Title: aP2-Cre-mediated inactivation of acetyl-CoA carboxylase 1 causes growth retardation and reduced lipid accumulation in adipose tissues Authors
|Mao, Jianqiang -|
|Yang, Tao -|
|Gu, Ziwei -|
|Heird, William -|
|Finegold, Milton -|
|Lee, Brendon -|
|Wakil, Salih -|
Submitted to: Proceedings of the National Academy of Sciences
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: August 21, 2009
Publication Date: October 13, 2009
Citation: Mao, J., Yang, T., Gu, Z., Heird, W.C., Finegold, M.J., Lee, B., Wakil, S.J. 2009. aP2-Cre-mediated inactivation of acetyl-CoA carboxylase 1 causes growth retardation and reduced lipid accumulation in adipose tissues. Proceedings of the National Academy of Sciences. 106(41):17576-17581. Interpretive Summary: Acetyl-CoA carboxylase 1 (ACC1) is an enzyme that catalyzes the synthesis of malonyl-CoA, however, the role of ACC1 in adipose function and energy homeostasis is still unknown. To identify the role of ACC1 in adipose tissue, we generated adipose (fat)-specific ACC1 knockout mice. These mice had prenatal growth retardation, but after weaning, their growth compared to that of wild-type mice fed a normal diet. However, under lipogenic conditions (i.e., fasting and re-feeding a fat-free diet), lipid accumulation in adipose tissues of ACC1 knockout mice was decreased. The ACC1 knockout mice also had skeletal growth retardation. Such findings help us to better understand possible inhibitors that could lead to a product that could be administered to target diet-induced obesity and diabetes.
Technical Abstract: Adipose tissue is one of the major sites for fatty acid synthesis and lipid storage. We generated adipose (fat)-specific ACC1 knockout (FACC1KO) mice using the aP2-Cre/loxP system. FACC1KO mice showed prenatal growth retardation; after weaning, however, their weight gain was comparable to that of wild-type (WT) mice on a normal diet. Under lipogenic conditions of fasting/re-feeding a fat-free diet, lipid accumulation in adipose tissues of FACC1KO mice was significantly decreased; this is consistent with a 50-66% reduction in the ACC activity in these tissues compared with that of WT mice. Surprisingly, FACC1KO mice manifested skeletal growth retardation phenotype accompanied by decreased chondrocyte proliferation in the growth plate and lower trabecular bone density. In addition, there was about a 30% decrease in serum insulin-like growth factor (IGF1), and while the serum leptin level was decreased by about 50%, it did not counteract the osteopenic effects of IGF1 on the bone. Fatty acid analyses of mutant bone lipids revealed relatively higher levels of C18:2n-6 and C18:3n-3 and lower levels of their elongation C20 homologs than that of WT cohorts, leading to lower levels of C20 homologs and bone development. Moreover, aP2-Cre-mediated ACC1 inactivation in bone tissue led to a decreased number of osteoblasts, but not of osteoclasts. The downregulation of ACC1 on osteoblastogenesis may be the cause for the osteopenia phenotype of FACC1KO bone homeostasis.