Summary: KLF14, a gene associated body shape in women, can increase the risk of developing type 2 diabetes if the variant of the gene forces fat storage around the abdomen.
Source: King’s College London.
Scientists at King’s College London have identified a gene that in women is linked to the creation and location of new fat cells and therefore is thought to contribute to the risk of type 2 diabetes.
Published in Nature Genetics, the paper examined the effect of a gene called KLF14. The researchers found that genetic variations that control KLF14 were associated with where in the body excess fat was stored. In women, versions of the gene that result in fat being stored around the hips, rather than the abdomen, were linked to a lower risk of diabetes.
The gene does not have an effect on overall weight but different variations of KLF14 were also related to the development and size of fat cells. Women with variations of the gene linked to the deposit of fat around the abdomen had fewer, larger fat cells which are less efficient. This means that the body’s sensitivity to insulin is decreased and therefore suggests that carriers of this variation of the gene are more at risk of diabetes.
The study, which was an international collaboration with the University of Oxford, MRC Harwell, University of California in Los Angeles, University of Pennsylvania and others, also showed that the effects of these gene variations were specific to females. This variant of the KLF14 gene is thought to be one of the strongest known genetic risk factors for type 2 diabetes in females. Only the version of the gene inherited from an individual’s mother is active – the father’s version is silent. Women who inherited the risk version of the gene from their mother had around a 30 per cent higher risk of diabetes than those without the risk version of the gene.
The researchers undertook analysis of biopsy and blood samples taken from 856 female participants from the TwinsUK cohort alongside fat biopsies from the Oxford BioBank and genetic data from the UK Biobank. The team also confirmed some of the findings in mouse models of the KLF14 variant although these models did not show the same female specific effects shown in human cell models.
The findings provide new insight in to a large genetic network involved in the mechanism of diabetes risk. It is hoped that this understanding may lead to better preventative measures and improved health advice in the future
Dr Kerrin Small, lead author of the study from the Department of Twin Research and Genetic Epidemiology said: ‘These findings provide one of the most complete understandings of a piece of genetic data – we have studied the type 2 diabetes associated version of the KLF14 gene to the point that we understand not only where and how it acts in the body but also who it acts in – women who inherit the diabetes associated version of the gene from their mother.
‘We hope that by building on these findings with further research to try and understand why the gene variant only affects diabetes risk in women that we can contribute towards better treatment plans and prevention and move towards more personalised approaches to medicine.’
Professor Mark McCarthy, another lead author, from the University of Oxford said: ‘Being over-weight is known to increase the risk of type 2 diabetes, but this study shows that not all fat is equal: where any excess fat is stored in the body has a big impact on disease risk. Here we identify a key gene involved in women in determining whether excess fat is stored around the hips (where it tends to be free of metabolic consequences) or around the waist (where it is particularly likely to increase diabetes risk).
Rather that assuming that genetic variations exert their effects in the same way in different people, our new work highlights the importance of taking a ‘holistic’ approach to understanding the causes of disease, interrogating how genes function in different tissues and in different sexes.’
Source: Hannah Pluthero – King’s College London
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Image Source: NeuroscienceNews.com image is adapted from the King’s College London news release.
Original Research: Abstract for “Regulatory variants at KLF14 influence type 2 diabetes risk via a female-specific effect on adipocyte size and body composition” by Kerrin S. Small, Marijana Todorčević, Mete Civelek, Julia S. El-Sayed Moustafa, Xiao Wang, Michelle M. Simon, Juan Fernandez-Tajes, Anubha Mahajan, Momoko Horikoshi, Alison Hugill, Craig A. Glastonbury, Lydia Quaye, Matt J. Neville, Siddharth Sethi, Marianne Yon, Calvin Pan, Nam Che, Ana Viñuela, Pei-Chien Tsai, Abhishek Nag, Alfonso Buil, Gudmar Thorleifsson, Avanthi Raghavan, Qiurong Ding, Andrew P. Morris, Jordana T. Bell, Unnur Thorsteinsdottir, Kari Stefansson, Markku Laakso, Ingrid Dahlman, Peter Arner, Anna L. Gloyn, Kiran Musunuru, Aldons J. Lusis, Roger D. Cox, Fredrik Karpe & Mark I. McCarthy in Nature Genetics. Published April 9 2018.
Regulatory variants at KLF14 influence type 2 diabetes risk via a female-specific effect on adipocyte size and body composition
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.