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Korean Society for Biochemistry and Molecular Biology (생화학분자생물학회)
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UCP2 KO mice exhibit ameliorated obesity and inflammation induced by high-fat diet feeding

  • Kim, Do Hyun (The Research Institute for Veterinary Science, College of Veterinary Medicine, Seoul National University) ;
  • Kim, Hye Jin (Laboratory of Developmental Biology and Genomics, BK21 Program for Veterinary Science, College of Veterinary Medicine, Seoul National University) ;
  • Seong, Je Kyung (The Research Institute for Veterinary Science, College of Veterinary Medicine, Seoul National University)
  • Received : 2022.03.23
  • Accepted : 2022.06.07
  • Published : 2022.10.31
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Abstract

Uncoupling protein 2 (Ucp2) was first introduced as a member of Uncoupling protein family and a regulator of ROS formation; however, its role in adipose tissue is not fully understood. In the present study, we have investigated the role of Ucp2 against high-fat diet (HFD)-induced obesity in epididymal white adipose tissue (eWAT) and browning of inguinal white adipose tissue (iWAT). Diet-induced obesity is closely related to macrophage infiltration and the secretion of pro-inflammatory cytokines. Macrophages surround adipocytes and form a crown-like-structure (CLS). Some reports have suggested that CLS formation requires adipocyte apoptosis. After 12 weeks of HFD challenge, Ucp2 knockout (KO) mice maintained relatively lean phenotypes compared to wild-type (WT) mice. In eWAT, macrophage infiltration, CLS formation, and inflammatory cytokines were reduced in HFD KO mice compared to HFD WT mice. Surprisingly, we found that apoptotic signals were also reduced in the Ucp2 KO mice. Our study suggests that Ucp2 deficiency may prevent diet-induced obesity by regulating adipocyte apoptosis. However, Ucp2 deficiency did not affect the browning capacity of iWAT.

Keywords

Acknowledgement

This study was partially supported by the Research Institute for Veterinary Science, Seoul National University. This study was supported by the Korea Mouse Phenotyping Project (NRF-2013M3A9D5072550) of the Ministry of Science and ICT, through the National Research Foundation.

References

  1. Zhang CY, Baffy G, Perret P et al (2001) Uncoupling protein-2 negatively regulates insulin secretion and is a major link between obesity, beta cell dysfunction, and type 2 diabetes. Cell 105, 745-755 https://doi.org/10.1016/S0092-8674(01)00378-6
  2. Bai Y, Onuma H, Bai X et al (2005) Persistent nuclear factor-kappa B activation in Ucp2-/- mice leads to enhanced nitric oxide and inflammatory cytokine production. J Biol Chem 280, 19062-19069 https://doi.org/10.1074/jbc.M500566200
  3. Arsenijevic D, Onuma H, Pecqueur C et al (2000) Disruption of the uncoupling protein-2 gene in mice reveals a role in immunity and reactive oxygen species production. Nat Genet 26, 435-439 https://doi.org/10.1038/82565
  4. Andrews ZB and Horvath TL (2009) Uncoupling protein-2 regulates lifespan in mice. Am J Physiol Endocrinol Metab 296, E621-E627 https://doi.org/10.1152/ajpendo.90903.2008
  5. Erlanson-Albertsson C (2002) Uncoupling proteins--a new family of proteins with unknown function. Nutr Neurosci 5, 1-11 https://doi.org/10.1080/10284150290007038
  6. Choe SS, Huh JY, Hwang IJ, Kim JI and Kim JB (2016) Adipose tissue remodeling: its role in energy metabolism and metabolic disorders. Front Endocrinol (Lausanne) 7, 30
  7. Cohen P and Spiegelman BM (2016) Cell biology of fat storage. Mol Biol Cell 27, 2523-2527 https://doi.org/10.1091/mbc.e15-10-0749
  8. Cha JH, Jeong Y, Oh AR, Lee SB, Hong SS and Kim K (2021) Emerging roles of PHLPP phosphatases in metabolism. BMB Rep 54, 451-457 https://doi.org/10.5483/BMBRep.2021.54.9.095
  9. Prunet-Marcassus B, Cousin B, Caton D, Andre M, Penicaud L and Casteilla L (2006) From heterogeneity to plasticity in adipose tissues: site-specific differences. Exp Cell Res 312, 727-736 https://doi.org/10.1016/j.yexcr.2005.11.021
  10. Lee MJ, Wu Y and Fried SK (2013) Adipose tissue heterogeneity: implication of depot differences in adipose tissue for obesity complications. Mol Aspects Med 34, 1-11 https://doi.org/10.1016/j.mam.2012.10.001
  11. Himms-Hagen J (1985) Brown adipose tissue metabolism and thermogenesis. Annu Rev Nutr 5, 69-94 https://doi.org/10.1146/annurev.nu.05.070185.000441
  12. Bartelt A and Heeren J (2014) Adipose tissue browning and metabolic health. Nat Rev Endocrinol 10, 24-36 https://doi.org/10.1038/nrendo.2013.204
  13. Hossain M, Imran KM, Rahman MS, Yoon D, Marimuthu V and Kim YS (2020) Sinapic acid induces the expression of thermogenic signature genes and lipolysis through activation of PKA/CREB signaling in brown adipocytes. BMB Rep 53, 142-147 https://doi.org/10.5483/BMBRep.2020.53.3.093
  14. Fedorenko A, Lishko PV and Kirichok Y (2012) Mechanism of fatty-acid-dependent UCP1 uncoupling in brown fat mitochondria. Cell 151, 400-413 https://doi.org/10.1016/j.cell.2012.09.010
  15. Madsen L, Pedersen LM, Lillefosse HH et al (2010) UCP1 induction during recruitment of brown adipocytes in white adipose tissue is dependent on cyclooxygenase activity. PLoS One 5, e11391 https://doi.org/10.1371/journal.pone.0011391
  16. Chang SH, Jang J, Oh S et al (2021) Nrf2 induces Ucp1 expression in adipocytes in response to β3-AR stimulation and enhances oxygen consumption in high-fat diet-fed obese mice. BMB Rep 54, 419-424 https://doi.org/10.5483/BMBRep.2021.54.8.023
  17. van Dierendonck X, Sancerni T, Alves-Guerra MC and Stienstra R (2020) The role of uncoupling protein 2 in macrophages and its impact on obesity-induced adipose tissue inflammation and insulin resistance. J Biol Chem 295, 17535-17548 https://doi.org/10.1074/jbc.RA120.014868
  18. Weisberg SP, McCann D, Desai M, Rosenbaum M, Leibel RL and Ferrante AW Jr (2003) Obesity is associated with macrophage accumulation in adipose tissue. J Clin Invest 112, 1796-1808 https://doi.org/10.1172/JCI200319246
  19. Trayhurn P (2007) Adipocyte biology. Obes Rev 8 Suppl 1, 41-44 https://doi.org/10.1111/j.1467-789X.2007.00316.x
  20. Xiao Y, Yuan T, Yao W and Liao K (2010) 3T3-L1 adipocyte apoptosis induced by thiazolidinediones is peroxisome proliferator-activated receptor-gamma-dependent and mediated by the caspase-3-dependent apoptotic pathway. FEBS J 277, 687-696 https://doi.org/10.1111/j.1742-4658.2009.07514.x
  21. Lindhorst A, Raulien N, Wieghofer P et al (2021) Adipocyte death triggers a pro-inflammatory response and induces metabolic activation of resident macrophages. Cell Death Dis 12, 579 https://doi.org/10.1038/s41419-021-03872-9
  22. Alkhouri N, Gornicka A, Berk MP et al (2010) Adipocyte apoptosis, a link between obesity, insulin resistance, and hepatic steatosis. J Biol Chem 285, 3428-3438 https://doi.org/10.1074/jbc.M109.074252
  23. Kim JG, Sun BH, Dietrich MO et al (2015) AgRP neurons regulate bone mass. Cell Rep 13, 8-14 https://doi.org/10.1016/j.celrep.2015.08.070
  24. Madreiter-Sokolowski CT, Gyorffy B, Klec C et al (2017) UCP2 and PRMT1 are key prognostic markers for lung carcinoma patients. Oncotarget 8, 80278-80285 https://doi.org/10.18632/oncotarget.20571
  25. Qin N, Cai T, Ke Q et al (2019) UCP2-dependent improvement of mitochondrial dynamics protects against acute kidney injury. J Pathol 247, 392-405 https://doi.org/10.1002/path.5198
  26. Joseph JW, Koshkin V, Zhang CY et al (2002) Uncoupling protein 2 knockout mice have enhanced insulin secretory capacity after a high-fat diet. Diabetes 51, 3211-3219 https://doi.org/10.2337/diabetes.51.11.3211
  27. Pi J, Bai Y, Daniel KW et al (2009) Persistent oxidative stress due to absence of uncoupling protein 2 associated with impaired pancreatic beta-cell function. Endocrinology 150, 3040-3048 https://doi.org/10.1210/en.2008-1642
  28. Eto H, Suga H, Matsumoto D et al (2009) Characterization of structure and cellular components of aspirated and excised adipose tissue. Plast Reconstr Surg 124, 1087-1097 https://doi.org/10.1097/PRS.0b013e3181b5a3f1
  29. Bora P and Majumdar AS (2017) Adipose tissue-derived stromal vascular fraction in regenerative medicine: a brief review on biology and translation. Stem Cell Res Ther 8, 145 https://doi.org/10.1186/s13287-017-0598-y
  30. Rondini EA and Granneman JG (2020) Single cell approaches to address adipose tissue stromal cell heterogeneity. Biochem J 477, 583-600 https://doi.org/10.1042/BCJ20190467
  31. Wang Y, Tang B, Long L et al (2021) Improvement of obesity-associated disorders by a small-molecule drug targeting mitochondria of adipose tissue macrophages. Nat Commun 12, 102 https://doi.org/10.1038/s41467-020-20315-9
  32. Bu L, Gao M, Qu S and Liu D (2013) Intraperitoneal injection of clodronate liposomes eliminates visceral adipose macrophages and blocks high-fat diet-induced weight gain and development of insulin resistance. AAPS J 15, 1001-1011 https://doi.org/10.1208/s12248-013-9501-7
  33. Sun X and Zemel MB (2004) Role of uncoupling protein 2 (UCP2) expression and 1alpha, 25-dihydroxyvitamin D3 in modulating adipocyte apoptosis. FASEB J 18, 1430-1432 https://doi.org/10.1096/fj.04-1971fje
  34. Caron A, Labbe SM, Carter S et al (2017) Loss of UCP2 impairs cold-induced non-shivering thermogenesis by promoting a shift toward glucose utilization in brown adipose tissue. Biochimie 134, 118-126 https://doi.org/10.1016/j.biochi.2017.01.006