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TRPC5 deletion in the central amygdala antagonizes high-fat diet-induced obesity by increasing sympathetic innervation

International Journal of Obesity volume 46, pages 1544–1555 (2022)Cite this article

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Abstract

Transient receptor potential channel 5 (TRPC5) is predominantly distributed in the brain, especially in the central amygdala (CeA), which is closely associated with pain and addiction. Although mounting evidence indicates that the CeA is related to energy homeostasis, the possible regulatory effect of TRPC5 in the CeA on metabolism remains unclear. Here, we reported that the expression of TRPC5 in the CeA of mice was increased under a high-fat diet (HFD). Specifically, the deleted TRPC5 protein in the CeA of mice using adeno-associated virus resisted HFD-induced weight gain, accompanied by increased food intake. Furthermore, the energy expenditure of CeA-specific TRPC5 deletion mice (TRPC5 KO) was elevated due to augmented white adipose tissue (WAT) browning and brown adipose tissue (BAT) activity. Mechanistically, deficiency of TRPC5 in the CeA boosted nonshivering thermogenesis under cold stimulation by stimulating sympathetic nerves, as the β3-adrenoceptor (Adrb3) antagonist SR59230A blocked the effect of TRPC5 KO on this process. In summary, TRPC5 deletion in the CeA alleviated the metabolic deterioration of mice fed a HFD, and these phenotypic improvements were correlated with the increased sympathetic distribution and activity of adipose tissue.

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Fig. 1: The expression of TRPC5 increased in the central amygdala (CeA) after high-fat feeding.
Fig. 2: Changes in body weight and metabolic parameters of TRPC5 KO and TRPC5+/+ mice after HFD feeding.
Fig. 3: TRPC5 deletion in the CeA alleviated HFD-induced adiposity and promoted WAT browning after HFD feeding.
Fig. 4: Deletion of TRPC5 in the CeA increased sympathetic distribution in WAT after high-fat feeding.
Fig. 5: TRPC5 deletion in the CeA enhanced BAT function in mice fed a HFD.
Fig. 6: Deletion of central amygdalar TRPC5 elevated adaptive thermogenesis under cold exposure.

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Data availability

The datasets generated during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

The authors thank Lutz Birnbaumer from the Laboratory of Neurobiology, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina for providing the TRPC5flox/flox mice.

Funding

This study was supported by grants from the National Natural Science Foundation of China (81920108010, 81900761, 81873657, 81721001, and 2018YFA0800601).

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Authors and Affiliations

  1. Department of Hypertension and Endocrinology, Center for Hypertension and Metabolic Diseases, Daping Hospital, Army Medical University, Chongqing Institute of Hypertension, Chongqing, 400042, China

    Huan Ma, Chengkang He, Li Li, Peng Gao, Zongshi Lu, Yingru Hu, Lijuan Wang, Yu Zhao, Tingbing Cao, Yuanting Cui, Zhencheng Yan, Daoyan Liu & Zhiming Zhu

  2. Department of Endocrinology, Translational Research Key Laboratory for Diabetes, Xinqiao Hospital, Army Medical University, Chongqing, 400037, China

    Hongting Zheng

  3. Department of Endocrinology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, 400010, China

    Gangyi Yang

  4. Chongqing Institute for Brain and Intelligence, Guangyang Bay Laboratory, Chongqing, 400064, China

    Zhiming Zhu

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  1. Huan Ma
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Contributions

HM carried out all experiments in mice, acquired and analyzed data, and wrote and edited the manuscript. CH drafted and revised the manuscript. LL conceived the work and performed metabolic testing. PG designed the research protocol and revised the manuscript. ZL and YH provided methodology and analyzed data. LW performed all western blotting experiments. YZ and TC contributed to purchase of all reagents and interpreting results. YC assisted with stereotaxic brain injection experiment. HZ, GY, ZY and DL supervised the research project. ZZ conceived and directed the work, revised the manuscript and approved the final version of paper.

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Correspondence to Zhiming Zhu.

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Ma, H., He, C., Li, L. et al. TRPC5 deletion in the central amygdala antagonizes high-fat diet-induced obesity by increasing sympathetic innervation. Int J Obes 46, 1544–1555 (2022). https://doi.org/10.1038/s41366-022-01151-x

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