UCLA

Obesity is associated with numerous metabolic disorders, including hypertension, hyperlipidemia, insulin resistance, and atherosclerosis. In addition, obesity is a risk factor for cardiovascular disease and cancer, the leading causes of mortality. It is thus critical to understand the environmental and genetic components that contribute to the development of obesity, one of which is sex.

The sexual dimorphism in fat accumulation and distribution has been well established for a few decades. Premenopausal women tend to gain fat near the hips and thighs, while men and postmenopausal women tend to accumulate fat in the abdominal cavity. These sex differences have often been attributed to sex hormones, but sex differences in metabolic traits remain long after gonadal hormones have declined. This suggests that factors other than sex hormones could contribute to sex differences in metabolism.

The sex chromosome complement is the fundamental difference between male and female cells. Because XX chromosomes often coexist with ovaries and XY chromosomes are coupled with testes, the distinct effects of gonadal type and sex chromosomes are difficult to distinguish. A unique mouse model called the Four Core Genotypes (FCG) generates XX female, XX male, XY female, and XY male mice, and is an innovative tool to study effects of the sex chromosome complement (XX male/female vs. XY male/female) independently from effects of gonadal hormones (XX/XY male vs. XX/XY female).

We used FCG mice to study sex differences in obesity and related metabolic disorders. We compared gonadally intact mice with gonadectomized mice to assess acute effects of gonadal hormones, and we nutritionally challenged mice with a high fat diet and a high cholesterol diet to identify diet-sex interactions. Male and female mice with two X chromosomes gain more weight, have increased adiposity, and accumulate more hepatic lipid compared to XY mice. In addition, XX mice have increased HDL cholesterol levels, regardless of the dietary or hormone milieu. Sex chromosome differences were also detected at the molecular level, modulating mRNA and microRNA expression.

Our studies demonstrate that the sex chromosome complement is a major determinant of body weight, adiposity, and associated metabolic traits such as hepatic lipid and plasma lipid levels. The key findings from this dissertation will shed light on sex differences in obesity and are important for improving prevention and treatment of metabolic disease.