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ChREBP-regulated lipogenesis is not required for the thermogenesis of brown adipose tissue

International Journal of Obesity volume 46, pages 1068–1075 (2022)Cite this article

Subjects

Abstract

Objectives

Brown adipose tissue (BAT) plays a critical role in energy expenditure by uncoupling protein 1 (UCP1)-mediated thermogenesis and represents an important therapeutic target for metabolic diseases. Carbohydrate response element-binding protein (ChREBP) is a key transcription factor regulating de novo lipogenesis, and its activity is associated with UCP1 expression and thermogenesis in BAT. However, the exact physiological role of endogenous ChREBP in BAT thermogenesis remains unclear.

Methods

We used the Cre/LoxP system to generate ChREBP BAT-specific knockout mice, and examined their BAT thermogenesis under acute cold exposure and long-term cold acclimation. Gene expression was analyzed at the mRNA and protein levels, and lipogenesis was examined by 3H-H2O incorporation assay.

Results

The mice lacking ChREBP specifically in BAT displayed a significant decrease in the expression levels of lipogenic genes and the activity of de novo lipogenesis in BAT after cold exposure, with UCP1 expression decreased under thermoneutral conditions or after acute cold exposure but not chronic cold acclimation. Unexpectedly, BAT-specific ChREBP deletion did not significantly affect body temperature as well as local temperature or morphology of BAT after acute cold exposure or chronic cold acclimation. Of note, ChREBP deletion mildly aggravated glucose intolerance induced by a high-fat diet.

Conclusions

Our work indicates that ChREBP regulates de novo lipogenesis in BAT and glucose tolerance, but is not required for non-shivering thermogenesis by BAT under acute or long-term cold exposure.

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Fig. 1: Generation of BAT-specific ChREBP knockout mice.
Fig. 2: ChREBP deletion in BAT does not impair cold tolerance.
Fig. 3: ChREBP deletion in BAT does not impair the energy homeostasis of cold-acclimated mice.
Fig. 4: ChREBP deletion has no impact on BAT morphology.
Fig. 5: Downregulated expression of Ucp1 in BAT from ChBO mice.
Fig. 6: Downregulated expression of DNL enzymes in BAT from ChBO mice.

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Funding

This work was supported by grants from the National Key Research and Development Project of China (2019YFA0802500), the National Natural Science Foundation of China (91857203, 31730042, 32100929), and the Collaborative Innovation Program of the Shanghai Municipal Health Commission (2020CXJQ01, 21ZR1477900).

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Author notes

  1. These authors contributed equally: Chunchun Wei, Ping Wang.

Authors and Affiliations

  1. Department of Pathophysiology, Naval Medical University, Shanghai, China

    Chunchun Wei, Xian-Hua Ma, Ming Lu, Shasha Qi, Jian-Hui Shi, An-Jing Ren & Weiping J. Zhang

  2. NHC Key Laboratory of Hormones and Development, Tianjin Key Laboratory of Metabolic Diseases, Chu Hsien-I Memorial Hospital & Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, China

    Ping Wang, Qi Dong & Weiping J. Zhang

  3. Ministry of Education-Shanghai Key Laboratory of Children’s Environmental Health, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China

    Zhifang Xie

  4. Experimental Teaching Center, Naval Medical University, Shanghai, China

    An-Jing Ren

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  1. Chunchun Wei
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Contributions

CW designed and carried out the study, interpreted and analyzed data, and drafted the article. PW and ZX analyzed the expressions of thermogenic genes. QD, ML, SQ, and J-HS performed animal studies. X-HM performed the immunochemistry studies. WJZ and A-JR designed and conceived the experiments, reviewed the data, edited the article, and approved the version to be published.

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Correspondence to An-Jing Ren or Weiping J. Zhang.

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Wei, C., Wang, P., Dong, Q. et al. ChREBP-regulated lipogenesis is not required for the thermogenesis of brown adipose tissue. Int J Obes 46, 1068–1075 (2022). https://doi.org/10.1038/s41366-022-01082-7

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