Altered metabolism and lipodystrophy in the early B-cell factor 1-deficient mouse.
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-gamma2 and CCAAT/enhancer-binding protein-beta 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 O(2) consumption, CO(2) 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.
Fretz
Jackie A
JA
Department of Orthopaedics and Rehabilitation, Yale University School of Medicine, P.O. Box 208071, TMP 516, New Haven, Connecticut 06520-8071. mark.horowitz@yale.edu.
Nelson
Tracy
T
Xi
Yougen
Y
Adams
Douglas J
DJ
Rosen
Clifford J
CJ
Horowitz
Mark C
MC
D052242:Adiponectin / Q000097:blood; D000273:Adipose Tissue / Q000378:metabolism*; D000818:Animals; D001786:Blood Glucose; D001853:Bone Marrow / Q000378:metabolism; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000235:genetics / Q000378:metabolism; D002151:Calorimetry; D004734:Energy Metabolism / Q000502:physiology*; D005934:Glucagon / Q000097:blood; D007328:Insulin / Q000097:blood; D020738:Leptin / Q000097:blood; D050356:Lipid Metabolism / Q000502:physiology*; D008060:Lipodystrophy / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018709:Statistics, Nonparametric; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*
D052242:Adiponectin; D001786:Blood Glucose; D022782:CCAAT-Enhancer-Binding Protein-beta; C489921:Ebf1 protein, mouse; D007328:Insulin; D020738:Leptin; D047495:PPAR gamma; D012333:RNA, Messenger; D015534:Trans-Activators; D005934:Glucagon