Sex Differences in Diet-induced Obesity: Identification of Key Genes in Association With Phenotypes

OBJECTIVES: Obesity is associated with many metabolic disorders requiring personalized management. In this study, we examined sex-dependent metabolic changes in diet-induced fat accumulation and tissue-specific transcriptomics to identify responsible genes. Estrogen-dependency was also evaluated. METHODS: Male, female and ovariectomized female C57BL/6J mice fed with high fat diet were maintained for 10wks. At sacrifice, body weight, tissue weight, fasting blood glucose and insulin, leptin and adiponectin were measured. Adipose tissue histology and the quantification of major proteins involved in fat synthesis and oxidation were carried out. Key genes in major tissues were identified based on microarray analyses followed by network analyses using protein-protein network and STRING programs. RESULTS: Female animals showed significantly lower body weight, adipocyte size, and the macrophage infiltration in white adipose tissue, which are increased by ovariectomy. Not like leptin, adiponectin concentration is significantly higher in female animals, which is maintained even after the ovariectomy. The expressions of proteins related to the regulation of lipid metabolism in adipose tissue show sex differences with or without estrogen depletion. Microarray analyses reveal that ovariectomized female group-specific genes up-regulated in fat, liver and muscle tissue are 251,148, and 49 in numbers, respectively. The number of down-regulated genes are 329, 86, and 37, respectively. PPI network analysis identified Cxcr3, Il2ra, Il2rg, Lck, and Ccl5 as top five up-regulated genes showing highest interaction score, while Cyc1, Uqcrc1, Atp5d, Ndufa9, and Ndufs8 are down-regulated with highest scores. Similarly, the top 5 genes up-regulated in liver tissue are Emr1, Itgb2, Igsf6, Clec4a3, and Aif1, while Eed, Myh11, and Tjp2 are down-regulated with highest scores. Cd4, Slco2b1, Fbxw11, Tub, Wnt5b, U2af2, and Cd38 are up-regulated and the Egfr is down-regulated with highest score in muscle tissue. CONCLUSIONS: This study suggests that biochemical alterations in abdominal obesity in females are different from males, and a part of mechanisms are estrogen-independent. Several key genes associated with these changes are suggested. FUNDING SOURCES: This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT).