Sex specific obesity gene identified!

Susceptibility to obesity, insulin resistance and other cardio-metabolic traits may also be dependent on a person's sex. An international research team studied sex differences and sex-specific interaction with the genetic background in cardio-metabolic phenotypes. The researchers discovered, among other things, a sex-specific obesity locus of the Lypla1 gene, which is associated with human obesity. The results of the study have now been published in Cell Metabolism.

Men and women may be differently susceptible to obesity, insulin resistance, and other cardio-metabolic traits. Women often have more advantageous metabolic profiles. This has been described for mice but also for humans. But how does sex interact with genes? What role does natural genetic variance play? And how does this affect the development of cardio-metabolic traits?

In order to answer these questions, an international team of researchers used an animal model (hybrid mouse diversity panel) to search for sex-specific differences in 50 cardio-metabolic traits. The effect of sex on cardio-metabolic traits was investigated in terms of sex-specific correlations with specific disease phenotypes, their genetic architecture and the underlying expression networks in fat and liver. It was found that sex - depending on the genetic background - plays a role in gene expression and the development of cardio-metabolic traits. The research team discovered a sex-specific obesity locus for the Lyplal1 gene.

"In addition, we were able to show that there is sex-specific regulation for the "beiging" of white adipose tissue and sex-specific interactions for mitochondrial function," said the senior author of the study. The study showed that females have a higher mitochondrial activity and produce more brown adipose tissue ("beiging"). This reduces fat mass and insulin resistance. In males, the interaction between genes and sex tends to lead to low mitochondrial activity and low beiging. Weight and insulin resistance increase.

"In the reference literature there are already indications of major differences in adipose biology between sexes also in humans. This study provides insights into the depth and breadth of sex differences in metabolism. We believe that our results provide compelling evidence as to why males and females in biological research should be treated as distinct organisms as a whole, rather than attempting to reconcile these differences one molecule at a time," said another author.

There are still many gaps in our understanding of the biology underlying these sex-specific differences. As a long-term goal, the researchers therefore want to develop a biological network model that describes the differences between men and women (the ''sex-ome'') at system level. Such a model will require identifying the primary and downstream sex-biased factors that act on the network and understanding how the sex-biased network interactions give rise to sex differences in the emergent phenotypes.