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Trends in Cognitive Sciences May 2017Recent work highlights the importance of genetic variants that influence brain structure and function in conferring risk for polygenic obesity. The neurotransmitter... (Review)
Review
Recent work highlights the importance of genetic variants that influence brain structure and function in conferring risk for polygenic obesity. The neurotransmitter dopamine (DA) has a pivotal role in energy balance by integrating metabolic signals with circuits supporting cognitive, perceptual, and appetitive functions that guide feeding. It has also been established that diet and obesity alter DA signaling, leading to compulsive-like feeding and neurocognitive impairments. This raises the possibility that genetic variants that influence DA signaling and adaptation confer risk for overeating and cognitive decline. Here, we consider the role of two common gene variants, FTO and TaqIA rs1800497 in driving gene × environment interactions promoting obesity, metabolic dysfunction, and cognitive change via their influence on DA receptor subtype 2 (DRD2) signaling.
Topics: Alpha-Ketoglutarate-Dependent Dioxygenase FTO; Dopamine; Gene-Environment Interaction; Genetic Predisposition to Disease; Humans; Obesity; Protein Serine-Threonine Kinases; Receptors, Dopamine D2
PubMed: 28372879
DOI: 10.1016/j.tics.2017.03.004 -
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 -
Neuroscience and Biobehavioral Reviews Feb 2020Obesity has dramatically increased during the last decades and is currently one of the most serious global health problems. We present a hypothesis that obesity is a... (Review)
Review
Obesity has dramatically increased during the last decades and is currently one of the most serious global health problems. We present a hypothesis that obesity is a neuro-behavioral disease having a strong genetic background mediated largely by eating behavior and is sensitive to the macro-environment; we study this hypothesis from the perspective of genetic research. Genetic family and genome-wide-association studies have shown well that body mass index (BMI, kg/m) is a highly heritable and polygenic trait. New genetic variation of BMI emerges after early childhood. Candidate genes of BMI notably express in brain tissue, supporting that this new variation is related to behavior. Obesogenic environments at both childhood family and societal levels reinforce the genetic susceptibility to obesity. Genetic factors have a clear influence on macro-nutrient intake and appetite-related eating behavior traits. Results on the gene-by-diet interactions in obesity are mixed, but emerging evidence suggests that eating behavior traits partly mediate the effect of genes on BMI. However, more rigorous prospective study designs controlling for measurement bias are still needed.
Topics: Body Mass Index; Feeding Behavior; Gene-Environment Interaction; Genetic Predisposition to Disease; Humans; Multifactorial Inheritance; Obesity
PubMed: 31959301
DOI: 10.1016/j.neubiorev.2019.12.012 -
Nutrients Jun 2023Obesity is a common, serious, and costly disease. More than 1 billion people worldwide are obese-650 million adults, 340 million adolescents, and 39 million children.... (Review)
Review
Obesity is a common, serious, and costly disease. More than 1 billion people worldwide are obese-650 million adults, 340 million adolescents, and 39 million children. The WHO estimates that, by 2025, approximately 167 million people-adults and children-will become less healthy because they are overweight or obese. Obesity-related conditions include heart disease, stroke, type 2 diabetes, and certain types of cancer. These are among the leading causes of preventable, premature death. The estimated annual medical cost of obesity in the United States was nearly $173 billion in 2019 dollars. Obesity is considered the result of a complex interaction between genes and the environment. Both genes and the environment change in different populations. In fact, the prevalence changes as the result of eating habits, lifestyle, and expression of genes coding for factors involved in the regulation of body weight, food intake, and satiety. Expression of these genes involves different epigenetic processes, such as DNA methylation, histone modification, or non-coding micro-RNA synthesis, as well as variations in the gene sequence, which results in functional alterations. Evolutionary and non-evolutionary (i.e., genetic drift, migration, and founder's effect) factors have shaped the genetic predisposition or protection from obesity in modern human populations. Understanding and knowing the pathogenesis of obesity will lead to prevention and treatment strategies not only for obesity, but also for other related diseases.
Topics: Adult; Child; Adolescent; Humans; United States; Diabetes Mellitus, Type 2; Obesity; Overweight; Body Weight; Life Style
PubMed: 37375686
DOI: 10.3390/nu15122782 -
Current Cardiology Reports Oct 2020Obesity is a significant international public health epidemic with major downstream consequences on morbidity and mortality. While lifestyle factors contribute, there is... (Review)
Review
PURPOSE OF REVIEW
Obesity is a significant international public health epidemic with major downstream consequences on morbidity and mortality. While lifestyle factors contribute, there is an evolving understanding of genomic and metabolomic pathways involved with obesity and its relationship with cardiometabolic risk. This review will provide an overview of some of these important findings from both a biologic and clinical perspective.
RECENT FINDINGS
Recent studies have identified polygenic risk scores and metabolomic biomarkers of obesity and related outcomes, which have also highlighted biological pathways, such as the branched-chain amino acid (BCAA) pathway that is dysregulated in this disease. These biomarkers may help in personalizing obesity interventions and for mitigation of future cardiometabolic risk. A multifaceted approach is necessary to impact the growing epidemic of obesity and related diseases. This will likely include incorporating precision medicine approaches with genomic and metabolomic biomarkers to personalize interventions and improve risk prediction.
Topics: Amino Acids, Branched-Chain; Biomarkers; Cardiovascular Diseases; Genomics; Humans; Metabolomics; Obesity
PubMed: 33040225
DOI: 10.1007/s11886-020-01422-x -
Cardiovascular Pathology : the Official... 2017Atherosclerosis and abdominal aortic aneurysms (AAAs) are multifactorial and polygenic diseases with known environmental and genetic risk factors that contribute toward... (Review)
Review
Atherosclerosis and abdominal aortic aneurysms (AAAs) are multifactorial and polygenic diseases with known environmental and genetic risk factors that contribute toward disease development. Atherosclerosis represents an important independent risk factor for AAA, as people with AAA often have atherosclerosis. Studies have shown that comorbidity is usually between ~25% and 55%, but it is still not fully known whether this association is causal or a result of common shared risk profiles. Most recent epidemiological, clinical, and biological evidence suggests that the two pathologies are more distinct than traditionally thought. For instance diabetes mellitus, hypercholesterolemia, and obesity are high risk for atherosclerosis development but are not as pronounced in AAA, whereas smoking, gender, and ethnicity are particularly high risk for AAA but less so for atherosclerosis. In addition, genetic and epigenetic studies have identified independent risk loci involved in AAA susceptibility that are not associated with other cardiovascular diseases, and research on important common cardiovascular biomarkers has illustrated discrepancies in those with AAA.
Topics: Aortic Aneurysm, Abdominal; Coronary Artery Disease; Humans; Risk Factors
PubMed: 28189002
DOI: 10.1016/j.carpath.2017.01.008 -
Journal of Affective Disorders Sep 2022Bipolar disorder (BD) presents with high obesity and type 2 diabetes (T2D) and pathophysiological and phenomenological abnormalities shared with cardiometabolic... (Review)
Review
BACKGROUND
Bipolar disorder (BD) presents with high obesity and type 2 diabetes (T2D) and pathophysiological and phenomenological abnormalities shared with cardiometabolic disorders. Genomic studies may help define if they share genetic liability. This selective review of BD with obesity and T2D will focus on genomic studies, stress their current limitations and guide future steps in developing the field.
METHODS
We searched electronic databases (PubMed, Scopus) until December 2021 to identify genome-wide association studies, polygenic risk score analyses, and functional genomics of BD accounting for body mass index (BMI), obesity, or T2D.
RESULTS
The first genome-wide association studies (GWAS) of BD accounting for obesity found a promising genome-wide association in an intronic gene variant of TCF7L2 that was further replicated. Polygenic risk scores of obesity and T2D have also been associated with BD, yet, no genetic correlations have been demonstrated. Finally, human-induced stem cell studies of the intronic variant in TCF7L2 show a potential biological impact of the products of this genetic variant in BD risk.
LIMITATIONS
The narrative nature of this review.
CONCLUSIONS
Findings from BD GWAS accounting for obesity and their functional testing, have prompted potential biological insights. Yet, BD, obesity, and T2D display high phenotypic, genetic, and population-related heterogeneity, limiting our ability to detect genetic associations. Further studies should refine cardiometabolic phenotypes, test gene-environmental interactions and add population diversity.
Topics: Bipolar Disorder; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Genetic Predisposition to Disease; Genome-Wide Association Study; Humans; Obesity; Polymorphism, Single Nucleotide
PubMed: 35780966
DOI: 10.1016/j.jad.2022.06.084 -
Metabolism: Clinical and Experimental Aug 2023The SREBP/SCAP/INSIG complex plays an essential role in SREBP activation and de novo lipogenesis. Whether the activation process is affected by hydroxysteroid 17-beta...
BACKGROUND
The SREBP/SCAP/INSIG complex plays an essential role in SREBP activation and de novo lipogenesis. Whether the activation process is affected by hydroxysteroid 17-beta dehydrogenase 6 (HSD17B6) remains unknown.
METHODS
SREBP's transcriptional activities were analyzed using an SRE-luciferase (SRE-luc) reporter in 293T cells, Huh7 hepatoma cells, and primary human hepatocytes following a variety of conditions, including ectopic expression of HSD17B6, HSD17B6 mutants defective in its enzymatic activities, knockdown of HSD17B6, and cholesterol starvation. The interaction between HSD17B6 and SREBP/SCAP/INSIG complex was analyzed in 293T cells, Huh7 cells and mouse liver upon ectopic expression of HSD17B6 and its mutants; the interaction was also analyzed using endogenous proteins. The impacts of HSD17B6 on SREBP target expression, glucose tolerance, diet-induced obesity, and type 2 diabetes (T2D) were examined using Huh7 cells in vitro, and with C57BL/6 and NONcNZO10/LtJ T2D mice in vivo.
RESULTS
HSD17B6 binds to the SREBP/SCAP/INSIG complex and inhibits SREBP signaling in cultured hepatocytes and mouse liver. Although HSD17B6 plays a role in maintaining the equilibrium of 5α-dihydrotestosterone (DHT) in the prostate, a mutant defective in androgen metabolism was as effective as HSD17B6 in inhibiting SREBP signaling. Hepatic expression of both HSD17B6 and the defective mutant improved glucose intolerance and reduced hepatic triglyceride content in diet-induced obese C57BL/6 mice, while hepatic knockdown of HSD17B6 exacerbated glucose intolerance. Consistent with these results, liver-specific expression of HSD17B6 in a polygenic NONcNZO10/LtJ T2D mice reduced T2D development.
CONCLUSIONS
Our study unveils a novel role of HSD17B6 in inhibiting SREBP maturation via binding to the SREBP/SCAP/INSIG complex; this activity is independent of HSD17B6's sterol oxidase activity. Through this action, HSD17B6 improves glucose tolerance and attenuates the development of obesity-induced T2D. These findings position HSD17B6 as a potential therapeutic target for T2D therapy.
Topics: Male; Mice; Humans; Animals; Sterol Regulatory Element Binding Protein 1; Diabetes Mellitus, Type 2; Glucose Intolerance; Intracellular Signaling Peptides and Proteins; Mice, Inbred C57BL; Obesity; Glucose; Racemases and Epimerases
PubMed: 37330135
DOI: 10.1016/j.metabol.2023.155631 -
Physiology & Behavior Nov 2023Modern food environments are conducive to overeating and weight gain, but not everyone develops obesity. One reason for this may be that individuals differ in appetitive... (Review)
Review
Modern food environments are conducive to overeating and weight gain, but not everyone develops obesity. One reason for this may be that individuals differ in appetitive characteristics, or traits, that manifest early in life and go on to influence their behavioral susceptibility to gain and maintain excess weight. Classic studies showing that eating behavior in children can be measured by behavioral paradigms such as tests of caloric compensation and eating in the absence of hunger inspired the development and validation of psychometric instruments to assess appetitive characteristics in children and infants. A large body of evidence now suggests that food approach traits increase obesity risk, while food avoidant traits, such as satiety responsiveness, decrease obesity risk. Twin studies and genetic association studies have demonstrated that appetitive characteristics are heritable, consistent with a biological etiology. However, family environment factors are also influential, with mounting evidence suggesting that genetic and environmental risk factors interact and correlate with consequences for child eating behavior and weight. Further, neuroimaging studies are revealing that individual differences in responses to visual food cues, as well as to small tastes and larger amounts of food, across a number of brain regions involved in reward/motivation, cognitive control and other functions, may contribute to individual variation in appetitive behavior. Growing evidence also suggests that variation on psychometric measures of appetite is associated with regional differences in brain structure, and differential patterns of resting state functional connectivity. Large prospective studies beginning in infancy promise to enrich our understanding of neural and other biological underpinnings of appetite and obesity development in early life, and how the interplay between genetic and environmental factors affects appetitive systems. The biobehavioral susceptibility model of obesity development and maintenance outlined in this narrative review has implications for prevention and treatment of obesity in childhood.
Topics: Child; Infant; Humans; Appetite; Pediatric Obesity; Prospective Studies; Feeding Behavior; Weight Gain; Neuroimaging; Body Mass Index
PubMed: 37544571
DOI: 10.1016/j.physbeh.2023.114313 -
Biomedicines Jan 2023Nonalcoholic fatty liver disease (NAFLD) is a common chronic condition associated with genetic and environmental factors in which fat abnormally accumulates in the... (Review)
Review
Nonalcoholic fatty liver disease (NAFLD) is a common chronic condition associated with genetic and environmental factors in which fat abnormally accumulates in the liver. NAFLD is epidemiologically associated with obesity, type 2 diabetes, and dyslipidemia. Environmental factors, such as physical inactivity and an unbalanced diet, interact with genetic factors, such as epigenetic mechanisms and polymorphisms for the genesis and development of the condition. Different genetic polymorphisms seem to be involved in this context, including variants in PNPLA3, TM6SF2, PEMT, and CHDH genes, playing a role in the disease's susceptibility, development, and severity. From carbohydrate intake and weight loss to omega-3 supplementation and caloric restriction, different dietary and nutritional factors appear to be involved in controlling the onset and progression of NAFLD conditions influencing metabolism, gene, and protein expression. The polygenic risk score represents a sum of trait-associated alleles carried by an individual and seems to be associated with NAFLD outcomes depending on the dietary context. Understanding the exact extent to which lifestyle interventions and genetic predispositions can play a role in the prevention and management of NAFLD can be crucial for the establishment of a personalized and integrative approach to patients.
PubMed: 36830856
DOI: 10.3390/biomedicines11020319