Grp78 Heterozygosity Promotes Adaptive Unfolded Protein Response and Attenuates Diet-induced Obesity and Insulin Resistance

Overview

Journal Diabetes

Specialty Endocrinology

Date 2009 Oct 8

PMID 19808896

Citations 98

Authors

Risheng Ye

Dae Young Jung

John Y Jun

Jianze Li

Shengzhan Luo

Hwi Jin Ko

Jason K Kim

Amy S Lee

Affiliations

Soon will be listed here.

Abstract

Objective: To investigate the role of the endoplasmic reticulum (ER) chaperone glucose-regulated protein (GRP) 78/BiP in the pathogenesis of obesity, insulin resistance, and type 2 diabetes.

Research Design And Methods: Male Grp78(+/-) mice and their wild-type littermates were subjected to a high-fat diet (HFD) regimen. Pathogenesis of obesity and type 2 diabetes was examined by multiple approaches of metabolic phenotyping. Tissue-specific insulin sensitivity was analyzed by hyperinsulinemic-euglycemic clamps. Molecular mechanism was explored via immunoblotting and tissue culture manipulation.

Results: Grp78 heterozygosity increases energy expenditure and attenuates HFD-induced obesity. Grp78(+/-) mice are resistant to diet-induced hyperinsulinemia, liver steatosis, white adipose tissue (WAT) inflammation, and hyperglycemia. Hyperinsulinemic-euglycemic clamp studies revealed that Grp78 heterozygosity improves glucose metabolism independent of adiposity and following an HFD increases insulin sensitivity predominantly in WAT. As mechanistic explanations, Grp78 heterozygosity in WAT under HFD stress promotes adaptive unfolded protein response (UPR), attenuates translational block, and upregulates ER degradation-enhancing alpha-mannosidase-like protein (EDEM) and ER chaperones, thus improving ER quality control and folding capacity. Further, overexpression of the active form of ATF6 induces protective UPR and improves insulin signaling upon ER stress.

Conclusions: HFD-induced obesity and type 2 diabetes are improved in Grp78(+/-) mice. Adaptive UPR in WAT could contribute to this improvement, linking ER homeostasis to energy balance and glucose metabolism.

Citing Articles

Skeletal muscle disorders as risk factors for type 2 diabetes.

Tammineni E, Manno C, Oza G, Figueroa L Mol Cell Endocrinol. 2025; 599:112466.

PMID: 39848431 PMC: 11886953. DOI: 10.1016/j.mce.2025.112466.

Folic Acid Prevents High-Fat Diet-Induced Postpartum Weight Retention in Rats, Which Is Associated with a Reduction in Endoplasmic Reticulum Stress-Mediated Hepatic Lipogenesis.

Zhang H, Zhang L, Zhao X, Ma Y, Sun D, Bai Y Nutrients. 2025; 16(24.

PMID: 39770997 PMC: 11676124. DOI: 10.3390/nu16244377.

Insulin Resistance, Obesity, and Lipotoxicity.

Yazici D, Demir S, Sezer H Adv Exp Med Biol. 2024; 1460:391-430.

PMID: 39287860 DOI: 10.1007/978-3-031-63657-8_14.

Long noncoding RNA protein-disulfide isomerase-associated 3 regulated high glucose-induced podocyte apoptosis in diabetic nephropathy through targeting miR-139-3p.

He Y, Wang T, Li W, Chen Y World J Diabetes. 2024; 15(2):260-274.

PMID: 38464366 PMC: 10921158. DOI: 10.4239/wjd.v15.i2.260.

COVID-19, Obesity, and GRP78: Unraveling the Pathological Link.

Shin J, Shimomura I J Obes Metab Syndr. 2023; 32(3):183-196.

PMID: 37752707 PMC: 10583770. DOI: 10.7570/jomes23053.

References

Ozcan U, Cao Q, Yilmaz E, Lee A, Iwakoshi N, Ozdelen E . Endoplasmic reticulum stress links obesity, insulin action, and type 2 diabetes. Science. 2004; 306(5695):457-61. DOI: 10.1126/science.1103160. View

Cusi K . Nonalcoholic fatty liver disease in type 2 diabetes mellitus. Curr Opin Endocrinol Diabetes Obes. 2009; 16(2):141-9. DOI: 10.1097/MED.0b013e3283293015. View

Guo L, Nakamura K, Lynch J, Opas M, Olson E, Agellon L . Cardiac-specific expression of calcineurin reverses embryonic lethality in calreticulin-deficient mouse. J Biol Chem. 2002; 277(52):50776-9. DOI: 10.1074/jbc.M209900200. View

Batchvarova N, Wang X, Ron D . Inhibition of adipogenesis by the stress-induced protein CHOP (Gadd153). EMBO J. 1995; 14(19):4654-61. PMC: 394562. DOI: 10.1002/j.1460-2075.1995.tb00147.x. View

Sabio G, Das M, Mora A, Zhang Z, Jun J, Ko H . A stress signaling pathway in adipose tissue regulates hepatic insulin resistance. Science. 2008; 322(5907):1539-43. PMC: 2643026. DOI: 10.1126/science.1160794. View

Ozcan U, Yilmaz E, Ozcan L, Furuhashi M, Vaillancourt E, Smith R . Chemical chaperones reduce ER stress and restore glucose homeostasis in a mouse model of type 2 diabetes. Science. 2006; 313(5790):1137-40. PMC: 4741373. DOI: 10.1126/science.1128294. View

Hendershot L . The ER function BiP is a master regulator of ER function. Mt Sinai J Med. 2004; 71(5):289-97. View

Ni M, Lee A . ER chaperones in mammalian development and human diseases. FEBS Lett. 2007; 581(19):3641-51. PMC: 2040386. DOI: 10.1016/j.febslet.2007.04.045. View

Ozcan U, Ozcan L, Yilmaz E, Duvel K, Sahin M, Manning B . Loss of the tuberous sclerosis complex tumor suppressors triggers the unfolded protein response to regulate insulin signaling and apoptosis. Mol Cell. 2008; 29(5):541-51. PMC: 2361721. DOI: 10.1016/j.molcel.2007.12.023. View

10.

Cunningham J, Rodgers J, Arlow D, Vazquez F, Mootha V, Puigserver P . mTOR controls mitochondrial oxidative function through a YY1-PGC-1alpha transcriptional complex. Nature. 2007; 450(7170):736-40. DOI: 10.1038/nature06322. View

11.

Luo S, Mao C, Lee B, Lee A . GRP78/BiP is required for cell proliferation and protecting the inner cell mass from apoptosis during early mouse embryonic development. Mol Cell Biol. 2006; 26(15):5688-97. PMC: 1592753. DOI: 10.1128/MCB.00779-06. View

12.

Bass J, Chiu G, Argon Y, Steiner D . Folding of insulin receptor monomers is facilitated by the molecular chaperones calnexin and calreticulin and impaired by rapid dimerization. J Cell Biol. 1998; 141(3):637-46. PMC: 2132748. DOI: 10.1083/jcb.141.3.637. View

13.

Harding H, Zeng H, Zhang Y, Jungries R, Chung P, Plesken H . Diabetes mellitus and exocrine pancreatic dysfunction in perk-/- mice reveals a role for translational control in secretory cell survival. Mol Cell. 2001; 7(6):1153-63. DOI: 10.1016/s1097-2765(01)00264-7. View

14.

Ramos R, Swanson A, Bass J . Calreticulin and Hsp90 stabilize the human insulin receptor and promote its mobility in the endoplasmic reticulum. Proc Natl Acad Sci U S A. 2007; 104(25):10470-5. PMC: 1965537. DOI: 10.1073/pnas.0701114104. View

15.

Fu Y, Wey S, Wang M, Ye R, Liao C, Roy-Burman P . Pten null prostate tumorigenesis and AKT activation are blocked by targeted knockout of ER chaperone GRP78/BiP in prostate epithelium. Proc Natl Acad Sci U S A. 2008; 105(49):19444-9. PMC: 2614780. DOI: 10.1073/pnas.0807691105. View

16.

Lee A, Iwakoshi N, Glimcher L . XBP-1 regulates a subset of endoplasmic reticulum resident chaperone genes in the unfolded protein response. Mol Cell Biol. 2003; 23(21):7448-59. PMC: 207643. DOI: 10.1128/MCB.23.21.7448-7459.2003. View

17.

Ma Y, Hendershot L . Delineation of a negative feedback regulatory loop that controls protein translation during endoplasmic reticulum stress. J Biol Chem. 2003; 278(37):34864-73. DOI: 10.1074/jbc.M301107200. View

18.

Lee A . The glucose-regulated proteins: stress induction and clinical applications. Trends Biochem Sci. 2001; 26(8):504-10. DOI: 10.1016/s0968-0004(01)01908-9. View

19.

Rutkowski D, Kaufman R . That which does not kill me makes me stronger: adapting to chronic ER stress. Trends Biochem Sci. 2007; 32(10):469-76. DOI: 10.1016/j.tibs.2007.09.003. View

20.

Lu P, Jousse C, Marciniak S, Zhang Y, Novoa I, Scheuner D . Cytoprotection by pre-emptive conditional phosphorylation of translation initiation factor 2. EMBO J. 2004; 23(1):169-79. PMC: 1271668. DOI: 10.1038/sj.emboj.7600030. View