Why females may be less likely to experience brain inflammation than males

  • Males show greater susceptibility to obesity-related cardiovascular and metabolic comorbidities than females.
  • Males also tend to store a greater amount of fat as visceral fat around the abdomen, whereas females store excess energy in fat depots under the skin, referred to as subcutaneous fat.
  • A recent animal study suggests that subcutaneous adipose tissue could help protect female mice from the inflammatory effects associated with obesity.

A recent study in mice shows that obesity induced by feeding a high-fat diet led to an increase in inflammation in the adipose (fat) tissue and brain of male mice.

In contrast, female mice were less susceptible to the pro-inflammatory effects of the high-fat diet.

However, surgical removal of subcutaneous fat in female mice before the initiation of a high-fat diet led to an increase in inflammation similar to that observed in obese male mice.

Thus, the study published in the journal Diabetes shows that subcutaneous fat could protect females from the pro-inflammatory effects associated with obesity.

Brain inflammation is linked with a higher risk of issues like dementia and cardiovascular events.

The results of the recent study suggest that sex differences associated with obesity may arise due to the difference in the distribution of body fat.

Study author Dr. Alexis Stranahan, a neuroscientist at the Medical College of Georgia at Augusta University, comments that:

“When people think about protection [against brain inflammation] in women, their first thought is estrogen. But we need to get beyond the kind of simplistic idea that every sex difference involves hormone differences and hormone exposure. We need to really think more deeply about the underlying mechanisms for sex differences so that we can treat them and acknowledge the role that sex plays in different clinical outcomes.”

Most of the fat in the body is either stored as subcutaneous or visceral adipose tissue. Subcutaneous adipose tissue is located under the skin, whereas visceral adipose tissue is the fat that surrounds internal organs in the abdominal cavity.

Intra-abdominal or visceral fat accumulation, instead of subcutaneous fat, is associated with an increased risk of cardiovascular diseases and insulin resistance.

Obesity in males is characterized primarily by the accumulation of excess calories as visceral adipose tissue, whereas premenopausal females tend to accumulate excess fat as both visceral and subcutaneous fat.

Studies suggest that subcutaneous fat accumulation in women could protect against obesity-associated metabolic and cardiovascular risks.

The lower risk of cardiometabolic comorbidities is often attributed to sex hormones. Yet, as Dr. Stranahan told Medical News Today, “[m]ost of what we know about relationships between sex hormones, metabolism, and immunity comes from surgical removal of reproductive organs — ovariectomy in mice, hysterectomy in humans.”

“However, rapid-onset hormonal disruption after surgery does not always have the same effect as gradual functional deficits with aging or obesity,” she pointed out.

“In the preclinical literature, most studies do not directly measure sex hormones because they are difficult to detect in low-volume rodent samples. There was general agreement that females are less susceptible to obesity-induced metabolic pathology — such as insulin resistance — and estrogens were often assumed to mediate these effects,” added Dr. Stranahan.

In the present study, the researchers further examined the association between changes in sex hormones and the development of obesity-associated comorbidities.

Storage of excess calories as fat is associated with inflammation of the adipose tissue. This inflammatory response is causally related to the metabolic dysfunction associated with obesity.

The adipose tissue can release inflammatory proteins, such as cytokines and chemokines, that lead to systemic inflammation and potentially induce inflammation in the brain.

In obese animals, the changes in the adipose tissue cause the activation of immune cells, such as macrophages, which also secrete pro-inflammatory cytokines. Activated macrophages can subsequently infiltrate other tissues, including the brain, and activate an immune response.

The hypothalamus area of the brain is involved in the regulation of energy balance, and is modulated by hormones released by the adipose tissue.

Previous studies have shown increased levels of macrophages and activated microglia, the primary immune cells in the brain, in the hypothalamus of obese male, but not female mice. These activated microglia can modulate the activity of the hypothalamus and energy balance, resulting in body weight gain.

Currently, there is a lack of animal studies examining the development of hormonal, metabolic, and immune changes during obesity.

Besides examining these factors during the progression of obesity, the present study’s authors also examined the protective effects of subcutaneous adipose tissue on obesity-associated symptoms.

A common method used for inducing obesity in rodents in the laboratory involves feeding them a high-fat diet over a sustained period. In the initial phase of the study, the researchers characterized the sequential changes in adipose tissue, immunity, and sex hormones in mice maintained on a high-fat diet.

The researchers fed 8-week-old (young adult) female and male mice a high-fat diet for 48 weeks. The researchers examined differences in fat distribution, inflammation, and sex hormone levels at 12 weeks, 24 weeks, and/ or 48 weeks.

Male and female mice experienced similar levels of weight gain during the study. At the onset of the experiment, female mice had lower levels of visceral fat than males.

As the experiment progressed, the levels of visceral fat increased in females, and sex differences in the levels of visceral fat were no longer present by 12 weeks.

An expansion of the size of the adipocytes is associated with an increase in inflammation observed in obesity. In the present study, the size of the cells in visceral adipose tissue was smaller in females that received a high-fat diet than in their male counterparts after 24 weeks.

This suggests that although females on a high-fat diet showed an increase in visceral adipose tissue, this increase in adipose tissue was metabolically healthy.

Female mice maintained on the high-fat diet showed a superior ability to regulate glucose metabolism at 24 weeks than their male counterparts.

However, after 48 weeks on the high-fat diet, female mice did not differ from male mice in their ability to regulate glucose levels. In other words, there was a delayed onset of insulin resistance in female mice than in males.

The researchers found that the high-fat diet did not influence estrogen and progesterone levels, which are involved in the female reproductive cycle.

However, the females stopped cycling by 48 weeks, suggesting that these hormonal changes in females could have mediated the development of insulin resistance.

The researchers then examined the impact of the high-fat diet on inflammation in the adipose tissue and the brain in male and female mice. The female mice maintained on a high-fat diet showed lower levels of local inflammation in the visceral and subcutaneous adipose tissue than males over 48 weeks.

Obesity is also associated with inflammation in the brain. Male mice maintained on a high-fat diet showed increased infiltration of macrophages from the periphery into the hypothalamus at 12 weeks than their female counterparts.

However, female mice fed a high-fat diet showed a delayed accumulation of macrophages and did not differ from males at 24 and 48 weeks.

Male mice maintained on the high-fat diet showed higher levels of activated microglia than their female counterparts at all time points. But female mice on a high-fat diet did show a delayed but less pronounced increase in the levels of activated microglia in the hypothalamus.

These results suggest that a higher ratio of visceral fat to subcutaneous fat before the initiation of the high-fat diet could have potentially resulted in increased inflammation in male mice.

Moreover, the absence of changes in estrogen and progesterone levels suggests that these hormones were not directly responsible for the lower inflammation levels in females on a high-fat diet.

To further examine the potential protective role of subcutaneous fat in female mice, the researchers surgically removed the subcutaneous fat in male and female mice before the initiation of a high-fat or low-fat diet regime.

“Adipose tissue grows back over time, but we wanted to eliminate that initial difference in subcutaneous fat between males and females,” explained Dr. Stranahan.

The researchers found that lipectomy, the surgical removal of the fat, did not influence the levels of gonadal hormones or glucose regulation in mice fed a high-fat diet.

However, the surgical removal of subcutaneous fat resulted in the male-like pattern of accumulation of visceral fat, including an increase in the size of adipose cells, at 12 weeks in female mice on a high-fat diet.

Removal of subcutaneous fat increased inflammation in the adipose tissue of females on a high-fat diet, whereas males on a high-fat diet showed higher levels of inflammation regardless of whether they underwent a lipectomy.

Specifically, female mice on a high-fat diet that underwent lipectomy showed increased markers of inflammation in the visceral adipose tissue at 12 weeks than females on a high-fat diet that underwent sham surgery.

Moreover, lipectomy, but not sham surgery, resulted in elevated levels of the pro-inflammatory proteins TNF-alpha and IL1-beta in the serum of female mice on a high-fat diet.

Lipectomy also had a similar impact on inflammation in the brain. Male mice maintained on a high-fat diet, regardless of lipectomy status, showed an accumulation of macrophages and an increase in the levels of activated microglia in the hypothalamus.

In contrast, these markers of brain inflammation were elevated only in the female mice on a high-fat diet that underwent lipectomy.

Together, these results show that subcutaneous fat protected females from the inflammatory effects associated with obesity.

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