Impaired adipogenic response to thiazolidinediones in mice expressing human
Authors Arbones-Mainar JM, Johnson LA, Altenburg MK, Kim HS, Maeda N
Submitted By Nobuyo Maeda on 5/2/2011
Status Published
Journal The FASEB journal : official publication of the Federation of American Societies for Experimental Biology
Year 2010
Date Published 10/1/2010
Volume : Pages 24 : 3809 - 3818
PubMed Reference 20501792
Abstract Thiazolidinediones (TZDs) are insulin sensitizers used to treat patients with
insulin resistance. To assess potential gene-drug interactions, mice expressing
human apolipoprotein E3 or E4 (APOE3 or APOE4) were fed a Western-type high-fat
diet for 12 wk, at which time they developed similarly impaired glucose
tolerance. Supplementing the diet with rosiglitazone (1.5 mg/g body weight) for
an additional 4 wk improved plasma lipid profiles in both APOE3 and APOE4 mice.
However, glucose tolerance improved only in APOE3 mice. Induction of
adipogenesis and lipogenesis was severely blunted in adipose tissues, but not in
the livers, of APOE4 mice. Consequently, lipids were channeled to the liver,
causing marked steatosis in these mice. Impaired glucose tolerance was not a
prerequisite for this adverse effect, and long-term treatment with rosiglitazone
altered liver enzymes and caused hepatic fibrosis in APOE4 mice. Finally, TZDs
failed to stimulate PPAR? activation and adipocyte differentiation in
preadipocytes and embryonic fibroblasts isolated from APOE4 mice compared to
those from APOE3 mice. We conclude that the effects of TZDs are APOE isoform
dependent, and that the metabolic damage observed in APOE4 mice is rooted in an
impaired activation of the adipogenic program in the adipose tissues expressing

Investigators with authorship
Nobuyo MaedaUniversity of North Carolina