Impact of Testosterone Deficiency on Adipose Tissue Metabolic Activity and Plasma Lipoprotein and Glucose Homeostasis: The Role of Apolipoprotein E2 and E4 Isoforms

Background: Recent findings indicate that testosterone deficiency (TD) affects key metabolic processes, such as lipid and carbohydrate metabolism. Apolipoprotein E (APOE) is the natural ligand for the low-density lipoprotein receptor (LDLR). The natural APOE isoforms APOE3 and APOE4 have a high affinity for LDLR, while APOE2 exhibits impaired binding to the receptor and an inability to promote lipoprotein remnant clearance. Previous work indicated that LDLR modulates the effects of TD on adipose tissue mitochondrial metabolic activity. Here, we investigated how APOE2 or APOE4 expression influences the effects of TD on plasma lipid and glucose homeostasis and white adipose tissue and brown adipose tissue (BAT) mitochondrial metabolic activity. Materials and Methods: APOE2 knock-in (Apoe2knock-in) and APOE4 knock-in (Apoe4knock-in) mice were subjected to surgical castration or sham operation. Mice were fed western-type diet for a period of 12 weeks, and a series of analyses were performed on live animals or specimens collected at the end of the study. Results: TD results in body weight loss only in Apoe4knock-in mice. Castrated Apoe2knock-in mice show much reduced BAT mitochondrial uncoupling protein 1 (Ucp1) and CytC expression, which may explain the body weight difference between castrated Apoe2knock-in and Apoe4knock-in mice. The reduced body weight gain in castrated APOE4-expressing mice did not alleviate the already much impaired glucose tolerance of these mice or their hepatic triglyceride levels. Quite strikingly, in both mouse strains hypogonadism brings about negative effects on lipoprotein metabolism, manifested by different disturbances. Conclusions: TD is associated with distinct metabolic abnormalities, which depend on the APOE isoform expressed.