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 August 8, 2019; First published July 16, 2019
Citation Information: JCI Insight. 2019;4(15):e129397. https://doi.org/10.1172/jci.insight.129397.
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Categories: Research Article Endocrinology Metabolism

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

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 3

mTORC1 is activated in response to a block in AT lipogenesis.

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mTORC1 is activated in response to a block in AT lipogenesis. (A) Repres...
(A) Representative Western blot for the specified proteins in the sWAT of control or ad-Insig1 mice exposed to dox for 12 hours or 2 weeks. (B and C) Densitometric quantification of Western blots for (B) pS6Ser240/244 or (C) pAKTThr308 and pAKTser473 following the indicated durations of dox exposure (n = 3–5). (D) Control and ad-Insig1 mice were injected with rapamycin (rapa;4 mg/kg) every second day for 2 weeks while on dox-containing chow. Lipogenic gene expression was determined in sWAT following the 2-week treatment (n = 5). (E) Representative Western blot and densitometry of sWAT FASN and ACC protein levels in control or ad-Insig1 mice with or without rapa (n = 5–7). (F) sWAT and eWAT weights after 2 weeks treatment with both dox and rapa (n = 5–6). (G) Triglyceride clearance test performed following 3 weeks of dox and rapa treatment (n = 6–7). (H) Oral glucose tolerance test conducted following 2 weeks of dox and rapa treatment (n = 6). (I) Insulin measurements during oral glucose tolerance (n = 6). (J) H&E stain of pancreatic islet (arrow). Original magnification, ×20. All data are presented as mean ± SEM. *P < 0.05, **P < 0.01, ***P < 0.001 by 2-tailed Student’s t test (bar graphs) or 2-way ANOVA (systemic assays). The Tukey correction was used for multiple comparisons. 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.