Glucose Starvation and Hypoxia, but Not the Saturated Fatty Acid Palmitic Acid or Cholesterol, Activate the Unfolded Protein Response in 3T3-F442A and 3T3-L1 Adipocytes

Overview

Journal Adipocyte

Specialties Cell Biology
Endocrinology
Physiology

Date 2015 Aug 11

PMID 26257992

Citations 10

Authors

Adina D Mihai

Martin Schroder

Affiliations

Soon will be listed here.

Abstract

Obesity is associated with endoplasmic reticulum (ER) stress and activation of the unfolded protein response (UPR) in adipose tissue. In this study we identify physiological triggers of ER stress and of the UPR in adipocytes in vitro. We show that two markers of adipose tissue remodelling in obesity, glucose starvation and hypoxia, cause ER stress in 3T3-F442A and 3T3-L1 adipocytes. Both conditions induced molecular markers of the IRE1α and PERK branches of the UPR, such as splicing of XBP1 mRNA and CHOP, as well as transcription of the ER stress responsive gene BiP. Hypoxia also induced an increase in phosphorylation of the PERK substrate eIF2α. By contrast, physiological triggers of ER stress in many other cell types, such as the saturated fatty acid palmitic acid, cholesterol, or several inflammatory cytokines including TNF-α, IL-1β, and IL-6, do not cause ER stress in 3T3-F442A and 3T3-L1 adipocytes. Our data suggest that physiological changes associated with remodelling of adipose tissue in obesity, such as hypoxia and glucose starvation, are more likely physiological ER stressors of adipocytes than the lipid overload or hyperinsulinemia associated with obesity.

Citing Articles

The tardigrade-derived mitochondrial abundant heat soluble protein improves adipose-derived stem cell survival against representative stressors.

Rolsma J, Darch W, Higgins N, Morgan J Sci Rep. 2024; 14(1):11834.

PMID: 38783150 PMC: 11116449. DOI: 10.1038/s41598-024-62693-w.

4-PBA inhibits hypoxia-induced lipolysis in rat adipose tissue and lipid accumulation in the liver through regulating ER stress.

Xiong Y, Wang Y, Xiong Y, Teng L Food Sci Nutr. 2023; 11(3):1223-1231.

PMID: 36911831 PMC: 10002945. DOI: 10.1002/fsn3.3156.

Mechanism of Hypoxia-Mediated Smooth Muscle Cell Proliferation Leading to Vascular Remodeling.

Huang X, Akgun E, Mehmood K, Zhang H, Tang Z, Li Y Biomed Res Int. 2023; 2022:3959845.

PMID: 36593773 PMC: 9805398. DOI: 10.1155/2022/3959845.

Low glucose and serum levels cause an increased inflammatory factor in 3T3-L1 cell through Akt, MAPKs and NF-кB activation.

Kugo H, Sukketsiri W, Iwamoto K, Suihara S, Moriyama T, Zaima N Adipocyte. 2021; 10(1):232-241.

PMID: 33896390 PMC: 8078669. DOI: 10.1080/21623945.2021.1914420.

Impact of serine protease inhibitor alpha1-antitrypsin on expression of endoplasmic reticulum stress-induced proinflammatory factors in adipocytes.

Ando Y, Kuroda A, Kusama K, Matsutani T, Matsuda A, Tamura K Biochem Biophys Rep. 2021; 26:100967.

PMID: 33732904 PMC: 7937654. DOI: 10.1016/j.bbrep.2021.100967.

References

Jiao P, Ma J, Feng B, Zhang H, Diehl J, Chin Y . FFA-induced adipocyte inflammation and insulin resistance: involvement of ER stress and IKKβ pathways. Obesity (Silver Spring). 2010; 19(3):483-91. DOI: 10.1038/oby.2010.200. View

Coenen K, Gruen M, Chait A, Hasty A . Diet-induced increases in adiposity, but not plasma lipids, promote macrophage infiltration into white adipose tissue. Diabetes. 2007; 56(3):564-73. DOI: 10.2337/db06-1375. View

Misaki Y, Miyauchi R, Mochizuki K, Takabe S, Shimada M, Ichikawa Y . Plasma interleukin-1β concentrations are closely associated with fasting blood glucose levels in healthy and preclinical middle-aged nonoverweight and overweight Japanese men. Metabolism. 2010; 59(10):1465-71. DOI: 10.1016/j.metabol.2010.01.011. View

Alhusaini S, McGee K, Schisano B, Harte A, McTernan P, Kumar S . Lipopolysaccharide, high glucose and saturated fatty acids induce endoplasmic reticulum stress in cultured primary human adipocytes: Salicylate alleviates this stress. Biochem Biophys Res Commun. 2010; 397(3):472-8. DOI: 10.1016/j.bbrc.2010.05.138. View

Tsuchiya S, Yamabe M, Yamaguchi Y, Kobayashi Y, Konno T, Tada K . Establishment and characterization of a human acute monocytic leukemia cell line (THP-1). Int J Cancer. 1980; 26(2):171-6. DOI: 10.1002/ijc.2910260208. View

Zhang K, Kaufman R . From endoplasmic-reticulum stress to the inflammatory response. Nature. 2008; 454(7203):455-62. PMC: 2727659. DOI: 10.1038/nature07203. View

Weigert C, Brodbeck K, Staiger H, Kausch C, Machicao F, Haring H . Palmitate, but not unsaturated fatty acids, induces the expression of interleukin-6 in human myotubes through proteasome-dependent activation of nuclear factor-kappaB. J Biol Chem. 2004; 279(23):23942-52. DOI: 10.1074/jbc.M312692200. View

Qiang L, Farmer S . C/EBPalpha-dependent induction of glutathione S-transferase zeta/maleylacetoacetate isomerase (GSTzeta/MAAI) expression during the differentiation of mouse fibroblasts into adipocytes. Biochem Biophys Res Commun. 2005; 340(3):845-51. DOI: 10.1016/j.bbrc.2005.12.067. View

Shiu R, Pouyssegur J, Pastan I . Glucose depletion accounts for the induction of two transformation-sensitive membrane proteinsin Rous sarcoma virus-transformed chick embryo fibroblasts. Proc Natl Acad Sci U S A. 1977; 74(9):3840-4. PMC: 431753. DOI: 10.1073/pnas.74.9.3840. View

10.

Dobrea G, Wieland R, Johnson M . The effect of rapid weight loss due to jejunoileal bypass on total cholesterol and high-density lipoprotein. Am J Clin Nutr. 1981; 34(10):1994-6. DOI: 10.1093/ajcn/34.10.1994. View

11.

Antuna-Puente B, Feve B, Fellahi S, Bastard J . Adipokines: the missing link between insulin resistance and obesity. Diabetes Metab. 2007; 34(1):2-11. DOI: 10.1016/j.diabet.2007.09.004. View

12.

Bi M, Naczki C, Koritzinsky M, Fels D, Blais J, Hu N . ER stress-regulated translation increases tolerance to extreme hypoxia and promotes tumor growth. EMBO J. 2005; 24(19):3470-81. PMC: 1276162. DOI: 10.1038/sj.emboj.7600777. View

13.

Bradley R, Fisher F, Maratos-Flier E . Dietary fatty acids differentially regulate production of TNF-alpha and IL-10 by murine 3T3-L1 adipocytes. Obesity (Silver Spring). 2008; 16(5):938-44. PMC: 4862864. DOI: 10.1038/oby.2008.39. View

14.

Wu J, Rutkowski D, Dubois M, Swathirajan J, Saunders T, Wang J . ATF6alpha optimizes long-term endoplasmic reticulum function to protect cells from chronic stress. Dev Cell. 2007; 13(3):351-64. DOI: 10.1016/j.devcel.2007.07.005. View

15.

Sun K, Kusminski C, Scherer P . Adipose tissue remodeling and obesity. J Clin Invest. 2011; 121(6):2094-101. PMC: 3104761. DOI: 10.1172/JCI45887. View

16.

Si Y, Yoon J, Lee K . Flux profile and modularity analysis of time-dependent metabolic changes of de novo adipocyte formation. Am J Physiol Endocrinol Metab. 2007; 292(6):E1637-46. DOI: 10.1152/ajpendo.00670.2006. View

17.

Cox D, Strudwick N, Ali A, Paton A, Paton J, Schroder M . Measuring signaling by the unfolded protein response. Methods Enzymol. 2011; 491:261-92. DOI: 10.1016/B978-0-12-385928-0.00015-8. View

18.

Rubin C, Hirsch A, Fung C, Rosen O . Development of hormone receptors and hormonal responsiveness in vitro. Insulin receptors and insulin sensitivity in the preadipocyte and adipocyte forms of 3T3-L1 cells. J Biol Chem. 1978; 253(20):7570-8. View

19.

Marciniak S, Yun C, Oyadomari S, Novoa I, Zhang Y, Jungreis R . CHOP induces death by promoting protein synthesis and oxidation in the stressed endoplasmic reticulum. Genes Dev. 2004; 18(24):3066-77. PMC: 535917. DOI: 10.1101/gad.1250704. View

20.

Sung H, Doh K, Son J, Park J, Bae Y, Choi S . Adipose vascular endothelial growth factor regulates metabolic homeostasis through angiogenesis. Cell Metab. 2013; 17(1):61-72. DOI: 10.1016/j.cmet.2012.12.010. View