• A lack of adequate expansion of blood vessels in response to the accumulation of excess energy as fat plays a role in the development of obesity and metabolic disorders.
• Research shows that female mice tend to show greater levels of growth of blood vessels in adipose (fat) tissue, and better metabolic health than males in response to a high-fat diet.
• Endothelial cells form the inner lining of blood vessels and play a critical role in the growth of new blood vessels.
• A recent study found that endothelial cells from male adipose tissue showed greater expression of inflammation-related genes, but lower levels of cell proliferation genes than those from females in response to the accumulation of body fat.
• These results suggest that sex differences in adipose endothelial cell behavior could explain, in part, the greater risk of obesity-related complications in males.

Women show differences in the distribution and function of adipose tissue than men and are at a lower risk of obesity-related disorders.

A recent study also showed that female mice show greater levels of blood vessel growth in adipose tissue and maintain better metabolic health than males in response to the accumulation of body fat.

A new study published in iScience compared the differences in gene expression patterns of adipose tissue endothelial cells obtained from male and female mice with obesity.

The study found that endothelial cells from the adipose tissue of males with obesity expressed higher levels of inflammation-associated genes, whereas those from female mice showed increased expression of cell proliferation-related genes.

These results could potentially contribute to the understanding of the mechanisms underlying sex differences in the development of obesity and related conditions.

Sex differences and heart health risk

The study’s lead author, Dr. Tara Haas, a professor of molecular biology and biochemistry at York University in Canada, explained for Medical News Today:

“We show in this study that male and female endothelial cells — these are the cells that compose blood vessels — from mice respond differently to the stress of a long-term high-fat diet. We found that endothelial cells in females displayed signals to grow and divide, but endothelial cells in males showed evidence of inflammation.”

“By identifying which specific genes that are controlled differently in the male and female endothelial cells, we can begin to understand what signals enable healthy endothelial cell function in females,” added Dr. Haas. “This knowledge can be used to design treatments that can improve the overall health of obese males and females by improving blood vessel health.”

Dr. Silvia Corvera, a professor in the Program in Molecular Medicine at the University of Massachusetts Medical School, not involved in this study, also noted that “[w]hile the precise reasons for [the sex differences in susceptibility to metabolic diseases] are unknown, they are associated with the distribution and function of adipose tissue within the body.”

“Adipose tissue is highly vascularized, and its function is greatly affected by the characteristics of its blood vessels,” she explained.

“Endothelial cells are the main components of blood vessels, so finding that they express different genes between male and female mice provides a clue as to why adipose tissue also differs and how these differences might influence disease risk,” said Dr. Corvera.

The importance of blood vessel formation

Tissue growth requires the growth of new blood vessels to meet the increased demand for oxygen and nutrients. This process of the generation of new blood vessels from pre-existing blood vessels is known as angiogenesis.

Endothelial cells that form the inner lining of the blood vessels play an important role in coordinating the process of angiogenesis.

Endothelial cells also influence energy balance by regulating the exchange of oxygen, nutrients, and other molecules between the blood vessels and their surroundings. More recently, studies have shown that endothelial cells can also modulate the inflammatory response.

The consumption of excess calories leads to their accumulation as white adipose tissue, which stores energy as fat. Similar to other tissues, the accumulation of white adipose tissue is accompanied by angiogenesis during the early stages.

Blood vessel formation in obesity

However, studies have shown that more pronounced levels of accumulation of white adipose tissue in obesity are accompanied by inadequate growth of blood vessels and impaired functioning of endothelial cells.

The inadequate growth of blood vessels and subsequent lack of sufficient oxygen can lead to stress and inflammation in the adipose tissue.

Moreover, impaired angiogenesis can hinder the ability of the adipose tissue to store excess energy and cause imbalances in the metabolism of the entire body.

The role of angiogenesis in obesity is underscored by evidence showing that increasing the growth of blood vessels can counteract the negative effects associated with excess accumulation of fat.

A recent study revealed that female mice show greater proliferation of blood vessels than males in response to fat accumulation.

Fat accumulation due to the mice being fed a high-fat diet resulted in impaired adipose tissue function in male but not female mice.

These findings are consistent with studies showing sex differences in adipose tissue function and distribution and the risk of cardiometabolic conditions.

Previous studies have found at least some of the sex differences in the gene expression profile of endothelial cells may be present from early developmental stages.

Given the role of endothelial cells in angiogenesis, the new study’s authors examined how sex differences in endothelial cell function could potentially explain the different patterns of angiogenesis in response to accumulating fat.

Differences in gene expression patterns

In the present study, the researchers maintained 7-week-old male and female mice on a high-fat diet for 7 weeks. After 7 weeks, the researchers isolated endothelial cells from the white adipose tissue of these animals to identify the genes that were differentially expressed in male and female endothelial cells.

The endothelial cells from the female mice fed a high-fat diet showed elevated expression of genes associated with the proliferation of endothelial tissue compared with male mice.

In contrast, genes associated with a proinflammatory state were elevated in the adipose endothelial cells of male mice maintained on a high-fat diet.

Using a stain to label proliferating cells, the researchers found that female mice showed higher levels of cell proliferation markers in adipose endothelial cells than male mice, confirming the sex differences observed in the gene expression profile.

The adipose endothelial cells from female mice also showed higher expression of genes involved in oxidative phosphorylation in response to the high-fat diet.

Fatty acids in the cell are broken down via the oxidative phosphorylation pathway to release energy, and the upregulation of the genes involved in this pathway could help meet the energetic costs associated with an increase in cell proliferation.

Inflammatory state and cellular aging

The gene expression profile in male mice suggested an increase in inflammation in the adipose endothelial cells in response to the high-fat diet. Such a state of increased inflammation is associated with cellular senescence (aging), a phenomenon involving the permanent cessation of cell proliferation in response to stress or aging.

Senescent cells secrete several immune molecules, growth factors, and enzymes that produce a proinflammatory state in the immediate tissue environment. This response of senescent cells is known as the senescence-associated secretory phenotype (SASP).

The researchers found that adipose endothelial cells of male mice on a high-fat diet showed higher expression of genes associated with senescence, including SASP-related genes.

Furthermore, adipose tissue from male and female mice on a high-fat diet did not differ in the expression of the genes for the cytokines TNF-alpha and IL-1beta, which are proteins involved in mediating a pro-inflammatory response.

This means that these cytokines in the adipose tissue were not responsible for the increased expression of pro-inflammatory genes by the adipose endothelial cells of male mice maintained on a high-fat diet.

The authors think that the inflammatory state observed in male mice could result in the upregulation of molecules that suppress angiogenesis and cause cellular senescence.

The lower levels of angiogenesis could then lead to adipose tissue dysfunction observed in male mice. The higher expression levels of cell proliferation-related genes may suggest that females are more resilient to stress associated with following a prolonged high-fat diet.

Factors mediating sex differences

The researchers then examined whether differences in the expression of molecules that can modulate angiogenesis in the surrounding adipose tissue could explain the diet-induced sex differences in endothelial tissue gene expression profiles.

Male and female mice did not differentially express genes for the vascular endothelial growth factors VEGF-A and VEGF-B, which play a critical role in endothelial cell proliferation.

Previous studies have shown that the hormone leptin — which plays a role in regulating the sensation of hunger — increases angiogenesis. However, in the present study, the researchers found that males expressed higher levels of the leptin gene.

This suggests that the sex differences in angiogenesis in response to the high-fat diet were not mediated by leptin.

Analysis of the potential transcription factors, the molecules that regulate gene transcription, also suggested that estrogen was unlikely to mediate the sex differences in gene expression in adipose endothelial cells.

Moreover, adipose endothelial cells from healthy female mice showed greater levels of proliferation when cultured in the laboratory than those from male mice.

These results suggest that the sex differences in adipose endothelial cells were likely intrinsic and were not influenced by the surrounding adipose tissue.

Dr. Haas notes that “[e]ven when we take them out of the body where they don’t have the circulating sex hormones or other kinds of factors, male and female endothelial cells still behave very differently from each other.”

Differences in immune-related genes

The researchers cultured endothelial cells from male and female mice that were not exposed to the high-fat diet in the laboratory to examine the differences in the expression of immune-related genes.

The adipose endothelial cells from male mice showed greater expression of specific immune-related genes at baseline. Moreover, TNF-alpha exposure induced a more pronounced expression of specific inflammation-associated genes.

These findings show that even isolated endothelial cells from healthy male mice cultured in the laboratory show a modestly greater expression of immune-related genes and are more responsive to an inflammatory stimulus.

Thus, adipose endothelial cells from male mice may be more sensitive to the stress caused by fat accumulation.

The researchers found similar sex differences when comparing the gene expression profile of adipose endothelial cells with female and male mice maintained on a high-fat diet with public datasets on endothelial cell gene expression from aged mice.

Specifically, the male mice on a high-fat diet and older male mice showed a similar elevation in the expression of genes associated with inflammation, whereas those on a high-fat diet and aged female mice showed increased expression of proliferation-related genes.

This suggests that a high-fat diet and aging could have a similar impact on male endothelial cells.

Dr. Haas said that “these distinctions in male and female endothelial cell gene profiles were seen in aging mice, which suggests an overall resilience of female blood vessels that keeps them healthier than male blood vessels over an individual’s lifespan.”

What are the implications?

Dr. Haas emphasizes:

“You can’t make the assumption that both sexes are going to respond to the same series of events the same way. This isn’t just an obesity-related issue — I think it’s a much broader conceptual problem that also encompasses healthy aging.”

There are important differences between males and females in their susceptibility to metabolic diseases such as type 2 diabetes, fatty liver disease, and cardiovascular disease.

Adipose tissue is highly vascularized, and its function is greatly affected by the characteristics of its blood vessels.

Endothelial cells are the main components of blood vessels, so finding that they express different genes between male and female mice provides a clue as to why adipose tissue also differs and how these differences might influence disease risk.

“In general, it is important to recognize that male and female cells behave in distinctively different ways because this suggests that they will respond differently to therapies, which can have an impact on determining which treatments are going to be the best option for an individual,” said Dr. Haas.

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