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Lancet (London, England) Apr 2023The goal of obesity management is to improve health. Sustained weight loss of more than 10% overall bodyweight improves many of the complications associated with obesity... (Review)
Review
The goal of obesity management is to improve health. Sustained weight loss of more than 10% overall bodyweight improves many of the complications associated with obesity (eg, prevention and control of type 2 diabetes, hypertension, fatty liver disease, and obstructive sleep apnoea), as well as quality of life. Maintenance of weight loss is the major challenge of obesity management. Like all chronic diseases, managing obesity requires a long-term, multimodal approach, taking into account each individual's treatment goals, and the benefit and risk of different therapies. In conjunction with lifestyle interventions, anti-obesity medications and bariatric surgery improve the maintenance of weight loss and associated health gains. Most available anti-obesity medications act on central appetite pathways to reduce hunger and food reward. In the past 5 years, therapeutic advances have seen the development of targeted treatments for monogenic obesities and a new generation of anti-obesity medications. These highly effective anti-obesity medications are associated with weight losses of more than 10% of overall bodyweight in more than two-thirds of clinical trial participants. Long-term data on safety, efficacy, and cardiovascular outcomes are awaited. Long-term studies have shown that bariatric surgical procedures typically lead to a durable weight loss of 25% and rapid, sustained improvements in complications of obesity, although they have not yet been compared with new-generation highly effective anti-obesity medications. Further work is required to determine optimal patient-specific treatment strategies, including combinations of lifestyle interventions, anti-obesity medications, endoscopic and bariatric surgical procedures, and to ensure equitable access to effective treatments.
Topics: Adult; Humans; Diabetes Mellitus, Type 2; Quality of Life; Obesity; Bariatric Surgery; Anti-Obesity Agents; Body Weight; Weight Loss
PubMed: 36774932
DOI: 10.1016/S0140-6736(22)02403-5 -
Gastroenterology Clinics of North... Dec 2023Similar to the general population, lifestyle interventions focused on nutrition and physical activity form the foundation for treating obesity caused by rare genetic... (Review)
Review
Similar to the general population, lifestyle interventions focused on nutrition and physical activity form the foundation for treating obesity caused by rare genetic disorders. Additional therapies, including metreleptin and setmelanotide, that target defects within the leptin signaling pathway can effectively synergize with lifestyle efforts to treat monogenic disorders of leptin, leptin receptor, proopiomelanocortin (POMC), and proprotein convertase subtilisin/kexin type 1 (PCSK1) and syndromic conditions, such as the ciliopathies Bardet-Biedl and Alström syndromes, whose pathophysiological mechanisms also converge on the leptin pathway. Investigational treatments for Prader-Willi syndrome target specific defects caused by reduced expression of paternally derived genes within the chromosome 15q region.
Topics: Humans; Leptin; Obesity; Prader-Willi Syndrome
PubMed: 37919024
DOI: 10.1016/j.gtc.2023.08.005 -
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 -
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 -
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 -
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 -
Metabolism: Clinical and Experimental Mar 2019Obesity is among the most threatening health burdens worldwide and its prevalence has markedly increased over the last decades. Obesity maybe considered a heritable... (Review)
Review
Obesity is among the most threatening health burdens worldwide and its prevalence has markedly increased over the last decades. Obesity maybe considered a heritable trait. Identifications of rare cases of monogenic obesity unveiled that hypothalamic circuits and the brain-adipose axis play an important role in the regulation of energy homeostasis, appetite, hunger and satiety. For example, mutations in the leptin gene cause obesity through almost unsuppressed overeating. Common (multifactorial) obesity, most likely resulting from a concerted interplay of genetic, epigenetic and environmental factors, is clearly linked to genetic predisposition by multiple risk variants, which, however only account for a minor part of the general BMI variability. Although GWAS opened new avenues in elucidating the complex genetics behind common obesity, understanding the biological mechanisms relative to the specific risk contributing to obesity remains poorly understood. Non-genetic factors such as eating behavior or physical activity strongly modulate the individual risk for developing obesity. These factors may interact with genetic predisposition for obesity through epigenetic mechanisms. Thus, here, we review the current knowledge about monogenic and common (multifactorial) obesity highlighting the important recent advances in our knowledge on how epigenetic regulation is involved in the etiology of obesity.
Topics: Epigenesis, Genetic; Genetic Predisposition to Disease; Humans; Obesity; Precision Medicine
PubMed: 30399374
DOI: 10.1016/j.metabol.2018.10.007 -
Obesity Surgery Dec 2019Obesity is a worldwide epidemic with rates nearly doubling over the last 30 years. Despite increasing prevalence, the multifactorial pathogenesis of obesity continues to... (Review)
Review
Obesity is a worldwide epidemic with rates nearly doubling over the last 30 years. Despite increasing prevalence, the multifactorial pathogenesis of obesity continues to be widely misunderstood. Investigating genetic drivers in the development of obesity is an important area of focus, as genetics move to the forefront of medicine and personalized treatment evolves. Thus, this narrative review focused on four genes which have genome-wide association study-documented links to obesity and obesity syndromes. We explored their involvement in the predisposition, progression, and prognosis of obesity. Leptin, leptin receptor, pro-opiomelanocortin, and melanocortin 4 receptor are our four genes of interest, and herein we elaborated on the current literature, pathogenesis, and available treatments for patients with these specific genetic mutations.
Topics: Disease Progression; Genetic Predisposition to Disease; Genome-Wide Association Study; Genotype; Humans; Leptin; Mutation; Obesity; Pro-Opiomelanocortin; Receptor, Melanocortin, Type 4; Receptors, Leptin
PubMed: 31641982
DOI: 10.1007/s11695-019-04200-z -
Frontiers of Hormone Research 2008We and others have identified several single gene defects that disrupt the molecules in the leptinmelanocortin pathway causing severe obesity in humans. In this review,... (Review)
Review
We and others have identified several single gene defects that disrupt the molecules in the leptinmelanocortin pathway causing severe obesity in humans. In this review, we consider these human monogenic obesity syndromes and discuss how far the characterisation of these patients has informed our understanding of the physiological role of leptin and the melanocortins in the regulation of human body weight and neuroendocrine function.
Topics: Body Weight; Child; Child, Preschool; Humans; Leptin; Mutation; Obesity; Phenotype; Pro-Opiomelanocortin; Proprotein Convertase 1; Receptor, Melanocortin, Type 4; Receptor, trkB; Receptors, Leptin; Recombinant Proteins
PubMed: 18230891
DOI: 10.1159/000115333 -
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