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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 5

Chronic compensation to DNL suppression is dependent on substrate availability.

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Chronic compensation to DNL suppression is dependent on substrate availa...
(A) GLUT5 mRNA expression in control or ad-Insig1 mice at the indicated time points on dox diet. (B) Western blot image and corresponding densitometry for GLUT4 and GLUT5 in sWAT of control or ad-Insig1 mice following the indicated duration of dox treatment in the diet (n = 3–8). (C) Representative Western blot of n = 3 from the sWAT of control or ad-Insig1 mice following 2 weeks of dox treatment with rapamycin (rapa) or vehicle injections. (D) Wild-type mice were treated with or without 20% fructose in the drinking water for 12 hours. A representative Western blot and densitometry for GLUT4 and GLUT5 in sWAT (n = 5) is shown. (E and F) Control and ad-Insig1 mice were supplied with a ketogenic diet containing dox for 3 weeks, after which (E) sWAT and eWAT weight were measured and (F) DNL gene expression was quantified (n = 5–7). (G and H) Mice were provided with 2-DG in the drinking water (0.5%) in addition to the dox diet. Following 2 weeks treatment (G) sWAT and eWAT weights were measured and (H) lipogenic enzyme mRNA was quantified (n = 5–6). All data are presented as mean ± SEM. *P < 0.05, **P < 0.01, ***P < 0.001 by 2-tailed Student’s t test. In all cases, for a given condition, representative Western blot images are from the same sample, although the target proteins may have been probed on separate membranes to facilitate clear visualization. All densitometry was conducted on samples run on the same gel.

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