NBR1 is a Critical Step in the Repression of Thermogenesis of P62-deficient Adipocytes Through PPARγ

Overview

Journal Nat Commun

Specialty Biology

Date 2021 May 18

PMID 34001883

Citations 10

Authors

Jianfeng Huang

Juan F Linares

Angeles Duran

Wenmin Xia

Alan R Saltiel

Timo D Muller

Maria T Diaz-Meco

Jorge Moscat

Affiliations

Soon will be listed here.

Abstract

Activation of non-shivering thermogenesis is considered a promising approach to lower body weight in obesity. p62 deficiency in adipocytes reduces systemic energy expenditure but its role in sustaining mitochondrial function and thermogenesis remains unresolved. NBR1 shares a remarkable structural similarity with p62 and can interact with p62 through their respective PB1 domains. However, the physiological relevance of NBR1 in metabolism, as compared to that of p62, was not clear. Here we show that whole-body and adipocyte-specific ablation of NBR1 reverts the obesity phenotype induced by p62 deficiency by restoring global energy expenditure and thermogenesis in brown adipose tissue. Impaired adrenergic-induced browning of p62-deficient adipocytes is rescued by NBR1 inactivation, unveiling a negative role of NBR1 in thermogenesis under conditions of p62 loss. We demonstrate that upon p62 inactivation, NBR1 represses the activity of PPARγ, establishing an unexplored p62/NBR1-mediated paradigm in adipocyte thermogenesis that is critical for the control of obesity.

Citing Articles

The autophagic regulation of rosiglitazone-promoted adipocyte browning.

Li Y, Zheng W, Li X, Lue Z, Liu Y, Wu J Front Pharmacol. 2024; 15:1412520.

PMID: 38895627 PMC: 11184087. DOI: 10.3389/fphar.2024.1412520.

Obesity causes mitochondrial fragmentation and dysfunction in white adipocytes due to RalA activation.

Xia W, Veeragandham P, Cao Y, Xu Y, Rhyne T, Qian J Nat Metab. 2024; 6(2):273-289.

PMID: 38286821 PMC: 10896723. DOI: 10.1038/s42255-024-00978-0.

LC3-independent autophagy is vital to prevent TNF cytotoxicity.

Priem D, Huyghe J, Bertrand M Autophagy. 2023; 19(9):2585-2589.

PMID: 37014272 PMC: 10392734. DOI: 10.1080/15548627.2023.2197760.

De novo lipogenesis fuels adipocyte autophagosome and lysosome membrane dynamics.

Rowland L, Guilherme A, Henriques F, DiMarzio C, Munroe S, Wetoska N Nat Commun. 2023; 14(1):1362.

PMID: 36914626 PMC: 10011520. DOI: 10.1038/s41467-023-37016-8.

Enhanced liquidity of p62 droplets mediated by Smurf1 links Nrf2 activation and autophagy.

Xia Q, Li Y, Xu W, Wu C, Zheng H, Liu L Cell Biosci. 2023; 13(1):37.

PMID: 36810259 PMC: 9945626. DOI: 10.1186/s13578-023-00978-9.

References

Duran A, Amanchy R, Linares J, Joshi J, Abu-Baker S, Porollo A . p62 is a key regulator of nutrient sensing in the mTORC1 pathway. Mol Cell. 2011; 44(1):134-46. PMC: 3190169. DOI: 10.1016/j.molcel.2011.06.038. View

Speakman J, Fletcher Q, Vaanholt L . The '39 steps': an algorithm for performing statistical analysis of data on energy intake and expenditure. Dis Model Mech. 2013; 6(2):293-301. PMC: 3597012. DOI: 10.1242/dmm.009860. View

Fischer K, Fenzl A, Liu D, Dyar K, Kleinert M, Brielmeier M . The scaffold protein p62 regulates adaptive thermogenesis through ATF2 nuclear target activation. Nat Commun. 2020; 11(1):2306. PMC: 7211001. DOI: 10.1038/s41467-020-16230-8. View

Cao W, Daniel K, Robidoux J, Puigserver P, Medvedev A, Bai X . p38 mitogen-activated protein kinase is the central regulator of cyclic AMP-dependent transcription of the brown fat uncoupling protein 1 gene. Mol Cell Biol. 2004; 24(7):3057-67. PMC: 371122. DOI: 10.1128/MCB.24.7.3057-3067.2004. View

Harms M, Seale P . Brown and beige fat: development, function and therapeutic potential. Nat Med. 2013; 19(10):1252-63. DOI: 10.1038/nm.3361. View

Valencia T, Kim J, Abu-Baker S, Moscat-Pardos J, Ahn C, Reina-Campos M . Metabolic reprogramming of stromal fibroblasts through p62-mTORC1 signaling promotes inflammation and tumorigenesis. Cancer Cell. 2014; 26(1):121-135. PMC: 4101061. DOI: 10.1016/j.ccr.2014.05.004. View

Lazarou M, Sliter D, Kane L, Sarraf S, Wang C, Burman J . The ubiquitin kinase PINK1 recruits autophagy receptors to induce mitophagy. Nature. 2015; 524(7565):309-314. PMC: 5018156. DOI: 10.1038/nature14893. View

Betz M, Enerback S . Targeting thermogenesis in brown fat and muscle to treat obesity and metabolic disease. Nat Rev Endocrinol. 2017; 14(2):77-87. DOI: 10.1038/nrendo.2017.132. View

Saito M, Okamatsu-Ogura Y, Matsushita M, Watanabe K, Yoneshiro T, Nio-Kobayashi J . High incidence of metabolically active brown adipose tissue in healthy adult humans: effects of cold exposure and adiposity. Diabetes. 2009; 58(7):1526-31. PMC: 2699872. DOI: 10.2337/db09-0530. View

10.

Tschop M, Speakman J, Arch J, Auwerx J, Bruning J, Chan L . A guide to analysis of mouse energy metabolism. Nat Methods. 2011; 9(1):57-63. PMC: 3654855. DOI: 10.1038/nmeth.1806. View

11.

Duran A, Linares J, Galvez A, Wikenheiser K, Flores J, Diaz-Meco M . The signaling adaptor p62 is an important NF-kappaB mediator in tumorigenesis. Cancer Cell. 2008; 13(4):343-54. DOI: 10.1016/j.ccr.2008.02.001. View

12.

Moscat J, Karin M, Diaz-Meco M . p62 in Cancer: Signaling Adaptor Beyond Autophagy. Cell. 2016; 167(3):606-609. PMC: 5114003. DOI: 10.1016/j.cell.2016.09.030. View

13.

Wu J, Bostrom P, Sparks L, Ye L, Choi J, Giang A . Beige adipocytes are a distinct type of thermogenic fat cell in mouse and human. Cell. 2012; 150(2):366-76. PMC: 3402601. DOI: 10.1016/j.cell.2012.05.016. View

14.

Moscat J, Diaz-Meco M . p62 at the crossroads of autophagy, apoptosis, and cancer. Cell. 2009; 137(6):1001-4. PMC: 3971861. DOI: 10.1016/j.cell.2009.05.023. View

15.

Basse A, Isidor M, Winther S, Skjoldborg N, Murholm M, Andersen E . Regulation of glycolysis in brown adipocytes by HIF-1α. Sci Rep. 2017; 7(1):4052. PMC: 5481455. DOI: 10.1038/s41598-017-04246-y. View

16.

Chawla A, REPA J, Evans R, Mangelsdorf D . Nuclear receptors and lipid physiology: opening the X-files. Science. 2001; 294(5548):1866-70. DOI: 10.1126/science.294.5548.1866. View

17.

Huang J, Duran A, Reina-Campos M, Valencia T, Castilla E, Muller T . Adipocyte p62/SQSTM1 Suppresses Tumorigenesis through Opposite Regulations of Metabolism in Adipose Tissue and Tumor. Cancer Cell. 2018; 33(4):770-784.e6. PMC: 5896786. DOI: 10.1016/j.ccell.2018.03.001. View

18.

Moscat J, Diaz-Meco M, Albert A, Campuzano S . Cell signaling and function organized by PB1 domain interactions. Mol Cell. 2006; 23(5):631-40. DOI: 10.1016/j.molcel.2006.08.002. View

19.

Lee S, Pfluger P, Kim J, Nogueiras R, Duran A, Pages G . A functional role for the p62-ERK1 axis in the control of energy homeostasis and adipogenesis. EMBO Rep. 2010; 11(3):226-32. PMC: 2838704. DOI: 10.1038/embor.2010.7. View

20.

Cannon B, Nedergaard J . Brown adipose tissue: function and physiological significance. Physiol Rev. 2004; 84(1):277-359. DOI: 10.1152/physrev.00015.2003. View