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Endocrine Reviews Jul 2022Lipid disorders involving derangements in serum cholesterol, triglycerides, or both are commonly encountered in clinical practice and often have implications for...
Lipid disorders involving derangements in serum cholesterol, triglycerides, or both are commonly encountered in clinical practice and often have implications for cardiovascular risk and overall health. Recent advances in knowledge, recommendations, and treatment options have necessitated an updated approach to these disorders. Older classification schemes have outlived their usefulness, yielding to an approach based on the primary lipid disturbance identified on a routine lipid panel as a practical starting point. Although monogenic dyslipidemias exist and are important to identify, most individuals with lipid disorders have polygenic predisposition, often in the context of secondary factors such as obesity and type 2 diabetes. With regard to cardiovascular disease, elevated low-density lipoprotein cholesterol is essentially causal, and clinical practice guidelines worldwide have recommended treatment thresholds and targets for this variable. Furthermore, recent studies have established elevated triglycerides as a cardiovascular risk factor, whereas depressed high-density lipoprotein cholesterol now appears less contributory than was previously believed. An updated approach to diagnosis and risk assessment may include measurement of secondary lipid variables such as apolipoprotein B and lipoprotein(a), together with selective use of genetic testing to diagnose rare monogenic dyslipidemias such as familial hypercholesterolemia or familial chylomicronemia syndrome. The ongoing development of new agents-especially antisense RNA and monoclonal antibodies-targeting dyslipidemias will provide additional management options, which in turn motivates discussion on how best to incorporate them into current treatment algorithms.
Topics: Cardiovascular Diseases; Cholesterol; Diabetes Mellitus, Type 2; Dyslipidemias; Humans; Risk Factors; Triglycerides
PubMed: 34676866
DOI: 10.1210/endrev/bnab037 -
Molecular Diagnosis & Therapy Dec 2020Obesity represents a major health burden to both developed and developing countries. Furthermore, the incidence of obesity is increasing in children. Obesity contributes... (Review)
Review
Obesity represents a major health burden to both developed and developing countries. Furthermore, the incidence of obesity is increasing in children. Obesity contributes substantially to mortality in the United States by increasing the risk for type 2 diabetes, cardiovascular-related diseases, and other comorbidities. Despite environmental changes over past decades, including increases in high-calorie foods and sedentary lifestyles, there is very clear evidence of a genetic predisposition to obesity risk. Childhood obesity cases can be categorized in one of two ways: syndromic or non-syndromic. Syndromic obesity includes disorders such as Prader-Willi syndrome, Bardet-Biedl syndrome, and Alström syndrome. Non-syndromic cases of obesity can be further separated into rarer instances of monogenic obesity and much more common forms of polygenic obesity. The advent of genome-wide association studies (GWAS) and next-generation sequencing has driven significant advances in our understanding of the genetic contribution to childhood obesity. Many rare and common genetic variants have been shown to contribute to the heritability in obesity, although the molecular mechanisms underlying most of these variants remain unclear. An important caveat of GWAS efforts is that they do not strictly represent gene target discoveries, rather simply the uncovering of robust genetic signals. One clear example of this is with progress in understanding the key obesity signal harbored within an intronic region of the FTO gene. It has been shown that the non-coding region in which the variant actually resides in fact influences the expression of genes distal to FTO instead, specifically IRX3 and IRX5. Such discoveries suggest that associated non-coding variants can be embedded within or next to one gene, but commonly influence the expression of other, more distal effector genes. Advances in genetics and genomics are therefore contributing to a deeper understanding of childhood obesity, allowing for development of clinical tools and therapeutic agents.
Topics: Child; Genetic Predisposition to Disease; Genetic Variation; Genome-Wide Association Study; Humans; Multifactorial Inheritance; Pediatric Obesity; Risk Factors
PubMed: 33006084
DOI: 10.1007/s40291-020-00496-1 -
Nature Reviews. Genetics Feb 2022The prevalence of obesity has tripled over the past four decades, imposing an enormous burden on people's health. Polygenic (or common) obesity and rare, severe,... (Review)
Review
The prevalence of obesity has tripled over the past four decades, imposing an enormous burden on people's health. Polygenic (or common) obesity and rare, severe, early-onset monogenic obesity are often polarized as distinct diseases. However, gene discovery studies for both forms of obesity show that they have shared genetic and biological underpinnings, pointing to a key role for the brain in the control of body weight. Genome-wide association studies (GWAS) with increasing sample sizes and advances in sequencing technology are the main drivers behind a recent flurry of new discoveries. However, it is the post-GWAS, cross-disciplinary collaborations, which combine new omics technologies and analytical approaches, that have started to facilitate translation of genetic loci into meaningful biology and new avenues for treatment.
Topics: Animals; Eating; Gene-Environment Interaction; Genetic Predisposition to Disease; Genetic Variation; Genome, Human; Genome-Wide Association Study; Humans; Multifactorial Inheritance; Obesity; Overweight; Whole Genome Sequencing
PubMed: 34556834
DOI: 10.1038/s41576-021-00414-z -
Minerva Endocrinologica Sep 2020Obese or overweight people exceed one-third of the global population and obesity along with diabetes mellitus consist basic components of metabolic syndrome, both of... (Review)
Review
Obese or overweight people exceed one-third of the global population and obesity along with diabetes mellitus consist basic components of metabolic syndrome, both of which are known cardio-cerebrovascular risk factors with detrimental consequences. These data signify the pandemic character of obesity and the necessity for effective treatments. Substantial advances have been accomplished in preclinical research of obesity by using animal models, which mimic the human disease. In particular, rodent models have been widely used for many decades with success for the elucidation of the pathophysiology of obesity, since they share physiological and genetic components with humans and appear advantageous in their husbandry. The most representative rodents include the laboratory mouse and rat. Within this review, we attempted to consolidate the most widely used mice and rat models of obesity and highlight their strengths as well as weaknesses in a critical way. Our aim was to bridge the gap between laboratory facilities and patient's bed and help the researcher find the appropriate animal model for his/her obesity research. This tactful selection of the appropriate model of obesity may offer more translational derived results. In this regard, we included, the main diet induced models, the chemical/mechanical ones, as well as a selection of monogenic or polygenic models.
Topics: Animals; Diet; Disease Models, Animal; Humans; Metabolic Syndrome; Mice; Obesity; Rats; Rodentia
PubMed: 31738033
DOI: 10.23736/S0391-1977.19.03058-X -
Comptes Rendus Biologies Feb 2017Obesity and its related health complications is a major problem worldwide. Hypothalamus and their signalling molecules play a critical role in the intervening and... (Review)
Review
Obesity and its related health complications is a major problem worldwide. Hypothalamus and their signalling molecules play a critical role in the intervening and coordination with energy balance and homeostasis. Genetic factors play a crucial role in determining an individual's predisposition to the weight gain and being obese. In the past few years, several genetic variants were identified as monogenic forms of human obesity having success over common polygenic forms. In the context of molecular genetics, genome-wide association studies (GWAS) approach and their findings signified a number of genetic variants predisposing to obesity. However, the last couple of years, it has also been noticed that alterations in the environmental and epigenetic factors are one of the key causes of obesity. Hence, this review might be helpful in the current scenario of molecular genetics of human obesity, obesity-related health complications (ORHC), and energy homeostasis. Future work based on the clinical discoveries may play a role in the molecular dissection of genetic approaches to find more obesity-susceptible gene loci.
Topics: Energy Metabolism; Genetic Predisposition to Disease; Genetics, Medical; Genome-Wide Association Study; Humans; Obesity
PubMed: 28089486
DOI: 10.1016/j.crvi.2016.11.007 -
International Journal of Molecular... Sep 2022Obesity is a complex multifactorial disorder with genetic and environmental factors. There is an increase in the worldwide prevalence of obesity in both developed and... (Review)
Review
Obesity is a complex multifactorial disorder with genetic and environmental factors. There is an increase in the worldwide prevalence of obesity in both developed and developing countries. The development of genome-wide association studies (GWAS) and next-generation sequencing (NGS) has increased the discovery of genetic associations and awareness of monogenic and polygenic causes of obesity. The genetics of obesity could be classified into syndromic and non-syndromic obesity. Prader-Willi, fragile X, Bardet-Biedl, Cohen, and Albright Hereditary Osteodystrophy (AHO) syndromes are examples of syndromic obesity, which are associated with developmental delay and early onset obesity. Non-syndromic obesity could be monogenic, polygenic, or chromosomal in origin. Monogenic obesity is caused by variants of single genes while polygenic obesity includes several genes with the involvement of members of gene families. New advances in genetic testing have led to the identification of obesity-related genes. Leptin (), the leptin receptor (), proopiomelanocortin (), prohormone convertase 1 (), the melanocortin 4 receptor (), single-minded homolog 1 (), brain-derived neurotrophic factor (), and the neurotrophic tyrosine kinase receptor type 2 gene () have been reported as causative genes for obesity. NGS is now in use and emerging as a useful tool to search for candidate genes for obesity in clinical settings.
Topics: Brain-Derived Neurotrophic Factor; Genome-Wide Association Study; Humans; Leptin; Obesity; Pro-Opiomelanocortin; Proprotein Convertase 1; Receptor, Melanocortin, Type 4; Receptor, trkB; Receptors, Leptin
PubMed: 36232301
DOI: 10.3390/ijms231911005 -
Adolescent Medicine: State of the Art... 2017Obesity is a complex, heritable trait influenced by the interplay of genetics, epigenetics, metagenomics and the environment. With the increasing access to high... (Review)
Review
Obesity is a complex, heritable trait influenced by the interplay of genetics, epigenetics, metagenomics and the environment. With the increasing access to high precision diagnostic tools for genetic investigations, numerous genes influencing the phenotype have been identified, especially in early onset severe obesity. This review summarizes the current knowledge on the known genetic causes of obesity and the available therapeutic options. Furthermore, we discuss the role and potential mechanism of epigenetic changes that may be involved as mediators of the environmental influences and that may provide future opportunities for intervention.
Topics: Epigenesis, Genetic; Humans; Obesity
PubMed: 30416642
DOI: No ID Found -
Journal of Clinical Research in... May 2023Obesity derives from impaired central control of body weight, implying interaction between environment and an individual genetic predisposition. Genetic obesities,... (Review)
Review
Obesity derives from impaired central control of body weight, implying interaction between environment and an individual genetic predisposition. Genetic obesities, including monogenic and syndromic obesities, are rare and complex neuro-endocrine pathologies where the genetic contribution is predominant. Severe and early-onset obesity with eating disorders associated with frequent comorbidities make these diseases challenging. Their current estimated prevalence of 5-10% in severely obese children is probably underestimated due to the limited access to genetic diagnosis. A central alteration of hypothalamic regulation of weight implies that the leptin-melanocortin pathway is responsible for the symptoms. The management of genetic obesity has so far been only based, above all, on lifestyle intervention, especially regarding nutrition and physical activity. New therapeutic options have emerged in the last years for these patients, raising great hope to manage their complex situation and improve quality of life. Implementation of genetic diagnosis in clinical practice is thus of paramount importance to allow individualized care. This review describes the current clinical management of genetic obesity and the evidence on which it is based. Some insights will also be provided into new therapies under evaluation.
Topics: Pediatric Obesity; Humans; Child; Genetic Predisposition to Disease; Male; Female; Quality of Life; Bariatric Surgery; Exercise; Diet, Healthy; Anti-Obesity Agents
PubMed: 37191347
DOI: 10.4274/jcrpe.galenos.2023.2023-3-2 -
Current Opinion in Endocrinology,... Feb 2021Childhood obesity is escalating globally. Lifestyle and behavioral changes, which are the frequently used interventions in clinical practice, lead to only modest... (Review)
Review
PURPOSE OF REVIEW
Childhood obesity is escalating globally. Lifestyle and behavioral changes, which are the frequently used interventions in clinical practice, lead to only modest improvements in children with established obesity. Bariatric surgery is currently the most effective obesity treatment but has very limited utilization in pediatric obesity and is preferentially used for children with worsening comorbidities. There exists a massive treatment gap for children suffering with obesity especially after the failure of lifestyle modifications. Pharmacotherapy that is an established management tool in adults is very infrequently used in children. Only two medications, Phentermine and Orlistat are approved by the Food and Drug Administration (FDA) for use in adolescent obesity. Herein, we discuss the current landscape and available literature on the use of antiobesity pharmacotherapy in children.
RECENT FINDINGS
There are emerging pediatric data about the efficacy of the many weight loss medications that are FDA approved in adults. Moreover, more clinical trials are underway on the rarer, intractable forms of obesity such as monogenic, syndromic, and hypothalamic obesity.
SUMMARY
Weight loss medications in children, like adults, have variable efficacy and similar side effect profiles. Rigorous research and improved education of providers about weight loss medications may address the huge treatment gap in severe pediatric obesity.
Topics: Anti-Obesity Agents; Child; Humans; Pediatric Obesity; Weight Loss
PubMed: 33186194
DOI: 10.1097/MED.0000000000000587