Dataset Information

Regulatory variants at KLF14 influence type 2 diabetes risk via a female-specific effect on adipocyte size and body composition.

ABSTRACT: Individual risk of type 2 diabetes (T2D) is modified by perturbations to the mass, distribution and function of adipose tissue. To investigate the mechanisms underlying these associations, we explored the molecular, cellular and whole-body effects of T2D-associated alleles near KLF14. We show that KLF14 diabetes-risk alleles act in adipose tissue to reduce KLF14 expression and modulate, in trans, the expression of 385 genes. We demonstrate, in human cellular studies, that reduced KLF14 expression increases pre-adipocyte proliferation but disrupts lipogenesis, and in mice, that adipose tissue-specific deletion of Klf14 partially recapitulates the human phenotype of insulin resistance, dyslipidemia and T2D. We show that carriers of the KLF14 T2D risk allele shift body fat from gynoid stores to abdominal stores and display a marked increase in adipocyte cell size, and that these effects on fat distribution, and the T2D association, are female specific. The metabolic risk associated with variation at this imprinted locus depends on the sex both of the subject and of the parent from whom the risk allele derives.

SUBMITTER: Small KS

PROVIDER: S-EPMC5935235 | biostudies-literature | 2018 Apr

REPOSITORIES: biostudies-literature

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Regulatory variants at KLF14 influence type 2 diabetes risk via a female-specific effect on adipocyte size and body composition.

Small Kerrin S KS Todorčević Marijana M Civelek Mete M El-Sayed Moustafa Julia S JS Wang Xiao X Simon Michelle M MM Fernandez-Tajes Juan J Mahajan Anubha A Horikoshi Momoko M Hugill Alison A Glastonbury Craig A CA Quaye Lydia L Neville Matt J MJ Sethi Siddharth S Yon Marianne M Pan Calvin C Che Nam N Viñuela Ana A Tsai Pei-Chien PC Nag Abhishek A Buil Alfonso A Thorleifsson Gudmar G Raghavan Avanthi A Ding Qiurong Q Morris Andrew P AP Bell Jordana T JT Thorsteinsdottir Unnur U Stefansson Kari K Laakso Markku M Dahlman Ingrid I Arner Peter P Gloyn Anna L AL Musunuru Kiran K Lusis Aldons J AJ Cox Roger D RD Karpe Fredrik F McCarthy Mark I MI

Nature genetics 20180409 4

Individual risk of type 2 diabetes (T2D) is modified by perturbations to the mass, distribution and function of adipose tissue. To investigate the mechanisms underlying these associations, we explored the molecular, cellular and whole-body effects of T2D-associated alleles near KLF14. We show that KLF14 diabetes-risk alleles act in adipose tissue to reduce KLF14 expression and modulate, in trans, the expression of 385 genes. We demonstrate, in human cellular studies, that reduced KLF14 expressio ...[more]

PMID: 29632379

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Project description:Background and objectives: Childhood obesity is one of the main public health issues facing advanced societies. The Spanish population presents 28.6% overweight or obese adolescents, and Extremadura, 22.3%. Physical fitness is considered one of the most important health markers and a common predictor of morbidity and mortality caused by cardiovascular diseases. Thus, fitness tests are needed for health monitoring, especially in overweight and obese adolescents. Therefore, this study aimed to explore the relationship between body composition and physical fitness in adolescents and to analyse if there are differences in physical condition and body composition between the sexes, as well as to compare the different body mass index (BMI) categories to each other. This project also tried to find regression equations to predict the physical fitness test results. Materials and Methods: A total of 225 adolescents were recruited. Weight status was classified according to WHO 2007 standards. Body composition variables (i.e., BMI, fat mass (FM), FM percentage (FM%), and fat-free mass (FFM)) and physical fitness (standing long jump (SLJ), speed-agility (SA), cardiorespiratory fitness (CF), and handgrip strength (HS)) were assessed. Results: Significant differences were found between the sexes in body composition (FM%, FM, and FFM) and physical fitness (SLJ, SA, CF, and HS) (p < 0.001) in favour of males. Significant differences were also found in speed (p = 0.002), CF (p < 0.001), and SLJ (p = 0.004) in favour of normal-weight adolescents compared to overweight and obese adolescents. Contrarily, the outcomes revealed a significantly greater HS (p = 0.014) in favour of overweight and obese participants compared to normal-weight adolescents. Moreover, the results showed that CF and SLJ correlated inversely with BMI, FM%, and total FM. There was also a direct relationship between SA and FM percentage, as well as between HS and FFM. Finally, four fitness test predictive models are proposed based on body composition, age, sex, and BMI. Conclusions: Overweight and obese adolescents have lower levels of physical fitness than their normal-weight peers, regardless of their sex. Normal-ranged body composition values are related to a greater physical fitness in adolescents. Furthermore, this study presents several equations that can help to predict the performance of different fitness tests in adolescents.

Dataset Information

Regulatory variants at KLF14 influence type 2 diabetes risk via a female-specific effect on adipocyte size and body composition.

Publications

Regulatory variants at KLF14 influence type 2 diabetes risk via a female-specific effect on adipocyte size and body composition.

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