Females have greater susceptibility than males to increased body fat content under a high-fat, high-sugar diet, a study in mice shows.
This gender-specific effect is mediated by increased activation of mitochondrial pathways in adipose tissue, researchers found.
The results were described in a study, “Gene-by-Sex Interactions in Mitochondrial Functions and Cardio-Metabolic Traits,” published in the journal Cell Metabolism.
Gender-specific differences in susceptibility to obesity, insulin resistance, and other cardio-metabolic disorders have been widely described in mice, humans, and other species.
Sex hormones, as well as chromosome complement elements, can play an important role in the regulation of gene levels across different tissues, including adipose tissue, liver, and brain. In addition, their impact can be permanent or reversible, which may suggest that modulation of gender effects may represent an alternative strategy to therapeutically regulate tissues’ responses.
An international research team explored the impact of gender in over 50 cardio-metabolic traits — including obesity, insulin resistance, and fatty liver disease — using a panel of more than 100 different strains of mice.
Mice were fed a high-fat, high-sugar diet for 8 weeks in order to mimic a typical western diet, which is known to contribute to the development of metabolic disorders.
Results showed that such a diet induced four main alterations in the animals: blood-related changes (including blood cell counts and percentages), body mass increases, food intake changes (behavioral changes), and changes in metabolic parameters (such as sugar and insulin measures).
Overall, with the exception of a specific type of blood cell (granulocytes), blood-related changes showed no significant differences between genders.
In turn, as researchers expected, sex had a profound impact on all body mass-related manifestations, such as organ weight, lean and fat mass, and growth, which could mostly be attributed to differences in body size. Once corrected for body size, however, these differences were no longer significant.
Also, although body fat increase and weight gain were similar between males and females, food intake was found to be significantly higher among females, suggesting differences in basic energy expenditure between genders.
To further explore the role of gender in cardio-metabolic regulation, the team analyzed the levels of 8,673 genes in adipose tissue, and 7,235 genes in the livers of mice.
This analysis revealed the activation of specific signaling pathways involving mitochondria (the cell’s powerhouses), in particular in female adipose tissue. This finding is consistent with the hypothesis that females may have increased energy expenditure.
Still, the team found that the observed changes are not only mediated by gender, but also the result of an interaction between gender and the genetic background of mice. To explore this relationship, the team analyzed the levels of Lyplal1 gene in both male and female mice. Of note, the Lyplal1 gene has been implicated in increased susceptibility for obesity in humans.
Female mice were found to have higher adipose Lyplal1 levels than males. Also, females, but not males, showed a significant negative correlation between adipose Lyplal1 levels and body fat percentage after two weeks of a high-fat/high-sugar diet.
Next, the team used mice that had been genetically engineered to lack the Lyplal1 gene, and fed them the same high-fat, high-sugar diet used before. After two weeks, females lacking Lyplal1 showed a significantly higher body fat percentage growth than both control mice and mice with some levels of the Lyplal1 gene. This effect was not seen in male mice.
“These observations indicate that Lyplal1 has a protective effect uniquely in females against the fat mass gain in response to switching to a high-fat/high-sugar diet,” researchers stated.
Supported by these findings, the researchers performed gonadectomies (removal of the glands responsible for the release of sex hormones) in mice to evaluate the impact of sex hormones in this gender-specific metabolic regulation.
They found that sex hormones had a significant effect on regulating the levels of genes in the liver, but had no significant effect on adipose tissue. Treatment with hormone replacement therapy could reverse the effect of the gonadectomy in the livers of male mice.
Overall, the team concluded that sex — depending on the genetic background — plays a role in gene expression and the development of cardio-metabolic traits, and that the Lyplal1 is a sex-specific obesity gene.
“In the reference literature there are already indications of major differences in adipose biology between sexes also in humans,” Susanna Hofmann, MD, researcher at the German Center for Diabetes Research (DZD) and one of the authors of the study, said in a news release.
“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,” Hofmann said.
Additional studies are still warranted to better understand the biology underlying these sex-specific differences.
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