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SREBP-regulated adipocyte lipogenesis is dependent on substrate availability and redox modulation of mTORC1
Clair Crewe, … , Jay D. Horton, Philipp E. Scherer
Clair Crewe, … , Jay D. Horton, Philipp E. Scherer
Published July 16, 2019
Citation Information: JCI Insight. 2019;4(15):e129397. https://doi.org/10.1172/jci.insight.129397.
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Research Article Endocrinology Metabolism

SREBP-regulated adipocyte lipogenesis is dependent on substrate availability and redox modulation of mTORC1

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Abstract

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.

Authors

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

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Figure 6

Model for mTORC1-mediated compensation of obstructed AT lipogenesis.

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Model for mTORC1-mediated compensation of obstructed AT lipogenesis.
Ins...
Insig1 overexpression results in general suppression of lipogenic gene expression, including that of the citrate transporter (CiC). Diminished efflux of citrate from the mitochondria results in a “backup” of the TCA cycle and mitochondrial ROS production, as citrate carbons are abruptly diverted into the TCA cycle for ATP production instead of lipogenesis. ROS activates mTORC1, which stimulates both SREBP1 transcription and the processing of SREBP1 into its nuclear/active from. High levels of glycolytic intermediates may also stimulate ChREBP activity. The consequence is restoration of lipogenic gene expression. This mechanism of compensation is transient, but chronic compensation is maintained by greater uptake of fructose via GLUT5. Both acute and chronic compensation is dependent on DNL substrate availability.

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