Our study demonstrated differences in body composition between men and women with overweight/obesity. While women had a higher percent total fat mass and men more lean and muscle mass, detailed assessment of ectopic fat compartments revealed higher VAT, IHL, and IMCL in men while women had more lower extremity fat. At similar age and BMI, this male anthropometric phenotype was associated with a more detrimental cardiometabolic risk profile compared to the female phenotype. However, VAT was more strongly associated with measures of adverse cardiometabolic risk in women compared to men, while IMCL were more detrimental in men. Interestingly, relatively higher lower extremity fat mass was associated with a more favorable cardiometabolic risk profile and this was stronger in women than in men. Relatively higher appendicular lean mass was protective against cardiometabolic risk, and this was seen in both sexes.
There has been great interest in physiologic differences between men and women and the risk of cardiometabolic disease. The incidence and health outcomes in cardiometabolic disease differ between the sexes with men having a higher prevalence of cardiometabolic disease. However, although mortality is higher in men than women across the weight spectrum, the sex-specific increase in mortality is greater in women than men as BMI increases [4, 5]. This may be at least in part related to sex-specific differences in body composition. While women have relatively more fat mass and men more lean mass, less is known about sex differences in ectopic fat depots and their impact on cardiometabolic risk. Advances in imaging technology allow the comprehensive assessment of different fat compartments, including ectopic lipids, lean, and muscle mass [9,10,11,12,13,14,15]. A unique aspect of our study is the assessment of body composition by a combination of anatomic and functional imaging techniques. We used DXA to determine total body and appendicular fat and lean mass. However, DXA is not able to accurately quantify VAT and SAT. We therefore used CT to assess VAT, SAT, and thigh muscle. 1H-MRS has been shown to be an accurate technique to measure IHL and IMCL non-invasively [12,13,14,15], and we were able to quantify IHL and IMCL in our subjects with overweight/obesity.
Our study showed higher VAT, a strong risk factor for impaired glucose homeostasis, dyslipidemia, and the metabolic syndrome [7, 27], in men compared to women despite similar age and BMI. This is consistent with the propensity of men to accumulate fat in the abdomen (apple-shaped body type) while women had more lower extremity fat mass (pear-shaped body type). However, when we analyzed women and men separately, VAT was more strongly associated with markers of cardiometabolic risk in women compared to men. This is consistent with a study from the Framingham Heart cohort, in which VAT was more strongly associated with cardiometabolic risk factors in women compared to men [16]. This suggests that although women have less VAT than men overall, VAT accumulation in women confers greater cardiometabolic risk compared to men.
An important complication of obesity is elevated IHL content, which can lead to nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH), which may progress to liver fibrosis and cirrhosis [6]. In our study, men had higher age-and BMI-adjusted IHL, assessed by a simple breath hold 1H-MRS sequence, compared to women of similar age and BMI. Men also had higher IMCL, which may play an etiologic role in the pathogenesis of insulin resistance. A recent study in lean men who underwent overfeeding for 8 weeks suggested that the size and location of lipid droplets, rather than the total IMCL content, are determinants of the increase in insulin resistance in this setting [28]. However, high IMCL content as determined by 1H-MRS has been shown in states of insulin resistance, type 2 diabetes mellitus (T2DM), and dyslipidemia [29]. Our finding of higher IMCL in men is consistent with a study by Machann et al. who assessed sex differences in body composition in 150 healthy volunteers across a wide age range who were at risk for developing T2DM [17].
Interestingly, IMCL were associated with higher inflammatory markers in men but not in women. We also found sex-specific differences in associations between IHL and cardiometabolic risk markers. While IHL was positively associated with fasting glucose, apolipoprotein B, and fibrinogen in women but not in men, IHL was associated with lower HDL cholesterol and higher hsCRP in men but not in women. This suggests that accumulation of IHL has different effects on glucose and lipid metabolism between the sexes.
Preferential accumulation of fat in the lower body (femorogluteal fat) has been shown to be relatively protective against cardiometabolic risk [7, 8, 30]. Consistent with this, we found more lower extremity fat in women than in men. Our observed more favorable cardiometabolic risk profile in women compared to men, despite similar age and BMI, might be in part due to greater lower extremity fat mass in women. Although lower extremity fat mass has been shown to be protective against cardiometabolic disease, sex differences between lower extremity fat and cardiometabolic risk are unknown. In our study, relative higher lower extremity fat mass was associated with more favorable measures of cardiometabolic risk and these associations were stronger in women than in men.
In our study, men had a worse cardiometabolic risk profile with impaired measures of glucose homeostasis, dyslipidemia and increased inflammatory markers and higher prevalence of the metabolic syndrome than women despite similar age and BMI. This is consistent with a study in premenopausal women and men of similar age, in which women were found to have more total body fat but lower VAT than men, which was associated with a more favorable cardiometabolic risk profile [31].
Skeletal muscle plays an important role in the regulation of glucose homeostasis [32], and low muscle mass contributes to increased risk of T2DM [33, 34]. Although men are known to have more muscle mass than women [1], less is known about sex differences in muscle mass and cardiometabolic risk. We found sex differences in appendicular lean mass normalized over weight which was associated with improved measures of glucose homeostasis in men, a more favorable lipid profile in women, and lower inflammatory markers in both sexes. These findings suggest that increasing muscle mass may be able to offset some of the detrimental effects of ectopic fat in men and women with obesity independent of changes in fat mass.
Potential mechanism for sex differences in body composition and its relationship with cardiometabolic risk include modulation by sex steroids. For example, low estrogen levels, as in menopause, are associated with preferential accumulation of VAT and increased cardiometabolic risk [35, 36], and low testosterone in men can lead to visceral adiposity [37]. Moreover, results of recent genome wide association studies (GWAS) have identified sex-specific genetic determinants of fat accumulation [38].
A limitation of our study is the cross-sectional study design. Longitudinal data are necessary to assess whether sex-specific differences in ectopic fat depots will translate into higher incidence of cardiometabolic disease. Furthermore, our observed sex differences and the differences in cardiometabolic risk do not imply causality and may be multifactorial, including lifestyle (diet, exercise) and genetic variations.