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Cells Apr 2022Obesity, one of the major problems in modern human society, is correlated with various diseases, including type 2 diabetes mellitus (T2DM). In particular,... (Review)
Review
Obesity, one of the major problems in modern human society, is correlated with various diseases, including type 2 diabetes mellitus (T2DM). In particular, epidemiological and experimental evidence indicates that obesity is closely linked to at least 13 different types of cancer. The mechanisms that potentially explain the link between obesity and cancer include hyperactivation of the IGF pathway, metabolic dysregulation, dysfunctional angiogenesis, chronic inflammation, and interaction between pro-inflammatory cytokines, endocrine hormones, and adipokines. However, how the largely uniform morbidity of obesity leads to different types of cancer still needs to be investigated. To study the link between obesity and cancer, researchers have commonly used preclinical animal models, particularly mouse models. These models include monogenic models of obesity (e.g., and mice) and genetically modified mouse models of human cancers (e.g., -driven pancreatic cancer, -mutated colorectal cancer, and Her2/neu-overexpressing breast cancer). The experimental results obtained using these mouse models revealed strong evidence of a link between obesity and cancer and suggested their underlying mechanisms.
Topics: Adipokines; Animals; Breast Neoplasms; Diabetes Mellitus, Type 2; Disease Models, Animal; Female; Humans; Mice; Obesity
PubMed: 35563777
DOI: 10.3390/cells11091472 -
Appetite Nov 2022Hyperphagia is a key symptom in patients with monogenic obesity, but the assessment is challenging.
BACKGROUND
Hyperphagia is a key symptom in patients with monogenic obesity, but the assessment is challenging.
OBJECTIVES
We aimed to investigate the applicability of Dykens' Hyperphagia Questionnaire in patients with monogenic and syndromic obesity to assess the quality and severity of hyperphagia, and to compare our results with those reported in the literature.
METHODS
Patients with biallelic leptin receptor variants (LEPR, n = 8), heterozygous melanocortin-4 receptor variants (MC4R, n = 7) and 16p11.2 deletions, leading to a deletion of the Src homology 2B adaptor protein gene (n = 5) were included in the study. Hyperphagia was assessed by the parent-based, 13-item hyperphagia questionnaire from Dykens et al. (2007). A literature research was performed to identify published hyperphagia scores assessed by Dykens' Hyperphagia Questionnaire.
RESULTS
The total hyperphagia scores were similar in patients with biallelic LEPR and monoallelic MC4R variants (32.0 ± 9.3 vs. 31.4 ± 5.4), but significantly lower in patients with 16p11.2 deletions (21.4 ± 5.5, p < 0.05). Compared to patients with syndromic obesity (27.6 ± 9.0) from the literature, patients with LEPR and MC4R variants had higher total hyperphagia scores. Total hyperphagia scores in patients with 16p11.2 deletions were lower than for patients with other syndromic obesity forms (21.4 ± 5.5 vs. 24.6 ± 8.1), but similar to those for individuals with obesity without a genetic cause (22.9 ± 7.2).
CONCLUSIONS
Dykens' Hyperphagia Questionnaire seems to be a useful tool to assess hyperphagic behaviour in patients with monogenic and syndromic obesity.
Topics: Autistic Disorder; Chromosome Deletion; Chromosome Disorders; Chromosomes, Human, Pair 16; Humans; Hyperphagia; Intellectual Disability; Obesity
PubMed: 35809703
DOI: 10.1016/j.appet.2022.106161 -
Journal of Obesity & Metabolic Syndrome Dec 2021Childhood obesity has been increasing steadily in recent decades, and severe childhood obesity has emerged as a major public health problem both nationally and... (Review)
Review
Childhood obesity has been increasing steadily in recent decades, and severe childhood obesity has emerged as a major public health problem both nationally and internationally. A current concern is that lockdown due to the coronavirus disease 2019 (COVID-19) pandemic could exacerbate the spread of childhood obesity and increase the gap in obesity risk. Recent research results indicate the aggravation of obesity after school closures. The consequences of severe childhood obesity are more devastating than those of mild to moderate obesity. Children with severe obesity are at greater risk than others for hypertension, type 2 diabetes, metabolic syndrome, non-alcoholic fatty liver disease, atherosclerosis, and adult obesity. Accurately assessing and diagnosing a child with severe obesity is the key to implementing successful therapy. A detailed and accurate patient history and physical examination are important to discriminate monogenic obesity and metabolic syndrome diagnoses from severe obesity without an underlying cause. Psychosocial factors, including eating behaviors, should be assessed to facilitate better weight management outcomes. Treatment options for severe pediatric obesity include lifestyle modification therapy, pharmacotherapy, and metabolic and bariatric surgery. However, lifestyle modification should be the priority. Although progress has been made, safe and effective treatment for severe pediatric obesity is still challenging. More efforts and innovations are needed to find a solution for the huge medical and emotional burden that these children and their families carry. Public health organizations also need to make efforts to encourage and normalize healthy eating habits and exercise to prevent severe obesity in childhood.
PubMed: 34924365
DOI: 10.7570/jomes21063 -
Frontiers in Endocrinology 2023Hypothalamic obesity (HO) is a complex and rare disorder affecting multiple regulatory pathways of energy intake and expenditure in the brain as well as the regulation... (Review)
Review
Hypothalamic obesity (HO) is a complex and rare disorder affecting multiple regulatory pathways of energy intake and expenditure in the brain as well as the regulation of the autonomic nervous system and peripheral hormonal signaling. It can be related to monogenic obesity syndromes which often affect the central leptin-melanocortin pathways or due to injury of the hypothalamus from pituitary and hypothalamic tumors, such as craniopharyngioma, surgery, trauma, or radiation to the hypothalamus. Traditional treatments of obesity, such as lifestyle intervention and specific diets, are still a therapeutic cornerstone, but often fail to result in meaningful and sustained reduction of body mass index. This review will give an update on pharmacotherapies of HO related to hypothalamic injury. Recent obesity drug developments are promising for successful obesity intervention outcomes.
Topics: Humans; Hypothalamic Diseases; Hypothalamus; Obesity; Craniopharyngioma; Brain Injuries, Traumatic; Pituitary Neoplasms
PubMed: 37780616
DOI: 10.3389/fendo.2023.1256514 -
Current Diabetes Reports Jul 2020The global prevalence of obesity has increased rapidly over the last decades, posing a severe threat to human health. Currently, bariatric surgery is the most effective... (Review)
Review
PURPOSE OF REVIEW
The global prevalence of obesity has increased rapidly over the last decades, posing a severe threat to human health. Currently, bariatric surgery is the most effective therapy for patients with morbid obesity. It is unknown whether this treatment is also suitable for patients with obesity due to a confirmed genetic defect (genetic obesity disorders). Therefore, this review aims to elucidate the role of bariatric surgery in the treatment of genetic obesity.
RECENT FINDINGS
In monogenic non-syndromic obesity, an underlying genetic defect seems to be the most important factor determining the efficacy of bariatric surgery. In syndromic obesity, bariatric surgery result data are scarce, and even though some promising follow-up results have been reported, caution is required as patients with more severe behavioral and developmental disorders might have poorer outcomes. There is limited evidence in support of bariatric surgery as a treatment option for genetic obesity disorders; hence, no strong statements can be made regarding the efficacy and safety of these procedures for these patients. However, considering that patients with genetic obesity often present with life-threatening obesity-related comorbidities, we believe that bariatric surgery could be considered a last-resort treatment option in selected patients.
Topics: Bariatric Surgery; Humans; Mass Screening; Obesity, Morbid; Prevalence
PubMed: 32729070
DOI: 10.1007/s11892-020-01327-7 -
The Journal of Clinical Endocrinology... Nov 2023Monogenic obesity is a rare form of obesity due to pathogenic variants in genes implicated in the leptin-melanocortin signaling pathway and accounts for around 5% of...
CONTEXT
Monogenic obesity is a rare form of obesity due to pathogenic variants in genes implicated in the leptin-melanocortin signaling pathway and accounts for around 5% of severe early-onset obesity. Mutations in the genes encoding the MC4R, leptin, and leptin receptor are commonly reported in various populations to cause monogenic obesity. Determining the genetic cause has important clinical benefits as novel therapeutic interventions are now available for some forms of monogenic obesity.
OBJECTIVE
To unravel the genetic causes of early-onset obesity in the population of Qatar.
METHODS
In total, 243 patients with early-onset obesity (above the 95% percentile) and age of onset below 10 years were screened for monogenic obesity variants using a targeted gene panel, consisting of 52 obesity-related genes.
RESULTS
Thirty rare variants potentially associated with obesity were identified in 36 of 243 (14.8%) probands in 15 candidate genes (LEP, LEPR, POMC, MC3R, MC4R, MRAP2, SH2B1, BDNF, NTRK2, DYRK1B, SIM1, GNAS, ADCY3, RAI1, and BBS2). Twenty-three of the variants identified were novel to this study and the rest, 7 variants, were previously reported in literature. Variants in MC4R were the most common cause of obesity in our cohort (19%) and the c.485C>T p.T162I variant was the most frequent MC4R variant seen in 5 patients.
CONCLUSION
We identified likely pathogenic/pathogenic variants that seem to explain the phenotype of around 14.8% of our cases. Variants in the MC4R gene are the commonest cause of early-onset obesity in our population. Our study represents the largest monogenic obesity cohort in the Middle East and revealed novel obesity variants in this understudied population. Functional studies will be required to elucidate the molecular mechanism of their pathogenicity.
Topics: Humans; Child; Leptin; Qatar; Obesity; Mutation; Phenotype; Receptor, Melanocortin, Type 4; Adaptor Proteins, Signal Transducing
PubMed: 37329217
DOI: 10.1210/clinem/dgad366 -
Journal of Pediatric Genetics Sep 2021One in five children and adolescents in the United States are diagnosed with obesity and nearly 6% of them are being classified under the severe obesity category. With... (Review)
Review
One in five children and adolescents in the United States are diagnosed with obesity and nearly 6% of them are being classified under the severe obesity category. With over 7% of severe obesity being attributed to genetic disorders, in this review we aim to focus on monogenic and syndromic obesity: its etiology, wide spectrum of clinical presentation, criticalness of early identification, and limited management options. Advanced genetic testing methods including microarray and whole genome sequencing are imperative to identify the spectrum of mutations and develop targeted treatment strategies including personalized multidisciplinary care, use of investigational drugs, and explore surgical options in this unique subset of severe pediatric obesity.
PubMed: 34504723
DOI: 10.1055/s-0041-1731035 -
Current Genomics Jul 2022Individuals with a phenotype of early-onset severe obesity associated with intellectual disability can have molecular diagnoses ranging from monogenic to complex... (Review)
Review
Individuals with a phenotype of early-onset severe obesity associated with intellectual disability can have molecular diagnoses ranging from monogenic to complex genetic traits. Severe overweight is the major sign of a syndromic physical appearance and predicting the influence of a single gene and/or polygenic risk profile is extremely complicated among the majority of the cases. At present, considering rare monogenic bases as the principal etiology for the majority of obesity cases associated with intellectual disability is scientifically poor. The diversity of the molecular bases responsible for the two entities makes the appliance of the current routinely powerful genomics diagnostic tools essential. Clinical investigation of these difficult-to-diagnose patients requires pediatricians and neurologists to use optimized descriptions of signs and symptoms to improve genotype correlations. The use of modern integrated bioinformatics strategies which are conducted by experienced multidisciplinary clinical teams. Evaluation of the phenotype of the patient's family is also of importance. The next step involves discarding the monogenic canonical obesity syndromes and considering infrequent unique molecular cases, and/or then polygenic bases. Adequate management of the application of the new technique and its diagnostic phases is essential for achieving good cost/efficiency balances. With the current clinical management, it is necessary to consider the potential coincidence of risk mutations for obesity in patients with genetic alterations that induce intellectual disability. In this review, we describe an updated algorithm for the molecular characterization and diagnosis of patients with a syndromic obesity phenotype.
PubMed: 36777005
DOI: 10.2174/1389202923666220426093436