The synthesis of lipid and sterol species through de novo lipogenesis (DNL) is regulated by 2 functionally overlapping but distinct transcription factors: the SREBPs and carbohydrate response element–binding protein (ChREBP). ChREBP is considered to be the dominant regulator of DNL in adipose tissue (AT); however, the SREBPs are highly expressed and robustly regulated in adipocytes, suggesting that the model of AT DNL may be incomplete. Here, we describe what we believe to be a new mouse model of inducible, adipocyte-specific overexpression of the insulin-induced gene 1 (Insig1), a negative regulator of SREBP transcriptional activity. Contrary to convention, Insig1 overexpression did block AT lipogenic gene expression. However, this was immediately met with a compensatory mechanism triggered by redox activation of mTORC1 to restore SREBP1 DNL gene expression. Thus, we demonstrate that SREBP1 activity sustains adipocyte lipogenesis, a conclusion that has been elusive due to the constitutive nature of current mouse models.
Clair Crewe, Yi Zhu, Vivian A. Paschoal, Nolwenn Joffin, Alexandra L. Ghaben, Ruth Gordillo, Da Young Oh, Guosheng Liang, Jay D. Horton, Philipp E. Scherer
Acute suppression of AT DNL induces mitochondrial oxidative stress, resulting in mTORC1 activation.