TY - JOUR
T1 - SREBP-regulated adipocyte lipogenesis is dependent on substrate availability and redox modulation of mTORC1
AU - Crewe, Clair
AU - Zhu, Yi
AU - Paschoal, Vivian A.
AU - Joffin, Nolwenn
AU - Ghaben, Alexandra L.
AU - Gordillo, Ruth
AU - Oh, Da Young
AU - Liang, Guosheng
AU - Horton, Jay D.
AU - Scherer, Philipp E.
N1 - Funding Information:
We thank the University of Texas Southwestern Transgenic Core for their help in the generation of mice. We also thank the University of Texas Southwestern Molecular Pathology Core for imbedding and sectioning samples for histology. The MitoQ compound was a gift from Mike Murphy. This study was supported by US NIH grants R01-DK55758, P01-DK088761, R01-DK099110, and P01-AG051459 as well as by an unrestricted grant from the Novo Nordisk Research Foundation (PES). The contributions of GL and JDH were supported by the NIH (HL-20948). CC is supported by NIH grant F32-DK113704. The contribution of DYO was supported by the NIH (R01-DK108773) and the American Heart Association (14SDG19880020). VAP is supported by American Diabetes Association (ADA 1-18-PMF-030). YZ is supported by NIH grant K99-DK114498.
Publisher Copyright:
© 2019, American Society for Clinical Investigation.
PY - 2019/8/8
Y1 - 2019/8/8
N2 - 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.
AB - 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.
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U2 - 10.1172/jci.insight.129397
DO - 10.1172/jci.insight.129397
M3 - Article
C2 - 31310592
AN - SCOPUS:85071091200
SN - 2379-3708
VL - 4
JO - JCI Insight
JF - JCI Insight
IS - 15
M1 - e129397
ER -