Altered Metabolism and Lipodystrophy in the Early B-Cell Factor 1-Deficient Mouse

Abstract

We previously reported that mice deficient for the transcription factor early B-cell factor (Ebf1) exhibit markedly increased numbers of osteoblasts, bone formation rate, and serum osteocalcin, but the bone marrow of Ebf1−/− mice is also striking in its increased marrow adiposity. The purpose of this work was to analyze the metabolic phenotype that accompanies the altered bone morphology of Ebf1−/− mice. Whereas marrow adiposity was increased, deposition of white adipose tissue in other regions of the body was severely reduced (sc 40–50%, abdominally 80–85%). Brown adipose exhibited decreased lipid deposition. Subcutaneous and perigonadal white adipose tissue showed a decrease in mRNA transcripts for peroxisomal proliferator-activated receptor-γ2 and CCAAT/enhancer-binding protein-β in Ebf1−/− tissue compared with wild type. Circulating levels of leptin were decreased in Ebf1−/− animals compared with their littermate controls (down 65-95%), whereas adiponectin remained comparable after 2 wk of age. Serum analysis also found the Ebf1−/− animals were hypoglycemic and hypotriglyceridemic. After ip injection of insulin, the serum glucose levels in Ebf1−/− mice took longer to recover, and after a glucose challenge the Ebf1−/− animals reached serum glucose levels almost twice that of their wild-type counterparts. Measurement of circulating pancreatic hormones revealed normal or reduced insulin levels in the Ebf1−/− mice, whereas glucagon was significantly increased (up 1.7- to 8.5-fold). Metabolically the Ebf1−/− mice had increased O2 consumption, CO2 production, food and water intake, and activity. Markers for gluconeogenesis, however, were decreased in the Ebf1−/− mice compared with controls. In conclusion, the Ebf1-deficient animals exhibit defects in adipose tissue deposition with increased marrow adiposity and impaired glucose mobilization.