The risk of developing diseases such as cardiovascular and metabolic diseases has been linked with where in our bodies we tend to accumulate fat. A large-scale genome-wide association study carried out by researchers at Uppsala University has now identified dozens of genetic factors that influence the distribution of fat, and found that genetic effects are more strongly associated with fat accumulation in women than in men.

Reporting their findings in Nature Communications, the Uppsala University scientists say that greater insights into the genetic factors and biological mechanisms that are involved in directing body fat distribution could help scientists to identify new approaches to preventing or treating obesity-related diseases. “The biological systems we highlight in our study have the potential to be used as points-of-intervention for new drugs that are aimed at improving the distribution of body fat and thereby reducing the risk of disease,” commented corresponding author Mathias Rask-Andersen, PhD, a researcher at the department of immunology, genetics and pathology, Uppsala University. The team’s paper is titled “Genome-wide association study of body fat distribution identifies adiposity loci and sex-specific genetic effects.”

More than 40% of the world’s population is now overweight, and 10.8% of people are obese, the authors wrote. “Obesity is set to become the world’s leading preventable risk factor for disease and early death due to increased risks of developing type 2 diabetes, cardiovascular disease, and cancer.”

After puberty, men and women tend to accumulate fat within different body compartments. Women commonly put on fat in their trunk and limbs more than in other parts of the body, whereas men tend to lay down most of their fat in the trunk, the researchers noted. Epidemiological evidence has suggested that the distribution of body fat within different body compartments is also associated with differential risks for developing cardiovascular and metabolic disorders.

The ability to store fat around the hips and legs is believed to give women some protection against cardiovascular disease, whereas men have more abdominal fat than women, which is thought to be at least in part explain the increased prevalence of cardiovascular disease in men. “… the preferential accumulation of adipose tissue in the lower extremities, i.e., the hips and legs, has been suggested as a factor contributing to the lower incidence of myocardial infarction and coronary death observed in women during middle age,” the team noted. And while sex-related differences in fat accumulation have been linked with the downstream activity of sex hormones, “… the biological mechanisms that underlie body fat distribution have not been fully elucidated.”

“We know that women and men tend to store fat differently—women have the ability to more easily store fat on the hips and legs, while men tend to accumulate fat around the abdomen to a higher extent,” commented Rask-Andersen. “This has been attributed to the effects of sex hormones such as estrogen. But the molecular mechanisms that control this phenomenon are fairly unknown.”

The team looked for genetic factors that might influence what fraction of total fat mass is accumulated in the arms, legs, and trunks of men and women. The Uppsala University team leveraged data from 362,499 participants in the UK Biobank cohort, to carry out a genome-wide association study to link genetic factors with body fat distribution to the trunk, arms, and legs. Fat measurements had been estimated in each participant using a technique known as segmental bioelectrical impedance analysis (BIA). The team’s analyses, which tested millions of different genetic variants, were also designed to identify genetic effects that were different between men and women.

The analyses identified 98 independent genetic signals that were associated with body fat distribution, including 29 that hadn’t previously been linked with fat-related phenotypes. Genetic associations also strongly differed between the sexes, “… in particular for distribution of adipose tissue to the legs and trunk where effects are primarily observed in females,” the authors wrote. “We were struck by the large number of genetic effects that were stronger, or only present, in females,” commented research lead Åsa Johansson, PhD.

A closer look at the genes identified in women suggested that body fat distribution to the trunk and legs in females involves mesenchyme-derived tissues and cell types, as well as factors involved in extracellular matrix modeling, and female endocrine tissues. “Upon closer examination, several of the associated genes were found to encode proteins that actively shape the extracellular matrix, which makes up the supporting structure around cells,” Johansson noted.

“This suggests that the distribution of fat to the legs and trunk in females is mainly driven by the effects of female gonadal hormones on mesenchymal progenitors of musculoskeletal and adipose tissue,” the authors stated. “Resolving the genetic determinants and mechanisms that lead to a favorable distribution of body fat may help in risk assessment and in identifying novel venues for intervention to prevent or treat obesity-related diseases.”

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