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Hepatocellular carcinoma induced by hepatocyte Pten deletion reduces BAT UCP-1 and thermogenic capacity in mice, despite increasing serum FGF-21 and iWAT browning

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Abstract

Hepatocellular carcinoma (HCC) markedly enhances liver secretion of fibroblast growth factor 21 (FGF-21), a hepatokine that increases brown and subcutaneous inguinal white adipose tissues (BAT and iWAT, respectively) uncoupling protein 1 (UCP-1) content, thermogenesis and energy expenditure. Herein, we tested the hypothesis that an enhanced BAT and iWAT UCP-1-mediated thermogenesis induced by high levels of FGF-21 is involved in HCC-associated catabolic state and fat mass reduction. For this, we evaluated body weight and composition, liver mass and morphology, serum and tissue levels of FGF-21, BAT and iWAT UCP-1 content, and thermogenic capacity in mice with Pten deletion in hepatocytes that display a well-defined progression from steatosis to steatohepatitis (NASH) and HCC upon aging. Hepatocyte Pten deficiency promoted a progressive increase in liver lipid deposition, mass, and inflammation, culminating with NASH at 24 weeks and hepatomegaly and HCC at 48 weeks of age. NASH and HCC were associated with elevated liver and serum FGF-21 content and iWAT UCP-1 expression (browning), but reduced serum insulin, leptin, and adiponectin levels and BAT UCP-1 content and expression of sympathetically regulated gene glycerol kinase (GyK), lipoprotein lipase (LPL), and fatty acid transporter protein 1 (FATP-1), which altogether resulted in an impaired whole-body thermogenic capacity in response to CL-316,243. In conclusion, FGF-21 pro-thermogenic actions in BAT are context-dependent, not occurring in NASH and HCC, and UCP-1-mediated thermogenesis is not a major energy-expending process involved in the catabolic state associated with HCC induced by Pten deletion in hepatocytes.

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Acknowledgements

The oxygen consumption ANCOVA analysis was provided by the NIDDK Mouse Metabolic Phenotyping Centers (MMPC, www.mmpc.org) using their Energy Expenditure Analysis page (http://www.mmpc.org/shared/regression.aspx) and supported by grants DK076169 and DK115255.

Funding

This work was supported by grants from the São Paulo Research Foundation (FAPESP #15/19530-5, 19/01763-4, and 20/04159-8) and the Brazilian National Council for Scientific and Technological Development (CNPq #301756/2019-8 and #303784/2022-9) to W.F. and FAPESP to A.A.S. (#2018/03418-0). A.S.P. (#2017/23040-9 and 2022/02123-1), M.F.M. (#2017/17582-3), E.C. (#2020/166566), L.A.P. (#2019/17660-0), T.B. (#2015/22983-1), T.E.O. (#2019/04271-5), T.S.V. (#2020/10215-8), B.F.L. (#2021/14419-0), M. O-S. (#2017/12260-8), and E.H.M (#2020/09399-7) were recipients of a Ph.D. studentship from FAPESP. G.R.G. and C.A.T. were recipients of Ph.D. fellowship from CNPq and Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), respectively.

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Authors and Affiliations

  1. Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of Sao Paulo, Av. Prof Lineu Prestes, 1524, 05508000, Sao Paulo, Brazil

    Álbert S. Peixoto, Mayara F. Moreno, Érique Castro, Luiz A. Perandini, Thiago Belchior, Tiago E. Oliveira, Thayna S. Vieira, Gustavo R. Gilio, Caroline A. Tomazelli, Bianca F. Leonardi, Milene Ortiz-Silva, Luciano P. Silva Junior & William T. Festuccia

  2. Department of Immunology, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, Brazil

    Eduardo H. Moretti & Alexandre A. Steiner

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  1. Álbert S. Peixoto
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Contributions

A.S.P., M.F.M., E.C., L.A.P., T.B., T.E.O., T.S.V., B.F.L., M.O-S., G.R.G., C.A.T., and L.P.S.J. performed the experiments and collected and analyzed the data. A.A.S. and E.H.M. performed the analysis of thermogenic capacity. W.F. performed the experiments, collected and analyzed the data, and wrote the paper. All authors revised the manuscript and declare that all data were generated in-house and that no paper mill was used.

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Correspondence to William T. Festuccia.

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Key points

• Hepatocellular carcinoma reduces BAT UCP-1 content and thermogenic capacity

• Thermogenic capacity was reduced despite increased serum FGF-21 and iWAT browning

• Pro-thermogenic actions of FGF-21 are context-dependent

• iWAT browning does not compensate for reduced BAT thermogenic capacity

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Peixoto, Á.S., Moreno, M.F., Castro, É. et al. Hepatocellular carcinoma induced by hepatocyte Pten deletion reduces BAT UCP-1 and thermogenic capacity in mice, despite increasing serum FGF-21 and iWAT browning. J Physiol Biochem 79, 731–743 (2023). https://doi.org/10.1007/s13105-023-00970-4

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