n=23], sleeve gastrectomy [n=2]) and -0·2 kg/m (0·4 kg; [n=23]) among participants in the intensive non-surgical treatment group (mean difference -12·4 kg/m [95% CI -15·5 to -9·3]; p<0·0001). Five (20%) patients in the intensive non-surgical group crossed over to MBS during the second year. Adverse events (n=4) after MBS were mild but included one cholecystectomy. Regarding safety outcomes, surgical patients had a reduction in bone mineral density, while controls were unchanged after 2 years (z-score change mean difference -0·9 [95% CI -1·2 to -0·6]). There were no significant differences between the groups in vitamin and mineral levels, gastrointestinal symptoms (except less reflux in the surgical group), or in mental health at the 2-year follow-up.
INTERPRETATION
MBS is an effective and well tolerated treatment for adolescents with severe obesity resulting in substantial weight loss and improvements in several aspects of metabolic health and physical quality of life over 2 years, and should be considered in adolescents with severe obesity.
FUNDING
Sweden's Innovation Agency, Swedish Research Council Health.
Topics: Male; Female; Humans; Adolescent; Child; Obesity, Morbid; Sweden; Quality of Life; Bariatric Surgery; Gastric Bypass
PubMed: 36848922
DOI: 10.1016/S2352-4642(22)00373-X -
Frontiers in Cell and Developmental... 2022A subset of genetic disorders termed ciliopathies are associated with obesity. The mechanisms behind cilia dysfunction and altered energy homeostasis in these syndromes... (Review)
Review
A subset of genetic disorders termed ciliopathies are associated with obesity. The mechanisms behind cilia dysfunction and altered energy homeostasis in these syndromes are complex and likely involve deficits in both development and adult homeostasis. Interestingly, several cilia-associated gene mutations also lead to morbid obesity. While cilia have critical and diverse functions in energy homeostasis, including their roles in centrally mediated food intake and peripheral tissues, many questions remain. Here, we briefly discuss syndromic ciliopathies and monogenic cilia signaling mutations associated with obesity. We then focus on potential ways neuronal cilia regulate energy homeostasis. We discuss the literature around cilia and leptin-melanocortin signaling and changes in ciliary G protein-coupled receptor (GPCR) signaling. We also discuss the different brain regions where cilia are implicated in energy homeostasis and the potential for cilia dysfunction in neural development to contribute to obesity. We close with a short discussion on the challenges and opportunities associated with studies looking at neuronal cilia and energy homeostasis. This review highlights how neuronal cilia-mediated signaling is critical for proper energy homeostasis.
PubMed: 36568981
DOI: 10.3389/fcell.2022.1082141 -
Revista Do Colegio Brasileiro de... Oct 2018Knowledge about animal models for metabolic study is the basis of research in this area. This work aims to review the main animal models used in the study of obesity and... (Review)
Review
Knowledge about animal models for metabolic study is the basis of research in this area. This work aims to review the main animal models used in the study of obesity and metabolic syndrome. For this, we performed a search in the Pubmed database using the terms "animal models", "obesity", "metabolic syndrome" and "bariatric surgery". Several species of animals can be used for the study of metabolic disorders. However, rodents are the most commonly used, both as monogenic models and as diet-induced obesity (DIO) ones. Monogenic animals are the best choice if only one aspect is being evaluated. DIO animals tend to better demonstrate the interaction between disease, environment and genetics. However, they are still not fully effective in providing understanding of all disease mechanisms.
Topics: Animals; Bariatric Surgery; Cats; Disease Models, Animal; Dogs; Haplorhini; Metabolic Syndrome; Mice; Obesity; Rats
PubMed: 30379216
DOI: 10.1590/0100-6991e-20181975