The gene IRS1, which is linked to having less body fat, also appears to be associated with having higher blood glucose and cholesterol levels, both key factors in heart disease and diabetes type 2 risk, researchers from the Medical Research Council, UK, reported in the journal Nature Genetics.

The scientists examined the genomes of over 75,000 individuals – they were seeking out genes that determine how much body fat we have. They found compelling evidence that the gene IRS1 is linked to lower levels of body fat.

They gathered data from 26 different genetic studies and liaised with researchers from 72 centers in 10 countries.

Dr. Ruth Loos, from the MRC (Medical Research Council) Epidemiology Unit and team set out to understand why a gene that keeps the body lean also raises the risk of metabolic disease. They examined fat distribution patterns in individuals who carry the IRS1 gene.

IRS1 does lower fat, but only subcutaneous fat – fat under the skin, and not visceral fat, the fat around organs.

The scientists suggest that individuals with the IRS1 gene may store fat in parts of the body that interfere with normal organ function because they are less able to store subcutaneous fat. This was found to be especially the case among males.

Dr Loos said:

“We’ve uncovered a truly fascinating genetic story and when we found the effect of this gene we were very intrigued by the unexpected finding. People, particularly men, with a specific form of the gene are more likely to be lean and to develop heart disease and type 2 diabetes. In simple terms, it is not only overweight individuals who can be predisposed for these metabolic diseases, and lean individuals shouldn’t make assumptions that they are healthy based on their appearance.

“What we’ve discovered is that certain genetic variants keep you lean by reducing how much fat you store under your skin. We don’t know for sure, but we can speculate that these individuals are then more predisposed to store fat elsewhere, such as in the liver and in muscle. The effect may be more pronounced in men due to the different body fat distributions between the sexes. Men store less fat than women, so they are more sensitive to changes in its distribution.

“Although our genetic make-up can help to determine whether we’re predisposed to certain diseases, we mustn’t forget that what we eat and how active we are also plays a vital role in maintaining good health.”

Director of the MRC Epidemiology Unit, Professor Nick Wareham, said:

“This is fantastic example of the MRC’s expertise in international collaborative research. The research will provide new insights into why not all lean people are healthy and, conversely, why not all overweight people are at risk of metabolic diseases. A better understanding of the links between body fat and risk of disease will help to develop more targeted treatments for these diseases, alongside recommended lifestyle changes.”

Dr. Kiel, a senior scientist at the Institute for Aging Research and a professor of medicine at Harvard Medical School, USA, who was also involved in this study, said:

“We’ve uncovered a truly fascinating genetic story and, when we found the effect of this gene, we were very intrigued by the unexpected finding. People, particularly men, with a specific form of the gene are both more likely to have lower percent body fat, but also to develop heart disease and type 2 diabetes. In simple terms, it is not only overweight individuals who can be predisposed for these metabolic diseases.”

“Genetic variation near IRS1 associates with reduced adiposity and an impaired metabolic profile”
Ruth J F Loos, Tuomas O Kilpeläinen, M Carola Zillikens, Alena Stančákova, Francis M Finucane, Janina S Ried, Claudia Langenberg, Weihua Zhang, Jacques S Beckmann, Jian’an Luan, Liesbeth Vandenput, Unnur Styrkarsdottir, Yanhua Zhou, Albert Vernon Smith, Jing-Hua Zhao, Najaf Amin, Sailaja Vedantam, So-Youn Shin, Talin Haritunians, Mao Fu, Mary F Feitosa, Meena Kumari, Bjarni V Halldorsson, Emmi Tikkanen, Massimo Mangino, Caroline Hayward et al
Nature Genetics (2011) doi:10.1038/ng.866

Written by Christian Nordqvist