The study theorized that men and women antagonized in a tradeoff between immunity and metabolism in the liver. This helped males fight off bacterial infections from wounds obtained in dominance fights, while females were able to store subcutaneous fat to survive when food was scarce.
Working in mice, the scientists characterize the activity of a signaling pathway that regulates lipid, fat deposits in the liver in males and the release of it into the bloodstream in females. This pathway also responds to growth hormone.
This phenomenon may have shaped male biology in ways that pose risks in today’s high-calorie environment. The findings are of particular relevance to fatty liver, which affects a quarter of the US population.
It is seen primarily in men until women reach menopause.” Scientists have only recently begun to understand that these are the profound differences between men and women,” says Holly Ingraham, PhD, Herzstein Professor of Molecular Physiology at UCSF and co-senior author. The study, which appears in Science on October 21, 2022.
Understanding these differences is going to be the key to unlocking therapeutics for sexually-biased diseases. Fatty liver is an example. Experiments found that male mice were three times more likely to survive infection with E. coli bacteria than females.
Women developed hyperlipidemia, a condition also seen in humans with severe sepsis. Lowering their lipid levels helped them survive. The investigators then examined how male and female rats responded to the contemporary environmental challenge of overeating by feeding them high-fat chow.
The men developed fatty liver and glucose intolerance, which can lead to type 2 diabetes, but the women did not. This was true even when men and women were of the same weight.
Searching the literature for something that could explain this, the team identified a transcription factor called BCL6, which inhibits the breakdown of fat in the liver and is highly present in male mice. Deleting the gene for this protein leads to the loss of liver fat in males, as well as their ability to ward off infection.
“Host defense programs in the liver are predisposing factors driving fatty liver in men,” said Joni Nikanan, a postdoctoral fellow in the Department of Cellular Molecular Pharmacology, who began the work with co-senior author Ajay Chawla, PhD, first of UCSF and now of UCSF. At Merck Research Labs.
“We have an evolutionary view of why such programs have evolved — because they protect males from bacterial infections,” he said. “But in another context, these same programs are no longer good for you, and you will develop more severe fatty liver.”
The team also examined how the presence of BCL6 affected gene expression in the liver. This process begins at puberty when men produce more testosterone, and their pituitary glands begin to secrete growth hormone in sharp peaks and valleys. These intermittent bursts, potentially controlled by testosterone, are important.
When the researchers continuously infected male mice with growth hormone, similar to the way it is secreted in females, BCL6 disappeared from their livers, and they lost their ability to fight off E. coli infections.
The results point to growth hormone as a potential therapy for adults with fatty liver disease, an idea that is currently being tested. Its effects are already well established in children whose pituitary gland does not produce enough growth hormone. Male children in particular have a tendency to develop fatty liver, but this goes away when they are given growth hormones to treat their short stature.
This work also expands the scientific approach to how the body fights infection to include organs such as the liver.” The battle is still between infection and the immune system,” says Omar Gökkumen, PhD, an evolutionary anthropologist at the University of Buffalo and said a co-author of the study. “But the liver is determining the battlefield.”