In a recent study published in the Frontiers of Immunology, researchers reviewed the sexual dimorphisms in obesity.
Obesity, the accumulation of excess body fat, is associated with a higher risk of health problems such as diabetes, cardiovascular disease (CVD), and stroke. Obesity prevalence has tripled in the past four decades, and globally around 30% of adults are affected. Notably, there are sexual dimorphisms in the pathophysiology and epidemiology of obesity.
Females are generally better protected against obesity than males, which is attributed to several biological processes such as the intestinal immune system, gut microbiome, sex hormones/chromosomes, and effects of adipose distribution. In the present review, researchers summarized the evidence for sexual dimorphisms and discussed the interplay between the gut microbiome, intestinal inflammation, and sex hormones.
Sexual dimorphisms in adipose tissue distribution, sex chromosomes, and hormones
Historically, females have been underrepresented in pre-clinical research and clinical trials. This was partly due to the misconception that females and males are the same. That males and females are unique at cellular levels is now evident. Although slightly more prevalent in females than males, women are protected from the metabolic disturbances and sequelae associated with disease progression in obesity.
Animal studies have demonstrated that male rodents are susceptible to early onset and a higher degree of obesity than their female counterparts. Intriguingly, older female or ovariectomized animals are less protected than younger animals with intact ovaries. This correlates with the epidemiology of obesity in humans, wherein males and post-menopausal females are at the highest risk of obesity complications, supporting that sex hormones (in pre-menopausal females) are protective against obesity.
Adipose tissue distribution differs between females and males. Females have greater subcutaneous fat predominantly in the gluteofemoral region, whereas males primarily accumulate visceral fat in the abdominal area. Higher visceral adiposity in males aggravates the secretion of pro-inflammatory molecules into systemic circulation, producing a knock-on effect that markedly increases the risk of cardiovascular events.
Sex chromosomes are crucial contributors to sexual dimorphisms of adipose tissue distribution. In a mouse model, gonadectomized female and male mice carrying XX chromosome complement had worse obesity outcomes than gonadectomized mice with XY chromosome complements.
Further, gonadectomized mice with XO and XXY complements revealed that the differences between XY and XX mice were due to the additional X chromosome. Therefore, the X chromosome might be an important factor, besides sex hormones/gonads, for sexual dimorphisms in obesity.
Gut microbiome changes in obesity
Additionally, the sex differences in obesity have been partly attributed to the inter-sex dimorphism in the intestinal microflora. Diets rich in bad fat and low in fiber could alter the microbial population within 24 hours. Dysbiosis occurs due to poor diet and could be identified by the loss of beneficial bacteria and increased prevalence of harmful bacteria.
Beneficial bacteria such as Bifidobacterium members and Akkermansia muciniphila negatively correlate with obesity, whereas harmful bacteria such as the members from Fusobacterium, Bilophila, and Desulfovibrio genera positive correlate with obesity. It is well known that sex steroid hormones drive sexual dimorphisms in females and males.
An observational study suggests that sex hormones influence gut microbiota. Elevated hormone levels were associated with greater gut microbial diversity compared to those with lower levels of hormones in either sex. Estradiol is used in hormone therapies to treat the loss of ovarian estrogen, typically in menopausal females.
In mice, high-fat diet-fed, estradiol-treated females were protected from cardiometabolic disease compared to untreated mice. In addition, estradiol affects the gut microbiome composition by slowing the increase in Firmicutes: Bacteroidetes ratio (an increased ratio is typically seen in obesity).
Sex differences in intestinal inflammation
Low-grade systemic inflammation is common in obesity. Multiple studies on obesity have focused on visceral adipose tissue as causing inflammation. Nevertheless, intestinal inflammation occurs before obese characteristics and adipose tissue inflammation. This is particularly significant as a considerable proportion of systemic innate and adaptive immune cells reside in the intestinal tract.
Moreover, gut microbiota also influences intestinal immunity. Due to their proximity, the interplay between the intestinal immune system and gut microbiota is known to develop and shape one another. This is highlighted in germ-free mice that lack gut microbes and consequently have poorly developed immune cell populations and intestinal lymphatic tissue.
Although a potent immune response is associated with an elevated inflammatory profile, this could be beneficial in the setting of obesity and intestinal inflammation. For instance, females are better at eliminating opportunistic and pathogenic gut bacteria that could be a by-product of the enhanced immune response.
This enhanced response might be the factor in females that delays the development of or protects them from obesity-related disturbances. Conversely, intestinal immune response in males is relatively smaller, thereby allowing deleterious microbes and possibly aggravating the development of obesity.
The sex differences in the pathophysiology and epidemiology of obesity leave men and post-menopausal women at the highest risks of metabolic disturbances. Although sex hormones/chromosomes and fat distribution serve as the basis for sexual dimorphisms, the function and composition of gut microbiota and the intestinal immune system also account for these dimorphisms. More studies are required in the future to assess the causality of and identify the specific imbalances in the gut microbiome that cause obesity.