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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 2

Manipulation of adipose DNL alters whole-body metabolism.

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Manipulation of adipose DNL alters whole-body metabolism.
(A–D) Twelve h...
(A–D) Twelve hours after dox injection (2 mg/kg) mice were subjected to an (A) oral glucose tolerance test (n = 6) and a (B) triglyceride clearance test (n = 9–10). At this 12-hour time point, another cohort of mice were used for (C) sWAT and eWAT depot weights (n = 8) and (D) total body weight (n = 8). (E–L) Mice were provided with chow diet containing dox for 3 days or 3 weeks, at which time mice were subjected to an (E and I) oral glucose tolerance test (n = 5–8) and a (F and J) triglyceride clearance test (n = 5–8) or (G and K) sacrificed for white AT weights. (H and L) Body weight measurements at the indicated times. (M) qPCR for lipogenic genes in liver of control and ad-Insig1 mice following 3 weeks of chow diet supplemented with dox (n = 7). 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).

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