Abstract
Brown adipose tissue (BAT) plays an essential role in non-shivering thermogenesis. The phosphatidylinositol transfer protein, cytoplasmic 1 (PITPNC1) is identified as a lipid transporter that reciprocally transfers phospholipids between intracellular membrane structures. However, the physiological significance of PITPNC1 and its regulatory mechanism remain unclear. Here, we demonstrate that PITPNC1 is a key player in thermogenesis of BAT. While Pitpnc1−/− mice do not differ with wildtype mice in body weight and insulin sensitivity on either chow or high-fat diet, they develop hypothermia when subjected to acute cold exposure at 4°C. The Pitpnc1−/− brown adipocytes exhibit defective β-oxidation and abnormal thermogenesis-related metabolism pathways in mitochondria. The deficiency of lipid mobilization in Pitpnc1−/− brown adipocytes might be the result of excessive accumulation of phosphatidylcholine and a reduction of phosphatidic acid. Our findings have uncovered significant roles of PITPNC1 in mitochondrial phospholipid homeostasis and BAT thermogenesis.
Article PDF
Similar content being viewed by others
Avoid common mistakes on your manuscript.
References
Alb Jr., J.G., Cortese, J.D., Phillips, S.E., Albin, R.L., Nagy, T.R., Hamilton, B.A., and Bankaitis, V.A. (2003). Mice lacking phosphatidylinositol transfer protein-α exhibit spinocerebellar degeneration, intestinal and hepatic steatosis, and hypoglycemia. J Biol Chem 278, 33501–33518.
Allen-Baume, V., Ségui, B., and Cockcroft, S. (2002). Current thoughts on the phosphatidylinositol transfer protein family. FEBS Lett 531, 74–80.
Ashlin, T.G., Blunsom, N.J., Ghosh, M., Cockcroft, S., and Rihel, J. (2018). Pitpnc1a regulates zebrafish sleep and wake behavior through modulation of insulin-like growth factor signaling. Cell Rep 24, 1389–1396.
Bast-Habersbrunner, A., and Fromme, T. (2020). Purine nucleotides in the regulation of brown adipose tissue activity. Front Endocrinol 11, 118.
Carvou, N., Holic, R., Li, M., Futter, C., Skippen, A., and Cockcroft, S. (2010). Phosphatidylinositol- and phosphatidylcholine-transfer activity of PITPβ is essential for COPI-mediated retrograde transport from the Golgi to the endoplasmic reticulum. J Cell Sci 123, 1262–1273.
Chaurasia, B., Ying, L., Talbot, C.L., Maschek, J.A., Cox, J., Schuchman, E.H., Hirabayashi, Y., Holland, W.L., and Summers, S.A. (2021). Ceramides are necessary and sufficient for diet-induced impairment of thermogenic adipocytes. Mol Metab 45, 101145.
Chaurasia, B., Kaddai, V.A., Lancaster, G.I., Henstridge, D.C., Sriram, S., Galam, D.L.A., Gopalan, V., Prakash, K.N.B., Velan, S.S., Bulchand, S., et al. (2016). Adipocyte ceramides regulate subcutaneous adipose browning, inflammation, and metabolism. Cell Metab 24, 820–834.
Cheng, L., Wang, J., Dai, H., Duan, Y., An, Y., Shi, L., Lv, Y., Li, H., Wang, C., Ma, Q., et al. (2021). Brown and beige adipose tissue: a novel therapeutic strategy for obesity and type 2 diabetes mellitus. Adipocyte 10, 48–65.
Chitraju, C., Fischer, A.W., Farese Jr., R.V., and Walther, T.C. (2020). Lipid droplets in brown adipose tissue are dispensable for cold-induced thermogenesis. Cell Rep 33, 108348.
Chondronikola, M., and Sidossis, L.S. (2019). Brown and beige fat: from molecules to physiology. Biochim Biophys Acta (BBA)-Mol Cell Biol Lipids 1864, 91–103.
Chouchani, E.T., and Kajimura, S. (2019). Metabolic adaptation and maladaptation in adipose tissue. Nat Metab 1, 189–200.
Cockcroft, S. (2001). Phosphatidylinositol transfer proteins couple lipid transport to phosphoinositide synthesis. Semin Cell Dev Biol 12, 183–191.
Cockcroft, S. (2012). The diverse functions of phosphatidylinositol transfer proteins. Curr Top Microbiol Immunol 362, 185–208.
Cockcroft, S., and Garner, K. (2011). Function of the phosphatidylinositol transfer protein gene family: is phosphatidylinositol transfer the mechanism of action? Crit Rev Biochem Mol Biol 46, 89–117.
Cockcroft, S., and Garner, K. (2012). 14–3-3 protein and ATRAP bind to the soluble class IIB phosphatidylinositol transfer protein RdgBβ at distinct sites. Biochem Soc Trans 40, 451–456.
Fromme, T., Kleigrewe, K., Dunkel, A., Retzler, A., Li, Y., Maurer, S., Fischer, N., Diezko, R., Kanzleiter, T., Hirschberg, V., et al. (2018). Degradation of brown adipocyte purine nucleotides regulates uncoupling protein 1 activity. Mol Metab 8, 77–85.
Garner, K., Hunt, A.N., Koster, G., Somerharju, P., Groves, E., Li, M., Raghu, P., Holic, R., and Cockcroft, S. (2012). Phosphatidylinositol transfer protein, cytoplasmic 1 (PITPNC1) binds and transfers phosphatidic acid. J Biol Chem 287, 32263–32276.
Glatz, J.F.C., and Luiken, J.J.F.P. (2018). Dynamic role of the transmembrane glycoprotein cd36 (sr-b2) in cellular fatty acid uptake and utilization. J Lipid Res 59, 1084–1093.
Grabon, A., Orłowski, A., Tripathi, A., Vuorio, J., Javanainen, M., Róg, T., Lönnfors, M., McDermott, M.I., Siebert, G., Somerharju, P., et al. (2017). Dynamics and energetics of the mammalian phosphatidylinositol transfer protein phospholipid exchange cycle. J Biol Chem 292, 14438–14455.
Gusarova, V., Brodsky, J.L., and Fisher, E.A. (2003). Apolipoprotein b100 exit from the endoplasmic reticulum (ER) is copii-dependent, and its lipidation to very low density lipoprotein occurs post-er. J Biol Chem 278, 48051–48058.
Halberg, N., Sengelaub, C.A., Navrazhina, K., Molina, H., Uryu, K., and Tavazoie, S.F. (2016). PITPNC1 recruits RAB1B to the golgi network to drive malignant secretion. Cancer Cell 29, 339–353.
Hammerschmidt, P., Ostkotte, D., Nolte, H., Gerl, M.J., Jais, A., Brunner, H.L., Sprenger, H.G., Awazawa, M., Nicholls, H.T., Turpin-Nolan, S. M., et al. (2019). CerS6-derived sphingolipids interact with Mff and promote mitochondrial fragmentation in obesity. Cell 177, 1536–1552.e23.
Hao, J. W., Wang, J., Guo, H., Zhao, Y. Y., Sun, H. H., Li, Y. F., Lai, X. Y., Zhao, N., Wang, X., Xie, C., et al. (2020). CD36 facilitates fatty acid uptake by dynamic palmitoylation-regulated endocytosis. Nat Commun 11, 4765.
Hernández-Alvarez, M.I., Sebastián, D., Vives, S., Ivanova, S., Bartoccioni, P., Kakimoto, P., Plana, N., Veiga, S.R., Hernández, V., Vasconcelos, N., et al. (2019). Deficient endoplasmic reticulum-mitochondrial phosphatidylserine transfer causes liver disease. Cell 177, 881–895.e17.
Hoffmann, L.S., Larson, C.J., and Pfeifer, A. (2016). cGMP and brown adipose tissue. Handb Exp Pharmacol 233, 283–299.
Hsuan, J., and Cockcroft, S. (2001). The PITP family of phosphatidylinositol transfer proteins. Genome Biol 2, reviews3011.1.
Hücking, K., Hamilton-Wessler, M., Ellmerer, M., and Bergman, R.N. (2003). Burst-like control of lipolysis by the sympathetic nervous system in vivo. J Clin Invest 111, 257–264.
Kahn, C.R., Wang, G., and Lee, K.Y. (2019). Altered adipose tissue and adipocyte function in the pathogenesis of metabolic syndrome. J Clin Invest 129, 3990–4000.
Kang, S. (2021). Adipose tissue malfunction drives metabolic dysfunction in Alström syndrome. Diabetes 70, 323–325.
Li, Y., Talbot, C.L., and Chaurasia, B. (2020). Ceramides in adipose tissue. Front Endocrinol 11, 407.
Litvak, V., Dahan, N., Ramachandran, S., Sabanay, H., and Lev, S. (2005). Maintenance of the diacylglycerol level in the golgi apparatus by the Nir2 protein is critical for golgi secretory function. Nat Cell Biol 7, 225–234.
Macher, G., Koehler, M., Rupprecht, A., Kreiter, J., Hinterdorfer, P., and Pohl, E.E. (2018). Inhibition of mitochondrial UCP1 and UCP3 by purine nucleotides and phosphate. Biochim Biophys Acta (BBA)-Biomembranes 1860, 664–672.
Mueez, U.D., Saari, T., Raiko, J., Kudomi, N., Maurer, S.F., Lahesmaa, M., Fromme, T., Amri, E.Z., Klingenspor, M., Solin, O., et al. (2018). Postprandial oxidative metabolism of human brown fat indicates thermogenesis. Cell Metab 28, 207–216.e3.
Mulder, P., Morrison, M.C., Verschuren, L., Liang, W., van Bockel, J.H., Kooistra, T., Wielinga, P.Y., and Kleemann, R. (2016). Reduction of obesity-associated white adipose tissue inflammation by rosiglitazone is associated with reduced non-alcoholic fatty liver disease in LDLr-deficient mice. Sci Rep 6, 31542.
Polyzos, S.A., Kountouras, J., and Mantzoros, C.S. (2017). Adipose tissue, obesity and non-alcoholic fatty liver disease. Minerva Endocrinol 42, 92–108.
Saraswathi, V., Kumar, N., Gopal, T., Bhatt, S., Ai, W., Ma, C., Talmon, G. A., and Desouza, C. (2020). Lauric acid versus palmitic acid: effects on adipose tissue inflammation, insulin resistance, and non-alcoholic fatty liver disease in obesity. Biology 9, 346.
Saxton, S.N., Clark, B.J., Withers, S.B., Eringa, E.C., and Heagerty, A.M. (2019). Mechanistic links between obesity, diabetes, and blood pressure: role of perivascular adipose tissue. Physiol Rev 99, 1701–1763.
Scheele, C., and Wolfrum, C. (2020). Brown adipose crosstalk in tissue plasticity and human metabolism. Endocrine Rev 41, 53–65.
Shadan, S., Holic, R., Carvou, N., Ee, P., Li, M., Murray-Rust, J., and Cockcroft, S. (2008). Dynamics of lipid transfer by phosphatidylinositol transfer proteins in cells. Traffic 9, 1743–1756.
Sigurdson, S.L., and Himms-Hagen, J. (1988). Control of norepinephrine turnover in brown adipose tissue of syrian hamsters. Am J Physiol 254, R960–R968.
Stephens, M., Ludgate, M., and Rees, D.A. (2011). Brown fat and obesity: the next big thing? Clin Endocrinol 74, 661–670.
Tan, Y., Shao, R., Li, J., Huang, H., Wang, Y., Zhang, M., Cao, J., Zhang, J., and Bu, J. (2020). PITPNC1 fuels radioresistance of rectal cancer by inhibiting reactive oxygen species production. Ann Transl Med 8, 126.
Tan, Y., Lin, K., Zhao, Y., Wu, Q., Chen, D., Wang, J., Liang, Y., Li, J., Hu, J., Wang, H., et al. (2018). Adipocytes fuel gastric cancer omental metastasis via PITPNC1-mediated fatty acid metabolic reprogramming. Theranostics 8, 5452–5468.
Turpin, S.M., Nicholls, H.T., Willmes, D.M., Mourier, A., Brodesser, S., Wunderlich, C.M., Mauer, J., Xu, E., Hammerschmidt, P., Brönneke, H. S., et al. (2014). Obesity-induced CerS6-dependent C16:0 ceramide production promotes weight gain and glucose intolerance. Cell Metab 20, 678–686.
Wang, J., Hao, J.W., Wang, X., Guo, H., Sun, H.H., Lai, X.Y., Liu, L.Y., Zhu, M., Wang, H.Y., Li, Y.F., et al. (2019). DHHC4 and DHHC5 facilitate fatty acid uptake by palmitoylating and targeting CD36 to the plasma membrane. Cell Rep 26, 209–221.e5.
Xu, D., Li, Y., Wu, L., Li, Y., Zhao, D., Yu, J., Huang, T., Ferguson, C., Parton, R.G., Yang, H., et al. (2018). Rab18 promotes lipid droplet (LD) growth by tethering the ER to LDs through SNARE and NRZ interactions. J Cell Biol 217, 975–995.
Ye, C., Duan, J., Zhang, X., Yao, L., Song, Y., Wang, G., Li, Q., Wang, B., Ai, D., Wang, C., et al. (2021). Cold-induced Yes-associated-protein expression through miR-429 mediates the browning of white adipose tissue. Sci China Life Sci 64, 404–418.
Zhang, X., Zhang, Y., Wang, P., Zhang, S.Y., Dong, Y., Zeng, G., Yan, Y., Sun, L., Wu, Q., Liu, H., et al. (2019). Adipocyte hypoxia-inducible factor 2α suppresses atherosclerosis by promoting adipose ceramide catabolism. Cell Metab 30, 937–951.e5.
Zhou, Z., Torres, M., Sha, H., Halbrook, C.J., Van den Bergh, F., Reinert, R.B., Yamada, T., Wang, S., Luo, Y., Hunter, A.H., et al. (2020). Endoplasmic reticulum-associated degradation regulates mitochondrial dynamics in brown adipocytes. Science 368, 54–60.
Acknowledgements
This work was supported by the National Key R&D Program of China (2018YFA0506900, 2018YFA0800301), the National Natural Science Foundation of China (91857103), Shanghai Basic Research Field Project “Science and Technology Innovation Action Plan” (21JC1400400), the Lingang Laboratory (LG-QS-202204-06), and Shanghai Municipal Science and Technology Major Project (2017SHZDZX01). We would like to thank the members of the P.L. laboratory at Fudan University for technical assistance and productive discussions; Ms. Ke Qiao and Ms. Na Wei at the Imaging Core Facility of IMIB at Fudan University for the fluorescent and H&E imaging supporting; Ms. Ke Qiao, Ms. Lanlan Zhang, and Ms. Hongfang Zhao for metabolomic and lipidomic data generation from the Single Cell Quantitative Metabolomics and Lipidomics Core Facility of IMIB at Fudan University.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Compliance and ethics The author(s) declare that they have no conflict of interest. All applicable institutional and/or national guidelines for the care and use of animals were followed.
Supplemental information
Rights and permissions
Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
About this article
Cite this article
Tang, G., Ma, C., Li, L. et al. PITPNC1 promotes the thermogenesis of brown adipose tissue under acute cold exposure. Sci. China Life Sci. 65, 2287–2300 (2022). https://doi.org/10.1007/s11427-022-2157-y
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11427-022-2157-y