p62 Links β-adrenergic input to mitochondrial function and thermogenesis

被引：105

作者：

Mueller, Timo D. ^{[1
,2
]}

Lee, Sang Jun ^{[3
]}

Jastroch, Martin ^{[1
,2
]}

Kabra, Dhiraj ^{[1
,2
]}

Stemmer, Kerstin ^{[1
,2
]}

Aichler, Michaela ^{[4
]}

Abplanalp, Bill ^{[5
]}

Ananthakrishnan, Gayathri ^{[5
]}

Bhardwaj, Nakul ^{[5
]}

Collins, Sheila ^{[6
]}

Divanovic, Senad ^{[7
,8
]}

Endele, Max ^{[9
]}

Finan, Brian ^{[1
,2
]}

Gao, Yuanqing ^{[5
]}

Habegger, Kirk M. ^{[5
]}

Hembree, Jazzmin ^{[5
]}

Heppner, Kristy M. ^{[5
]}

Hofmann, Susanna ^{[10
]}

Holland, Jenna ^{[5
]}

Kuechler, Daniela ^{[1
,2
]}

Kutschke, Maria ^{[1
,2
]}

Krishna, Radha ^{[5
]}

Lehti, Maarit ^{[5
]}

Oelkrug, Rebecca ^{[11
]}

Ottaway, Nickki ^{[5
]}

Perez-Tilve, Diego ^{[5
]}

Raver, Christine ^{[5
]}

Walch, Axel K. ^{[4
]}

Schriever, Sonja C. ^{[1
,2
]}

Speakman, John ^{[12
,13
]}

Tseng, Yu-Hua ^{[14
]}

Diaz-Meco, Maria ^{[3
]}

Pfluger, Paul T. ^{[1
,2
,5
]}

Moscat, Jorge ^{[3
]}

Tschoep, Matthias H. ^{[1
,2
,5
]}

机构：

[1] Tech Univ Munich, Inst Diabet & Obes, Helmholtz Zentrum Muenchen, D-85764 Munich, Germany

[2] Tech Univ Munich, Dept Med, D-85764 Munich, Germany

[3] Sanford Burnham Med Res Inst, La Jolla, CA 92037 USA

[4] Helmholtz Ctr Munich, Inst Pathol, Res Unit Analyt Pathol, Munich, Germany

[5] Univ Cincinnati, Dept Internal Med, Metabol Dis Inst, Cincinnati, OH USA

[6] Sanford Burnham Med Res Inst, Diabetes & Obes Res Ctr, Orlando, FL USA

[7] Cincinnati Childrens Hosp Res Fdn, Div Mol Immunol, Cincinnati, OH USA

[8] Univ Cincinnati, Coll Med, Cincinnati, OH USA

[9] German Res Ctr Environm Hlth, Helmholtz Ctr Munich, Res Unit Stem Cell Dynam, Neuherberg, Germany

[10] Helmholtz Ctr Munich, Inst Expt Genet, Munich, Germany

[11] Univ Marburg, Dept Anim Physiol, Marburg, Germany

[12] Inst Genet & Dev Biol, Beijing, Peoples R China

[13] Univ Aberdeen, Inst Biol & Environm Sci, Aberdeen, Scotland

[14] Harvard Univ, Sch Med, Joslin Diabet Ctr, Boston, MA 02115 USA

来源：

JOURNAL OF CLINICAL INVESTIGATION | 2013年 / 123卷 / 01期

关键词：

BROWN ADIPOSE-TISSUE; P38 MAP KINASE; ACTIVATED PROTEIN-KINASE; TRANSCRIPTIONAL CONTROL; INSULIN-RESISTANCE; FAT; P62/SQSTM1; GENE; MITOPHAGY; AUTOPHAGY;

D O I：

10.1172/JCI64209

中图分类号：

R-3 [医学研究方法]; R3 [基础医学];

学科分类号：

1001 ;

摘要：

The scaffold protein p62 (sequestosome 1; SQSTM1) is an emerging key molecular link among the metabolic, immune, and proliferative processes of the cell. Here, we report that adipocyte-specific, but not CNS-, liver-, muscle-, or myeloid-specific p62-deficient mice are obese and exhibit a decreased metabolic rate caused by impaired nonshivering thermogenesis. Our results show that p62 regulates energy metabolism via control of mitochondrial function in brown adipose tissue (BAT). Accordingly, adipocyte-specific p62 deficiency led to impaired mitochondrial function, causing BAT to become unresponsive to beta-adrenergic stimuli. Ablation of p62 leads to decreased activation of p38 targets, affecting signaling molecules that control mitochondrial function, such as ATF2, CREB, PGC1 alpha, DIO2, NRF1, CYTC, COX2, ATP5 beta, and UCP1.p62 ablation in HIB1B and BAT primary cells demonstrated that p62 controls thermogenesis in a cell-autonomous manner, independently of brown adipocyte development or differentiation. Together, our data identify p62 as a novel regulator of mitochondrial function and brown fat thermogenesis.

引用

页码：469 / 478

页数：10

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