Sexual Dimorphism in Developmental and Diet-dependent Circulating Retinol Binding Protein 4

Objective: Retinol binding protein 4 (RBP4) transports vitamin A (Retinol) in the blood and contributes mechanistically to the linkage between obesity, insulin resistance and associated comorbidities including type 2 diabetes mellitus, coronary artery and neoplastic diseases. Circulating RBP4 levels have variably been associated with body mass and gender differences. Many of these differences have been demonstrated after limited dietary interventions, and/or at single unique time points. This study investigated the impact of sex and age as biologic variables as well as high versus low fat diets on development of obesity, RBP4 levels and insulin resistance in C57BL/6J mice.

Methods: Male and female C57BL/6J mice were fed for 400 days with either low or high fat diets. Female mice were also evaluated on same diets after ovariectomy or sham ovariectomy. Mice were monitored for changes in weight, circulating levels RBP4, glucose and insulin at 100-day intervals and also by 2-hour glucose tolerance tests.

Results: All mice on low or high fat diets gained weight. Mice on high fat diets showed significantly greater weight gain than those on low fat. Male mice showed significantly greater weight gain compared with females on corresponding diet. Male mice compared with females already showed significantly higher RBP4 levels even before starting diets. Sex differences were maintained for more than 1 year. Gender differences in RBP4 were associated with significant differences in development of glucose intolerance and insulin resistance.

Conclusions: Male compared with female C57BL/6J mice show significant gender differences in circulating RBP4 levels from 6 weeks of age, extending more than 1 year. Gender differences in RBP4 may be mechanistically associated with protection against glucose intolerance and insulin resistance. Targeting RBP4 pathways could be useful to disrupt gender differences in insulin resistance and disparities in comorbidities.