Dataset Information

Novel Genetic Locus of Visceral Fat and Systemic Inflammation.

ABSTRACT: CONTEXT:Visceral fat (VF), more than fat elsewhere in the body [mostly subcutaneous fat (SF)], promotes systemic inflammation and related disease. The mechanisms of preferentially visceral accumulation of body fat are largely unknown. OBJECTIVE:To identify genetic loci and mechanistic pathways of preferential accumulation of VF and associated low-grade systemic inflammation. DESIGN:Genome-wide association study (GWAS). SETTING AND PARTICIPANTS:Population-based cohort of 1586 adolescents (aged 12 to 19 years) and adults (aged 36 to 65 years). MAIN OUTCOME MEASURES:Abdominal VF and SF were measured with MRI, total body fat (TBF) was assessed with bioimpedance, and low-grade systemic inflammation was examined by serum C-reactive protein (CRP) measurement. RESULTS:This GWAS of preferential accumulation of VF identified a significant locus on chromosome 6 at rs803522 (P = 1.1 × 10-9 or 4.3 × 10-10 for VF adjusted for SF or TBF, respectively). The major allele was associated with more VF; the association was similar in adolescents and adults. The allele was also associated with higher CRP level, but this association was stronger in adults than adolescents (P for interaction = 4.5 × 10-3). In adults, VF was a significant mediator (P = 1.9× 10-4) in the association between the locus and CRP, explaining 30% of the mediation. The locus was near ATG5, encoding an autophagy molecule reported to modulate adipocyte size and macrophage polarization. CONCLUSION:A genetic locus near ATG5 regulates preferential accumulation of VF (vs SF) in youth and adulthood and contributes to the development of systemic inflammation in adulthood.

SUBMITTER: Shin J

PROVIDER: S-EPMC6642667 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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Novel Genetic Locus of Visceral Fat and Systemic Inflammation.

Shin Jean J Syme Catriona C Wang Dominic D Richer Louis L Pike G Bruce GB Gaudet Daniel D Paus Tomas T Pausova Zdenka Z

The Journal of clinical endocrinology and metabolism 20190901 9

<h4>Context</h4>Visceral fat (VF), more than fat elsewhere in the body [mostly subcutaneous fat (SF)], promotes systemic inflammation and related disease. The mechanisms of preferentially visceral accumulation of body fat are largely unknown.<h4>Objective</h4>To identify genetic loci and mechanistic pathways of preferential accumulation of VF and associated low-grade systemic inflammation.<h4>Design</h4>Genome-wide association study (GWAS).<h4>Setting and participants</h4>Population-based cohort ...[more]

PMID: 30942860

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Project description:Body fat distribution, particularly centralized obesity, is associated with metabolic risk above and beyond total adiposity. We performed genome-wide association of abdominal adipose depots quantified using computed tomography (CT) to uncover novel loci for body fat distribution among participants of European ancestry. Subcutaneous and visceral fat were quantified in 5,560 women and 4,997 men from 4 population-based studies. Genome-wide genotyping was performed using standard arrays and imputed to ~2.5 million Hapmap SNPs. Each study performed a genome-wide association analysis of subcutaneous adipose tissue (SAT), visceral adipose tissue (VAT), VAT adjusted for body mass index, and VAT/SAT ratio (a metric of the propensity to store fat viscerally as compared to subcutaneously) in the overall sample and in women and men separately. A weighted z-score meta-analysis was conducted. For the VAT/SAT ratio, our most significant p-value was rs11118316 at LYPLAL1 gene (p = 3.1 × 10E-09), previously identified in association with waist-hip ratio. For SAT, the most significant SNP was in the FTO gene (p = 5.9 × 10E-08). Given the known gender differences in body fat distribution, we performed sex-specific analyses. Our most significant finding was for VAT in women, rs1659258 near THNSL2 (p = 1.6 × 10-08), but not men (p = 0.75). Validation of this SNP in the GIANT consortium data demonstrated a similar sex-specific pattern, with observed significance in women (p = 0.006) but not men (p = 0.24) for BMI and waist circumference (p = 0.04 [women], p = 0.49 [men]). Finally, we interrogated our data for the 14 recently published loci for body fat distribution (measured by waist-hip ratio adjusted for BMI); associations were observed at 7 of these loci. In contrast, we observed associations at only 7/32 loci previously identified in association with BMI; the majority of overlap was observed with SAT. Genome-wide association for visceral and subcutaneous fat revealed a SNP for VAT in women. More refined phenotypes for body composition and fat distribution can detect new loci not previously uncovered in large-scale GWAS of anthropometric traits.

Project description:Disturbance of sleep homeostasis encompasses health issues, including metabolic disorders like obesity, diabetes, and augmented stress vulnerability. Sleep and stress interact bidirectionally to influence the central nervous system and metabolism. Murine models demonstrate that decreased sleep time is associated with an increased systemic stress response, characterized by endocrinal imbalance, including the elevated activity of hypothalamic-pituitary-adrenal axis, augmented insulin, and reduced adiponectin, affecting peripheral organs physiology, mainly the white adipose tissue (WAT). Within peripheral organs, a local stress response can also be activated by promoting the formation of corticosterone. This local amplifying glucocorticoid signaling is favored through the activation of the enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1). In WAT, 11β-HSD1 activity is upregulated by the sympathetic nervous system, suggesting a link between sleep loss, augmented stress response, and a potential WAT metabolic disturbance. To gain more understanding about this relationship, metabolic and stress responses of WAT-sympathectomized rats were analyzed to identify the contribution of the autonomic nervous system to stress response-related metabolic disorders during chronic sleep restriction. Male Wistar rats under sleep restriction were allowed just 6 h of daily sleep over eight weeks. Results showed that rats under sleep restriction presented higher serum corticosterone, increased adipose tissue 11β-HSD1 activity, weight loss, decreased visceral fat, augmented adiponectin, lower leptin levels, glucose tolerance impairment, and mildly decreased daily body temperature. In contrast, sympathectomized rats under sleep restriction exhibited decreased stress response (lower serum corticosterone and 11β-HSD1 activity). In addition, they maintained weight loss, explained by a reduced visceral fat pad, leptin, and adiponectin, improved glucose management, and persisting decline in body temperature. These results suggest autonomic nervous system is partially responsible for the WAT-exacerbated stress response and its metabolic and physiological disturbances.

Dataset Information

Novel Genetic Locus of Visceral Fat and Systemic Inflammation.

Publications

Novel Genetic Locus of Visceral Fat and Systemic Inflammation.

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