-
Nature Reviews. Endocrinology Oct 2022Obesity is a multifactorial and complex disease that often manifests in early childhood with a lifelong burden. Polygenic and monogenic obesity are driven by the... (Review)
Review
Obesity is a multifactorial and complex disease that often manifests in early childhood with a lifelong burden. Polygenic and monogenic obesity are driven by the interaction between genetic predisposition and environmental factors. Polygenic variants are frequent and confer small effect sizes. Rare monogenic obesity syndromes are caused by defined pathogenic variants in single genes with large effect sizes. Most of these genes are involved in the central nervous regulation of body weight; for example, genes of the leptin-melanocortin pathway. Clinically, patients with monogenic obesity present with impaired satiety, hyperphagia and pronounced food-seeking behaviour in early childhood, which leads to severe early-onset obesity. With the advent of novel pharmacological treatment options emerging for monogenic obesity syndromes that target the central melanocortin pathway, genetic testing is recommended for patients with rapid weight gain in infancy and additional clinical suggestive features. Likewise, patients with obesity associated with hypothalamic damage or other forms of syndromic obesity involving energy regulatory circuits could benefit from these novel pharmacological treatment options. Early identification of patients affected by syndromic obesity will lead to appropriate treatment, thereby preventing the development of obesity sequelae, avoiding failure of conservative treatment approaches and alleviating stigmatization of patients and their families.
Topics: Child, Preschool; Genetic Predisposition to Disease; Humans; Hyperphagia; Leptin; Melanocortins; Obesity; Phenotype; Receptors, Leptin
PubMed: 35902734
DOI: 10.1038/s41574-022-00716-0 -
European Heart Journal Feb 2023Heart failure with preserved ejection fraction (HFpEF) is a major driver of cardiac morbidity and mortality in developed countries, due to ageing populations and the... (Review)
Review
Heart failure with preserved ejection fraction (HFpEF) is a major driver of cardiac morbidity and mortality in developed countries, due to ageing populations and the increasing prevalence of comorbidities. While heart failure with reduced ejection fraction is dominated by left ventricular impairment, HFpEF results from a complex interplay of cardiac remodelling, peripheral circulation, and concomitant features including age, hypertension, obesity, and diabetes. In an important subset, however, HFpEF is subtended by specific diseases of the myocardium that are genetically determined, have distinct pathophysiology, and are increasingly amenable to targeted, innovative treatments. While each of these conditions is rare, they collectively represent a relevant subset within HFpEF cohorts, and their prompt recognition has major consequences for clinical practice, as access to dedicated, disease-specific treatments may radically change the quality of life and outcome. Furthermore, response to standard heart failure treatment will generally be modest for these individuals, whose inclusion in registries and trials may dilute the perceived efficacy of treatments targeting mainstream HFpEF. Finally, a better understanding of the molecular underpinnings of monogenic myocardial disease may help identify therapeutic targets and develop innovative treatments for selected HFpEF phenotypes of broader epidemiological relevance. The field of genetic cardiomyopathies is undergoing rapid transformation due to recent, groundbreaking advances in drug development, and deserves greater awareness within the heart failure community. The present review addressed existing and developing therapies for genetic causes of HFpEF, including hypertrophic cardiomyopathy, cardiac amyloidosis, and storage diseases, discussing their potential impact on management and their broader implications for our understanding of HFpEF at large.
Topics: Humans; Heart Failure; Quality of Life; Stroke Volume; Myocardium; Cardiomyopathies; Ventricular Dysfunction, Left; Ventricular Function, Left
PubMed: 36582184
DOI: 10.1093/eurheartj/ehac764 -
Endocrine Reviews Mar 2023The etiology of central precocious puberty (CPP) is multiple and heterogeneous, including congenital and acquired causes that can be associated with structural or...
The etiology of central precocious puberty (CPP) is multiple and heterogeneous, including congenital and acquired causes that can be associated with structural or functional brain alterations. All causes of CPP culminate in the premature pulsatile secretion of hypothalamic GnRH and, consequently, in the premature reactivation of hypothalamic-pituitary-gonadal axis. The activation of excitatory factors or suppression of inhibitory factors during childhood represent the 2 major mechanisms of CPP, revealing a delicate balance of these opposing neuronal pathways. Hypothalamic hamartoma (HH) is the most well-known congenital cause of CPP with central nervous system abnormalities. Several mechanisms by which hamartoma causes CPP have been proposed, including an anatomical connection to the anterior hypothalamus, autonomous neuroendocrine activity in GnRH neurons, trophic factors secreted by HH, and mechanical pressure applied to the hypothalamus. The importance of genetic and/or epigenetic factors in the underlying mechanisms of CPP has grown significantly in the last decade, as demonstrated by the evidence of genetic abnormalities in hypothalamic structural lesions (eg, hamartomas, gliomas), syndromic disorders associated with CPP (Temple, Prader-Willi, Silver-Russell, and Rett syndromes), and isolated CPP from monogenic defects (MKRN3 and DLK1 loss-of-function mutations). Genetic and epigenetic discoveries involving the etiology of CPP have had influence on the diagnosis and familial counseling providing bases for potential prevention of premature sexual development and new treatment targets in the future. Global preventive actions inducing healthy lifestyle habits and less exposure to endocrine-disrupting chemicals during the lifespan are desirable because they are potentially associated with CPP.
Topics: Humans; Puberty, Precocious; Gonadotropin-Releasing Hormone; Hypothalamic Diseases; Hypothalamus; Puberty; Ubiquitin-Protein Ligases
PubMed: 35930274
DOI: 10.1210/endrev/bnac020 -
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 -
Nature Nov 2021Oestrogen depletion in rodents and humans leads to inactivity, fat accumulation and diabetes, underscoring the conserved metabolic benefits of oestrogen that inevitably...
Oestrogen depletion in rodents and humans leads to inactivity, fat accumulation and diabetes, underscoring the conserved metabolic benefits of oestrogen that inevitably decrease with age. In rodents, the preovulatory surge in 17β-oestradiol (E2) temporarily increases energy expenditure to coordinate increased physical activity with peak sexual receptivity. Here we report that a subset of oestrogen-sensitive neurons in the ventrolateral ventromedial hypothalamic nucleus (VMHvl) projects to arousal centres in the hippocampus and hindbrain, and enables oestrogen to rebalance energy allocation in female mice. Surges in E2 increase melanocortin-4 receptor (MC4R) signalling in these VMHvl neurons by directly recruiting oestrogen receptor-α (ERα) to the Mc4r gene. Sedentary behaviour and obesity in oestrogen-depleted female mice were reversed after chemogenetic stimulation of VMHvl neurons expressing both MC4R and ERα. Similarly, a long-term increase in physical activity is observed after CRISPR-mediated activation of this node. These data extend the effect of MC4R signalling - the most common cause of monogenic human obesity - beyond the regulation of food intake and rationalize reported sex differences in melanocortin signalling, including greater disease severity of MC4R insufficiency in women. This hormone-dependent node illuminates the power of oestrogen during the reproductive cycle in motivating behaviour and maintaining an active lifestyle in women.
Topics: Animals; Brain; CRISPR-Cas Systems; Energy Metabolism; Estrogen Receptor alpha; Estrogens; Female; Gene Editing; Hippocampus; Male; Melanocortins; Mice; Neurons; Obesity; Physical Exertion; Receptor, Melanocortin, Type 4; Rhombencephalon; Sedentary Behavior; Sex Characteristics; Signal Transduction; Ventromedial Hypothalamic Nucleus
PubMed: 34646010
DOI: 10.1038/s41586-021-04010-3 -
Journal of Diabetes and Its... Jan 2021Maturity onset diabetes of the young (MODY) is the most common form of monogenic diabetes and is currently believed to have 14 subtypes. While much is known about the... (Review)
Review
Maturity onset diabetes of the young (MODY) is the most common form of monogenic diabetes and is currently believed to have 14 subtypes. While much is known about the common subtypes of MODY (MODY-1, 2, 3 and 5) little is known about its rare subtypes (MODY4, 6-14). With the advent of next-generation sequencing (NGS) there are several reports of the rarer subtypes of MODY emerging from across the world. Therefore, a greater understanding on these rarer subtypes is needed. A search strategy was created, and common databases were searched, and 51 articles finally selected. INS-(MODY10) and ABCC8-(MODY12) mutations were reported in relatively large numbers compared to the other rare subtypes. The clinical characteristics of the rare MODY subtypes exhibited heterogeneity between families reported with the same mutation. Obesity and diabetic ketoacidosis (DKA) were also reported among rarer MODY subtypes which presents as a challenge as these are not part of the original description of MODY by Tattersal and Fajans. The treatment modalities of the rarer subtypes included oral drugs, predominantly sulfonylureas, insulin but also diet alone. Newer drugs like DPP-4 and SGLT2 inhibitors have also been tried as new modes of treatment. The microvascular and macrovascular complications among the patients with various MODY subtypes are less commonly reported. Recently, there is a view that not all the 14 forms of 'MODY' are true MODY and the very existence of some of these rarer subtypes as MODY has been questioned. This scoping review aims to report on the clinical characteristics, treatment and complications of the rarer MODY subtypes published in the literature.
Topics: Diabetes Mellitus, Type 2; Humans; Insulin; Pharmaceutical Preparations; Sulfonylurea Compounds
PubMed: 32763092
DOI: 10.1016/j.jdiacomp.2020.107640 -
Acta Bio-medica : Atenei Parmensis Sep 2019Obesity is highly heritable and arises from the interplay of many genes and environmental factors. It can be defined as the result of prolonged imbalance between calorie... (Review)
Review
Obesity is highly heritable and arises from the interplay of many genes and environmental factors. It can be defined as the result of prolonged imbalance between calorie intake and energy utilization. About 5% of cases of non-syndromic obesity are monogenic (Mendelian obesity). The amount of adipose tissue in the body is mainly regulated by leptin, a hormone produced by adipocytes, and Mendelian obesity is mainly caused by mutations that disrupt the leptin/melanocortin pathway. In this article, we summarize the genes involved in genetic obesity and the test we use for genetic analysis.
Topics: Adipogenesis; Genetic Predisposition to Disease; Genetic Testing; High-Throughput Nucleotide Sequencing; Humans; Leptin; Melanocortins; Mutation; Obesity
PubMed: 31577261
DOI: 10.23750/abm.v90i10-S.8766 -
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 -
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