Lactobacillus amylovorus KU4 induces adipose browning in obese mice by regulating PP4C

in Journal of Endocrinology
Authors:
Garam Yang Department of Biological Sciences, College of Natural Sciences, Chonnam National University, Buk-Gu, Gwangju, Republic of Korea

Search for other papers by Garam Yang in
Current site
Google Scholar
PubMed
Close
,
Eunjeong Hong Department of Biological Sciences, College of Natural Sciences, Chonnam National University, Buk-Gu, Gwangju, Republic of Korea

Search for other papers by Eunjeong Hong in
Current site
Google Scholar
PubMed
Close
,
Sejong Oh Division of Animal Science, College of Agriculture & Life Sciences, Chonnam National University, Buk-Gu, Gwangju, Republic of Korea

Search for other papers by Sejong Oh in
Current site
Google Scholar
PubMed
Close
, and
Eungseok Kim Department of Biological Sciences, College of Natural Sciences, Chonnam National University, Buk-Gu, Gwangju, Republic of Korea

Search for other papers by Eungseok Kim in
Current site
Google Scholar
PubMed
Close
https://orcid.org/0000-0003-4935-7839

Correspondence should be addressed to E Kim: ekim@jnu.ac.kr
Restricted access
Rent on DeepDyve

Sign up for journal news

We previously reported that Lactobacillus amylovorus KU4 (LKU4) promotes adipocyte browning in mice fed a high-fat diet (HFD mice) in part by remodeling the PPARγ transcription complex. However, the mechanism through which LKU4 enables PPARγ to drive adipocyte browning remains elusive. Here, we report that LKU4 inhibits the expression of PP4C in inguinal white adipose tissue of HFD mice and in insulin-resistant 3T3-L1 adipocytes, which promotes SIRT1-dependent PPARγ deacetylation by activating AMPK, leading to the browning of adipocytes. Consistently, the silencing of PP4C further enhances this pathway. Furthermore, we observed that lactate, a key LKU4 metabolite, reduces insulin-induced PP4C expression and suppresses PP4C inhibition of PPARγ deacetylation and transcriptional activity via AMPK–SIRT1, thereby facilitating the browning of adipocytes. Together, these data demonstrate that LKU4 promotes the AMPK–SIRT1–PPARγ pathway by inhibiting PP4C, thereby facilitating adipocyte browning in HFD mice.

Supplementary Materials

 

  • Collapse
  • Expand
  • Bettedi L & & Foukas LC 2017 Growth factor, energy and nutrient sensing signalling pathways in metabolic ageing. Biogerontology 18 913929. (https://doi.org/10.1007/s10522-017-9724-6)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Chang HC & & Guarente L 2014 SIRT1 and other sirtuins in metabolism. Trends in Endocrinology and Metabolism 25 138145. (https://doi.org/10.1016/j.tem.2013.12.001)

  • Choi H, Kim SJ, Park SS, Chang C & & Kim E 2011 TR4 activates FATP1 gene expression to promote lipid accumulation in 3T3-L1 adipocytes. FEBS Letters 585 27632767. (https://doi.org/10.1016/j.febslet.2011.08.002)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Cohen PT, Philp A & & Vazquez-Martin C 2005 Protein phosphatase 4–from obscurity to vital functions. FEBS Letters 579 32783286. (https://doi.org/10.1016/j.febslet.2005.04.070)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Gomes AP & & Blenis J 2015 A nexus for cellular homeostasis: the interplay between metabolic and signal transduction pathways. Current Opinion in Biotechnology 34 110117. (https://doi.org/10.1016/j.copbio.2014.12.007)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Hong E, Kang H, Yang G, Oh S & & Kim E 2023 The PKA-SREBP1c pathway plays a key role in the protective effects of Lactobacillus johnsonii JNU3402 against diet-induced fatty liver in mice. Molecular Nutrition and Food Research 67 e2200496. (https://doi.org/10.1002/mnfr.202200496)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Li G, Xie C, Lu S, Nichols RG, Tian Y, Li L, Patel D, Ma Y, Brocker CN, Yan T, et al.2017 Intermittent fasting promotes white adipose browning and decreases obesity by shaping the gut microbiota. Cell Metabolism 26 672685.e4. (https://doi.org/10.1016/j.cmet.2017.08.019)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Lipinszki Z, Lefevre S, Savoian MS, Singleton MR, Glover DM & & Przewloka MR 2015 Centromeric binding and activity of protein phosphatase 4. Nature Communications 6 5894. (https://doi.org/10.1038/ncomms6894)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Liu HW, Kao HH & & Wu CH 2019 Exercise training upregulates SIRT1 to attenuate inflammation and metabolic dysfunction in kidney and liver of diabetic db/db mice. Nutrition and Metabolism 16 22. (https://doi.org/10.1186/s12986-019-0349-4)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Lo KA, Labadorf A, Kennedy NJ, Han MS, Yap YS, Matthews B, Xin X, Sun L, Davis RJ, Lodish HF, et al.2013 Analysis of in vitro insulin-resistance models and their physiological relevance to in vivo diet-induced adipose insulin resistance. Cell Reports 5 259270. (https://doi.org/10.1016/j.celrep.2013.08.039)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Nin V, Escande C, Chini CC, Giri S, Camacho-Pereira J, Matalonga J, Lou Z & & Chini EN 2012 Role of deleted in breast cancer 1 (DBC1) protein in SIRT1 deacetylase activation induced by protein kinase A and AMP-activated protein kinase. Journal of Biological Chemistry 287 2348923501. (https://doi.org/10.1074/jbc.M112.365874)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Park J & & Lee DH 2020 Functional roles of protein phosphatase 4 in multiple aspects of cellular physiology: a friend and a foe. BMB Reports 53 181190. (https://doi.org/10.5483/BMBRep.2020.53.4.019)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Park SS, Lee YJ, Song S, Kim B, Kang H, Oh S & & Kim E 2018 Lactobacillus acidophilus NS1 attenuates diet-induced obesity and fatty liver. Journal of Endocrinology 237 87100. (https://doi.org/10.1530/JOE-17-0592)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Park SS, Lee YJ, Kang H, Yang G, Hong EJ, Lim JY, Oh S & & Kim E 2019 Lactobacillus amylovorus KU4 ameliorates diet-induced obesity in mice by promoting adipose browning through PPARgamma signaling. Scientific Reports 9 20152. (https://doi.org/10.1038/s41598-019-56817-w)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Qiang L, Wang L, Kon N, Zhao W, Lee S, Zhang Y, Rosenbaum M, Zhao Y, Gu W, Farmer SR, et al.2012 Brown remodeling of white adipose tissue by SirT1-dependent deacetylation of PPARgamma. Cell 150 620632. (https://doi.org/10.1016/j.cell.2012.06.027)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Romieu I, Dossus L, Barquera S, Blottiere HM, Franks PW, Gunter M, Hwalla N, Hursting SD, Leitzmann M, Margetts B, et al.2017 Energy balance and obesity: what are the main drivers? Cancer Causes and Control 28 247258. (https://doi.org/10.1007/s10552-017-0869-z)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Shamsi F, Xue R, Huang TL, Lundh M, Liu Y, Leiria LO, Lynes MD, Kempf E, Wang CH, Sugimoto S, et al.2020 FGF6 and FGF9 regulate UCP1 expression independent of brown adipogenesis. Nature Communications 11 1421. (https://doi.org/10.1038/s41467-020-15055-9)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Thomson MJ, Williams MG & & Frost SC 1997 Development of insulin resistance in 3T3-L1 adipocytes. Journal of Biological Chemistry 272 77597764. (https://doi.org/10.1074/jbc.272.12.7759)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Tomar D, Jana F, Dong Z, Quinn WJ, Jadiya P, Breves SL, Daw CC, Srikantan S, Shanmughapriya S, Nemani N, et al.2019 Blockade of MCU-mediated Ca(2+) uptake perturbs lipid metabolism via PP4-dependent AMPK dephosphorylation. Cell Reports 26 37093725.e7. (https://doi.org/10.1016/j.celrep.2019.02.107)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Wei XJ, Jia R, Yang Z, Jiang JN, Huang JQ, Yan JQ & & Luo X 2020 NAD(+)/sirtuin metabolism is enhanced in response to cold-induced changes in lipid metabolism in mouse liver. FEBS Letters 594 17111725. (https://doi.org/10.1002/1873-3468.13779)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Yang G, Hong E, Oh S & & Kim E 2020 Non-viable Lactobacillus johnsonii JNU3402 protects against diet-induced obesity. Foods 9 1494. (https://doi.org/10.3390/foods9101494)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Yoon YS, Lee MW, Ryu D, Kim JH, Ma H, Seo WY, Kim YN, Kim SS, Lee CH, Hunter T, et al.2010 Suppressor of MEK null (SMEK)/protein phosphatase 4 catalytic subunit (PP4C) is a key regulator of hepatic gluconeogenesis. PNAS 107 1770417709. (https://doi.org/10.1073/pnas.1012665107)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Zhao H, Huang X, Jiao J, Zhang H, Liu J, Qin W, Meng X, Shen T, Lin Y, Chu J, et al.2015 Protein phosphatase 4 (PP4) functions as a critical regulator in tumor necrosis factor (TNF)-alpha-induced hepatic insulin resistance. Scientific Reports 5 18093. (https://doi.org/10.1038/srep18093)

    • PubMed
    • Search Google Scholar
    • Export Citation