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Determinants of body fat distribution in humans may provide insight about obesity-related health risks.

ABSTRACT: Obesity increases the risks of developing cardiovascular and metabolic diseases and degrades quality of life, ultimately increasing the risk of death. However, not all forms of obesity are equally dangerous: some individuals, despite higher percentages of body fat, are at less risk for certain chronic obesity-related complications. Many open questions remain about why this occurs. Data suggest that the physical location of fat and the overall health of fat dramatically influence disease risk; for example, higher concentrations of visceral relative to subcutaneous adipose tissue are associated with greater metabolic risks. As such, understanding the determinants of the location and health of adipose tissue can provide insight about the pathological consequences of obesity and can begin to outline targets for novel therapeutic approaches to combat the obesity epidemic. Although age and sex hormones clearly play roles in fat distribution and location, much remains unknown about gene regulation at the level of adipose tissue or how genetic variants regulate fat distribution. In this review, we discuss what is known about the determinants of body fat distribution, and we highlight the important roles of sex hormones, aging, and genetic variation in the determination of body fat distribution and its contribution to obesity-related comorbidities.

SUBMITTER: Frank AP

PROVIDER: S-EPMC6795075 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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Determinants of body fat distribution in humans may provide insight about obesity-related health risks.

Frank Aaron P AP de Souza Santos Roberta R Palmer Biff F BF Clegg Deborah J DJ

Journal of lipid research 20180810 10

Obesity increases the risks of developing cardiovascular and metabolic diseases and degrades quality of life, ultimately increasing the risk of death. However, not all forms of obesity are equally dangerous: some individuals, despite higher percentages of body fat, are at less risk for certain chronic obesity-related complications. Many open questions remain about why this occurs. Data suggest that the physical location of fat and the overall health of fat dramatically influence disease risk; fo ...[more]

PMID: 30097511

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Project description:Objective The observational studies indicate an association between obesity and epilepsy, but it is unclear whether such an association responds to causality. The objective of this study was to determine the causal relationship between obesity and fat distribution and epilepsy subtypes based on waist circumference, hip circumference (HP), waist-hip ratio (WHR), and body mass index (BMI). Methods A two-sample Mendelian randomization study was conducted separately for the four indicators of obesity and epilepsy and its seven subtypes, with reverse Mendelian randomization and multivariate Mendelian randomization for significant outcomes. Results A two-sample Mendelian randomized analysis informed us that waist circumference was a risk factor for juvenile myoclonic epilepsy (beta = 0.0299, P = 4.60 × 10−3). The increase in hip circumference increased the risk of juvenile myoclonic epilepsy and epilepsy, with effect values of 0.0283 (P = 2.01 × 10−3) and 0.0928 (P = 1.40 × 10−2), respectively. Furthermore, children with a higher BMI exhibit a higher risk of epilepsy (beta = 0.0148 P = 1.05 × 10−3). The reverse Mendelian randomization study revealed that childhood absence epilepsy increased its BMI (beta = 0.8980, P = 7.52 × 10−7), and juvenile myoclonic epilepsy increased its waist circumference (beta = 0.7322, P = 3.26 × 10−2). Multivariate Mendelian randomization revealed that an increase in hip circumference and waist-hip ratio increased the risk of juvenile myoclonic epilepsy, with an effect value of 0.1051 (P = 9.75 × 10−4) and 0.1430 (P = 3.99 × 10−3), respectively, while an increase in BMI and waist circumference instead decreased their risk, with effect values of −0.0951 (P = 3.14 × 10−2) and−0.0541 (P = 1.71 × 10−2). In contrast, multivariate Mendelian randomization for childhood absence epilepsy and epilepsy did not identify any independent risk factors. Significance Our findings provide novel evidence in favor of obesity as a risk factor for epilepsy and waist circumference as a risk factor for juvenile myoclonic epilepsy. Increased hip circumference confers an elevated risk of juvenile myoclonic epilepsy and epilepsy (all documented cases), and a high BMI increases the risk of childhood absence epilepsy. With this, new insights are provided into the energy metabolism of epilepsy, which supports further nutritional interventions and the search for new therapeutic targets.

Project description:Tetrahydrobiopterin (BH4) is an essential cofactor for several metabolic enzymes, including the aromatic amino acid hydroxylases, alkylglycerol mono-oxygenase and NO synthases. BH4 deficiency due to an autosomal recessive defect in its biosynthetic enzyme 6-pyruvoyltetrahydropterin synthase (PTPS, encoded by the PTS gene) leads to a variant form of hyperphenylalaninemia concomitant with severe deficiency of brain monoamine neurotransmitters. In contrast, augmentation of BH4 by pharmacological supplementation or stimulation of its biosynthesis is thought to correct eNOS dysfunction, to protect from (cardio) vascular disease and/or to prevent from abdominal obesity and development of the metabolic syndrome. We have previously reported that complete Pts knock-out (ko) mice die after birth (Elzaouk et al JBC 2003). Here we generated a murine Pts-knock-in (ki) allele expressing a PTPS-p.Arg15Cys mutant enzyme with low residual activity (12% of wild-type in vitro) and investigated heterozygous Pts-ko/wt, homozygous Pts-ki/ki and compound heterozygous Pts-ki/ko mutant mice. All mice were viable and, depending on the severity of the Pts alleles, exhibited up to 90% reduction of PTPS activity in liver and brain tissues concomitant with high neopterin, but neither an elevation of blood L-Phe, nor a decrease in brain monoamine neurotransmitters dopamine or serotonin. Upon a standard systemic and comprehensive phenotyping of Pts-ki/ki mice, we found alterations in energy metabolites with reduced body mass, higher fat content, lower lean mass, and increased blood glucose and cholesterol in mutant animals. Furthermore, heterozygous Pts-ko/wt and/or homozygous Pts-ki/ki mice exhibited increased body weight and elevated intra-abdominal fat tissue when fed with normal chow or high fat diet. We conclude that a reduced BH4-biosynthetic activity in mice leads to abnormal body fat distribution and abdominal obesity potentially through a mildly compromised eNOS function.

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Determinants of body fat distribution in humans may provide insight about obesity-related health risks.

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Determinants of body fat distribution in humans may provide insight about obesity-related health risks.

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