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Animal Models

Dietary choline increases brown adipose tissue activation markers and improves cholesterol metabolism in female APOE*3-Leiden.CETP mice

International Journal of Obesity volume 47, pages 236–243 (2023)Cite this article

Subjects

Abstract

Objectives

Studies in mice have recently linked increased dietary choline consumption to increased incidence of obesity-related metabolic diseases, while several clinical trials have reported an anti-obesity effect of high dietary choline intake. Since the underlying mechanisms by which choline affects obesity are incompletely understood, the aim of the present study was to investigate the role of dietary choline supplementation in adiposity.

Methods

Female APOE*3-Leiden.CETP mice, a well-established model for human-like lipoprotein metabolism and cardiometabolic diseases, were fed a Western-type diet supplemented with or without choline (1.2%, w/w) for up to 16 weeks.

Results

Dietary choline reduced body fat mass gain, prevented adipocyte enlargement, and attenuated adipose tissue inflammation. Besides, choline ameliorated liver steatosis and damage, associated with an upregulation of hepatic genes involved in fatty acid oxidation. Moreover, choline reduced plasma cholesterol, as explained by a reduction of plasma non-HDL cholesterol. Mechanistically, choline reduced hepatic VLDL-cholesterol secretion and enhanced the selective uptake of fatty acids from triglyceride-rich lipoprotein (TRL)-like particles by brown adipose tissue (BAT), consequently accelerating the clearance of the cholesterol-enriched TRL remnants by the liver.

Conclusions

In APOE*3-Leiden.CETP mice, dietary choline reduces body fat by enhancing TRL-derived fatty acids by BAT, resulting in accelerated TRL turnover to improve hypercholesterolemia. These data provide a mechanistic basis for the observation in human intervention trials that high choline intake is linked with reduced body weight.

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Fig. 1: Choline attenuates fat mass gain and improves WAT function.
Fig. 2: Choline reduces hepatic steatosis and inflammation.
Fig. 3: Choline ameliorates hypercholesterolemia.
Fig. 4: Choline activates BAT to accelerate TG-derived FA uptake, accompanied by increased hepatic uptake of cholesterol-enriched remnants.

Data availability

The data underlying this article will be shared on reasonable request to the corresponding author.

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Acknowledgements

We thank T.C.M. Streefland, A.C.M. Pronk, R.A. Lalai, and S. Afkir from the Department of Medicine, Division of Endocrinology, Leiden University Medical Center for technical assistance. This work was supported by the Leiden University Fund/Mulder-Hamelers Fonds (W18307-2-53 to YW), Leiden University Fund/Elise Mathilde Fund (W213045-2 to ZL), the Dutch Diabetes Research Foundation (2015.81.1808 to MRB), an NWO-VENI grant (09150161910073 to MRB), the Netherlands Cardiovascular Research Initiative: an initiative with support of the Dutch Heart Foundation (CVON-GENIUS-2 to PCNR), and the Department of Science and Technology Foundation of Shaanxi province (2021SF-021 to YW). ZL is supported by the China Scholarship Council (CSC 201506170051); MS is supported by Novo Nordisk Foundation (NNF18OC0032394); YW is supported by the China “Thousand Talents Plan” (Young Talents), Shaanxi province “Thousand Talents Plan” (Young Talents), Foundation of Xi’an Jiaotong University (Plan A).

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Authors and Affiliations

  1. Department of Medicine, Division of Endocrinology, Leiden University Medical Center, Leiden, The Netherlands

    Cong Liu, Zikuan Song, Zhuang Li, Mariëtte R. Boon, Milena Schönke, Patrick C. N. Rensen & Yanan Wang

  2. Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, The Netherlands

    Cong Liu, Zikuan Song, Zhuang Li, Mariëtte R. Boon, Milena Schönke, Patrick C. N. Rensen & Yanan Wang

  3. Med-X institute, Center for Immunological and Metabolic Diseases, and Department of Endocrinology, First Affiliated Hospital of Xi’an Jiaotong University, Xi’an Jiaotong University, Xi’an, China

    Patrick C. N. Rensen & Yanan Wang

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Contributions

CL designed the study, carried out the research, analyzed and interpreted the results, and wrote and revised the manuscript. ZS carried out the research, interpreted the results, reviewed and revised the manuscript. ZL carried out the research, interpreted the results, reviewed and revised the manuscript, and obtained funding. MRB advised the study and reviewed the manuscript. MS interpreted the results, reviewed and revised the manuscript. PCNR designed and advised the study, interpreted the results, edited, reviewed, and revised the manuscript and obtained funding. YW designed and advised the study, interpreted the results, reviewed and revised the manuscript, and obtained funding.

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Correspondence to Yanan Wang.

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Liu, C., Song, Z., Li, Z. et al. Dietary choline increases brown adipose tissue activation markers and improves cholesterol metabolism in female APOE*3-Leiden.CETP mice. Int J Obes 47, 236–243 (2023). https://doi.org/10.1038/s41366-023-01269-6

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