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Cell Metabolism Mar 2017Except in rare cases, obesity tends to be a consequence of both an unhealthy lifestyle and a genetic susceptibility to gain weight. With more than 200 common genetic... (Review)
Review
Except in rare cases, obesity tends to be a consequence of both an unhealthy lifestyle and a genetic susceptibility to gain weight. With more than 200 common genetic variants identified, there is a growing interest in developing personalized preventive and treatment strategies to predict an individual's obesity risk. We review the literature on the prediction of obesity and show that models based on the established genetic variants have poorer predictive ability than traditional predictors, such as family history of obesity and childhood obesity. Current findings suggest that opportunities for precision medicine in common obesity may be limited.
Topics: Genetic Predisposition to Disease; Genetic Variation; Humans; Life Style; Multifactorial Inheritance; Obesity; Risk Factors
PubMed: 28273476
DOI: 10.1016/j.cmet.2017.02.013 -
GeroScience Aug 2023Frailty is an aging-related clinical phenotype defined as a state in which there is an increase in a person's vulnerability for dependency and/or mortality when exposed...
Frailty is an aging-related clinical phenotype defined as a state in which there is an increase in a person's vulnerability for dependency and/or mortality when exposed to a stressor. While underlying mechanisms leading to the occurrence of frailty are complex, the importance of genetic factors has not been fully investigated. We conducted a large-scale genome-wide association study (GWAS) of frailty, as defined by the five criteria (weight loss, exhaustion, physical activity, walking speed, and grip strength) captured in the Fried Frailty Score (FFS), in 386,565 European descent participants enrolled in the UK Biobank (mean age 57 [SD 8] years, 208,481 [54%] females). We identified 37 independent, novel loci associated with the FFS (p < 5 × 10), including seven loci without prior described associations with other traits. The variants associated with FFS were significantly enriched in brain tissues as well as aging-related pathways. Our post-GWAS bioinformatic analyses revealed significant genetic correlations between FFS and cardiovascular-, neurological-, and inflammation-related diseases/traits, and subsequent Mendelian Randomization analyses identified causal associations with chronic pain, obesity, diabetes, education-related traits, joint disorders, and depressive/neurological, metabolic, and respiratory diseases. The GWAS signals were replicated in the Health and Retirement Study (HRS, n = 9,720, mean age 73 [SD 7], 5,582 [57%] females), where the polygenic risk score built from UKB GWAS was significantly associated with the FFS in HRS individuals (OR per SD of the score 1.27, 95% CI 1.22-1.31, p = 1.3 × 10). These results provide new insight into the biology of frailty by comprehensively evaluating its genetic architecture.
Topics: Female; Humans; Aged; Male; Genome-Wide Association Study; Frailty; Obesity; Phenotype; Inflammation
PubMed: 36928559
DOI: 10.1007/s11357-023-00771-z -
Journal of Clinical Medicine Feb 2024Obesity remains a common metabolic disorder and a threat to health as it is associated with numerous complications. Lifestyle modifications and caloric restriction can... (Review)
Review
Obesity remains a common metabolic disorder and a threat to health as it is associated with numerous complications. Lifestyle modifications and caloric restriction can achieve limited weight loss. Bariatric surgery is an effective way of achieving substantial weight loss as well as glycemic control secondary to weight-related type 2 diabetes mellitus. It has been suggested that an anorexigenic gut hormone response following bariatric surgery contributes to weight loss. Understanding the changes in gut hormones and their contribution to weight loss physiology can lead to new therapeutic treatments for weight loss. Two distinct types of neurons in the arcuate hypothalamic nuclei control food intake: proopiomelanocortin neurons activated by the anorexigenic (satiety) hormones and neurons activated by the orexigenic peptides that release neuropeptide Y and agouti-related peptide (hunger centre). The arcuate nucleus of the hypothalamus integrates hormonal inputs from the gut and adipose tissue (the anorexigenic hormones cholecystokinin, polypeptide YY, glucagon-like peptide-1, oxyntomodulin, leptin, and others) and orexigeneic peptides (ghrelin). Replicating the endocrine response to bariatric surgery through pharmacological mimicry holds promise for medical treatment. Obesity has genetic and environmental factors. New advances in genetic testing have identified both monogenic and polygenic obesity-related genes. Understanding the function of genes contributing to obesity will increase insights into the biology of obesity. This review includes the physiology of appetite control, the influence of genetics on obesity, and the changes that occur following bariatric surgery. This has the potential to lead to the development of more subtle, individualised, treatments for obesity.
PubMed: 38546831
DOI: 10.3390/jcm13051347 -
Obesity Pillars Sep 2024Obesity is a multifactorial neurohormonal disease that results from dysfunction within energy regulation pathways and is associated with increased morbidity, mortality,... (Review)
Review
BACKGROUND
Obesity is a multifactorial neurohormonal disease that results from dysfunction within energy regulation pathways and is associated with increased morbidity, mortality, and reduced quality of life. The most common form is polygenic obesity, which results from interactions between multiple gene variants and environmental factors. Highly penetrant monogenic and syndromic obesities result from rare genetic variants with minimal environmental influence and can be differentiated from polygenic obesity depending on key symptoms, including hyperphagia; early-onset, severe obesity; and suboptimal responses to nontargeted therapies. Timely diagnosis of monogenic or syndromic obesity is critical to inform management strategies and reduce disease burden. We outline the physiology of weight regulation, role of genetics in obesity, and differentiating characteristics between polygenic and rare genetic obesity to facilitate diagnosis and transition toward targeted therapies.
METHODS
In this narrative review, we focused on case reports, case studies, and natural history studies of patients with monogenic and syndromic obesities and clinical trials examining the efficacy, safety, and quality of life impact of nontargeted and targeted therapies in these populations. We also provide comprehensive algorithms for diagnosis of patients with suspected rare genetic causes of obesity.
RESULTS
Patients with monogenic and syndromic obesities commonly present with hyperphagia (ie, pathologic, insatiable hunger) and early-onset, severe obesity, and the presence of hallmark characteristics can inform genetic testing and diagnostic approach. Following diagnosis, specialized care teams can address complex symptoms, and hyperphagia is managed behaviorally. Various pharmacotherapies show promise in these patient populations, including setmelanotide and glucagon-like peptide-1 receptor agonists.
CONCLUSION
Understanding the pathophysiology and differentiating characteristics of monogenic and syndromic obesities can facilitate diagnosis and management and has led to development of targeted pharmacotherapies with demonstrated efficacy for reducing body weight and hunger in the affected populations.
PubMed: 38766314
DOI: 10.1016/j.obpill.2024.100110 -
Genome Biology Mar 2023Phosphorylation of proteins is a key step in the regulation of many cellular processes including activation of enzymes and signaling cascades. The abundance of a...
BACKGROUND
Phosphorylation of proteins is a key step in the regulation of many cellular processes including activation of enzymes and signaling cascades. The abundance of a phosphorylated peptide (phosphopeptide) is determined by the abundance of its parent protein and the proportion of target sites that are phosphorylated.
RESULTS
We quantified phosphopeptides, proteins, and transcripts in heart, liver, and kidney tissue samples of mice from 58 strains of the Collaborative Cross strain panel. We mapped ~700 phosphorylation quantitative trait loci (phQTL) across the three tissues and applied genetic mediation analysis to identify causal drivers of phosphorylation. We identified kinases, phosphatases, cytokines, and other factors, including both known and potentially novel interactions between target proteins and genes that regulate site-specific phosphorylation. Our analysis highlights multiple targets of pyruvate dehydrogenase kinase 1 (PDK1), a regulator of mitochondrial function that shows reduced activity in the NZO/HILtJ mouse, a polygenic model of obesity and type 2 diabetes.
CONCLUSIONS
Together, this integrative multi-omics analysis in genetically diverse CC strains provides a powerful tool to identify regulators of protein phosphorylation. The data generated in this study provides a resource for further exploration.
Topics: Mice; Animals; Phosphorylation; Diabetes Mellitus, Type 2; Multiomics; Quantitative Trait Loci; Peptides
PubMed: 36944993
DOI: 10.1186/s13059-023-02892-2 -
Nature Communications May 2023Narcolepsy type 1 (NT1) is caused by a loss of hypocretin/orexin transmission. Risk factors include pandemic 2009 H1N1 influenza A infection and immunization with...
Narcolepsy type 1 (NT1) is caused by a loss of hypocretin/orexin transmission. Risk factors include pandemic 2009 H1N1 influenza A infection and immunization with Pandemrix®. Here, we dissect disease mechanisms and interactions with environmental triggers in a multi-ethnic sample of 6,073 cases and 84,856 controls. We fine-mapped GWAS signals within HLA (DQ0602, DQB1*03:01 and DPB1*04:02) and discovered seven novel associations (CD207, NAB1, IKZF4-ERBB3, CTSC, DENND1B, SIRPG, PRF1). Significant signals at TRA and DQB1*06:02 loci were found in 245 vaccination-related cases, who also shared polygenic risk. T cell receptor associations in NT1 modulated TRAJ*24, TRAJ*28 and TRBV*4-2 chain-usage. Partitioned heritability and immune cell enrichment analyses found genetic signals to be driven by dendritic and helper T cells. Lastly comorbidity analysis using data from FinnGen, suggests shared effects between NT1 and other autoimmune diseases. NT1 genetic variants shape autoimmunity and response to environmental triggers, including influenza A infection and immunization with Pandemrix®.
Topics: Humans; Autoimmunity; Influenza, Human; Influenza A Virus, H1N1 Subtype; Autoimmune Diseases; Influenza Vaccines; Narcolepsy
PubMed: 37188663
DOI: 10.1038/s41467-023-36120-z -
Maedica Sep 2022Obesity is defined by an imbalance between energy expenditure and energy consumption. Presently, it is considered a global problem because people are consuming junk food...
Obesity is defined by an imbalance between energy expenditure and energy consumption. Presently, it is considered a global problem because people are consuming junk food and doing less physical activity in every country of the world. It is all due to sedentary life style. The currently available drugs for the treatment of obesity are not giving satisfactory results as they have many adverse effects along with rebound obesity complications. To evaluate new drug in pre-clinical study, we need to have better supportive animal models. Obesity can be induced by giving drugs, fat food, surgical procedures, and by genetic modifications. In the present review, various obesity induced models have been explained to evaluate new compounds. In experimental animal models, monogenic and polygenic obesity models have been reviewed, with a proper pathway to prepare new drugs being given. While in the existing models, genetic obesity models were not explained so far, here genetic engineered transgenic models were described to evaluate new anti-obesity drugs. This short review on chemically and surgically induced obesity models aimed to provide a better understanding of the experimental design of obesity.
PubMed: 36540593
DOI: 10.26574/maedica.2022.17.3.706 -
PeerJ 2015Obesity is a major public health concern. This condition results from a constant and complex interplay between predisposing genes and environmental stimuli. Current... (Review)
Review
Obesity is a major public health concern. This condition results from a constant and complex interplay between predisposing genes and environmental stimuli. Current attempts to manage obesity have been moderately effective and a better understanding of the etiology of obesity is required for the development of more successful and personalized prevention and treatment options. To that effect, mouse models have been an essential tool in expanding our understanding of obesity, due to the availability of their complete genome sequence, genetically identified and defined strains, various tools for genetic manipulation and the accessibility of target tissues for obesity that are not easily attainable from humans. Our knowledge of monogenic obesity in humans greatly benefited from the mouse obesity genetics field. Genes underlying highly penetrant forms of monogenic obesity are part of the leptin-melanocortin pathway in the hypothalamus. Recently, hypothesis-generating genome-wide association studies for polygenic obesity traits in humans have led to the identification of 119 common gene variants with modest effect, most of them having an unknown function. These discoveries have led to novel animal models and have illuminated new biologic pathways. Integrated mouse-human genetic approaches have firmly established new obesity candidate genes. Innovative strategies recently developed by scientists are described in this review to accelerate the identification of causal genes and deepen our understanding of obesity etiology. An exhaustive dissection of the molecular roots of obesity may ultimately help to tackle the growing obesity epidemic worldwide.
PubMed: 25825681
DOI: 10.7717/peerj.856 -
Nature Communications Jan 2024To date only a fraction of the genetic footprint of thyroid function has been clarified. We report a genome-wide association study meta-analysis of thyroid function in... (Meta-Analysis)
Meta-Analysis
To date only a fraction of the genetic footprint of thyroid function has been clarified. We report a genome-wide association study meta-analysis of thyroid function in up to 271,040 individuals of European ancestry, including reference range thyrotropin (TSH), free thyroxine (FT4), free and total triiodothyronine (T3), proxies for metabolism (T3/FT4 ratio) as well as dichotomized high and low TSH levels. We revealed 259 independent significant associations for TSH (61% novel), 85 for FT4 (67% novel), and 62 novel signals for the T3 related traits. The loci explained 14.1%, 6.0%, 9.5% and 1.1% of the total variation in TSH, FT4, total T3 and free T3 concentrations, respectively. Genetic correlations indicate that TSH associated loci reflect the thyroid function determined by free T3, whereas the FT4 associations represent the thyroid hormone metabolism. Polygenic risk score and Mendelian randomization analyses showed the effects of genetically determined variation in thyroid function on various clinical outcomes, including cardiovascular risk factors and diseases, autoimmune diseases, and cancer. In conclusion, our results improve the understanding of thyroid hormone physiology and highlight the pleiotropic effects of thyroid function on various diseases.
Topics: Humans; Thyroid Gland; Thyroxine; Genome-Wide Association Study; Triiodothyronine; Thyrotropin
PubMed: 38291025
DOI: 10.1038/s41467-024-44701-9