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The Lypla1 Gene Impacts Obesity in a Gender-Specific Manner

An international research team studied gender differences and gender-specific interaction with the genetic background in cardio-metabolic phenotypes.

Susceptibility to obesity, insulin resistance and other cardio-metabolic traits may also be dependent on a person's gender. An international research team of the University of California (UCLA), Helmholtz Zentrum München, a partner of the DZD, and Ludwig-Maximilians-Universität München studied gender differences and gender-specific interaction with the genetic background in cardio-metabolic phenotypes. The researchers discovered, among other things, a gender-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 gender 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 gender-specific differences in 50 cardio-metabolic traits. The effect of gender on cardio-metabolic traits was investigated in terms of gender-specific correlations with specific disease phenotypes, their genetic architecture and the underlying expression networks in fat and liver. It was found that gender -- depending on the genetic background -- plays a role in gene expression and the development of cardio-metabolic traits. The research team discovered a gender-specific obesity locus for the Lyplal1 gene.

"In addition, we were able to show that there is gender-specific regulation for the "beiging" of white adipose tissue* and gender-specific interactions for mitochondrial function," said UCLA Professor Aldons J. Lusis, last author and head 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 gender 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 genders also in humans. This study provides insights into the depth and breadth of gender 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 DZD researcher Professor Susanna Hofmann, MD of the Institute for Diabetes and Regenerative Research of the Helmholtz Diabetes Center. Her group, together with Professor Axel Walch from the Core Facility Pathology & Tissue Analytics at Helmholtz Zentrum München, examined the adipose tissue and analyzed the gender differences in the browning of white adipose tissue.

There are still many gaps in our understanding of the biology underlying these gender-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 ''gender-ome'') at system level.

Such a model will require identifying the primary and downstream gender-biased factors that act on the network and understanding how the gender-biased network interactions give rise to gender differences in the emergent phenotypes.

*Beiging (browning)

Brown adipose tissue can produce heat through the oxidation of fatty acids. This takes place in numerous mitochondria, which are also responsible for the brownish coloration of the tissue. If the "good" brown fat is activated, the metabolism is stimulated and the "bad" white fat deposits are reduced. The occurrence of brown or beige adipocytes in white adipose tissue is called browning or beiging, a phenomenon associated with increased energy consumption and, at least in the mouse model, with protection against obesity.

Illustration: The development of cardio-metabolic traits such as obesity and insulin resistance may also depend on gender. Source: HMGU.

Read more...

German Center for Diabetes Research (DZD) News Release (02/14/19)

Science Daily (02/15/19)

Abstract (Cell Metabolism, 2019.)