Genetic Basis for Sex Differences in Obesity and Lipid Metabolism

Abstract

Men and women exhibit significant differences in obesity, cardiovascular disease, and diabetes. To provide better diagnosis and treatment for both sexes, it is important to identify factors that underlie the observed sex differences. Traditionally, sex differences have been attributed to the differential effects of male and female gonadal secretions (commonly referred to as sex hormones), which substantially influence many aspects of metabolism and related diseases. Less appreciated as a contributor to sex differences are the fundamental genetic differences between males and females, which are ultimately determined by the presence of an XX or XY sex chromosome complement. Here, we review the mechanisms by which gonadal hormones and sex chromosome complement each contribute to lipid metabolism and associated diseases, and the current approaches that are used to study them. We focus particularly on genetic approaches including genome-wide association studies in humans and mice, -omics and systems genetics approaches, and unique experimental mouse models that allow distinction between gonadal and sex chromosome effects.

Keywords: adipose tissue; glucose metabolism; gonadal hormones; metabolic syndrome; microbiome; sex chromosome complement.

Figure 1. Sex differences in metabolic syndrome (MetSyn) components

Risk factors for the MetSyn include visceral obesity, elevated triglyceride levels, low high density lipoprotein levels, hypertension, and elevated fasting glucose levels. Sex differences occur in most of these traits. Women tend to have increased fat mass proportional to their body weight, increased subcutaneous adipose tissue, and elevated HDL cholesterol levels. Men generally have greater proportional lean mass, increased visceral adipose tissue, and elevated plasma triglyceride levels. Cardiovascular disease incidence also differs by sex, with women having higher incidence of ischemic stroke, and men higher incidence of myocardial infarction.

Figure 2. Genetic and hormonal components of sex

Male and female sex differences may result from genetic or hormonal components. Normal females and males differ in their sex chromosome complement of XX or XY, respectively. They also differ in the presence of ovarian or testicular gonadal hormones. In standard humans and mouse models, the genetic and gonadal contributions to sex differences cannot be easily distinguished.

Figure 3. Distinction of gonadal and chromosomal contributions to sex differences using the Four Core Genotypes mouse model

The Four Core Genotypes mouse model breaks sex into gonadal type and sex chromosome complement as independent determinants. The four genotypes can be used to study the contribution of gonadal and chromosomal sex to traits of interest.

Figure 4. Using the Four Core Genotypes mouse model to study sex differences

Studies with the Four Core Genotypes are performed in a 2 x 2 comparison, using gonadal type (ovaries vs. testes) and chromosomal type (XX vs. XY) as the categories. A comparison of XX vs. XY mice (on both gonadal backgrounds) allows detection of effects due to sex chromosome complement. A comparison of female vs. male mice (with both sex chromosome genotypes) allows detection of effects due to gonadal type.

Figure 5. Sex chromosome complement confers sex differences in MetSyn traits

Studies using the Four Core Genotypes mouse model have revealed that sex differences in some traits associated with MetSyn are influenced by the sex chromosome complement. For example, XX mice, regardless of having ovaries or testes, have increased fat mass relative to body weight, are susceptible to fatty liver, and exhibit increased HDL cholesterol. XY mice have been shown to have greater inflammation in the central nervous system (33) and improved cardiac recovery after ischemia injury (67).

Figure 6. Sex differences in metabolism are influenced by many factors

Two primary sex-biasing sources are the sex chromosome complement and gonadal hormones, which in turn are influenced by other factors. The white arrows represent mediators of regulation, including gene expression changes and altered protein signaling pathways. In addition to the number of X chromosomes and the presence of a Y chromosome, XX and XY cells differ by the occurrence of X chromosome inactivation (exclusively in XX cells) and by the parent-of-origin X chromosome imprinting (only XX cells have X chromosome imprints from both parents). The gut microbiome and environmental factors such as diet, pollutants, and circadian cycle may interact with the sex chromosome complement and gonadal hormones to affect metabolism differently between males and females.