p62 Links β-adrenergic input to mitochondrial function and thermogenesis
Timo D. Müller, … , Jorge Moscat, Matthias H. Tschöp
Timo D. Müller, … , Jorge Moscat, Matthias H. Tschöp
Published December 21, 2012
Citation Information: J Clin Invest. 2013;123(1):469-478. https://doi.org/10.1172/JCI64209.
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Research Article Metabolism

p62 Links β-adrenergic input to mitochondrial function and thermogenesis

Abstract

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 β-adrenergic stimuli. Ablation of p62 leads to decreased activation of p38 targets, affecting signaling molecules that control mitochondrial function, such as ATF2, CREB, PGC1α, DIO2, NRF1, CYTC, COX2, ATP5β, 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.

Authors

Timo D. Müller, Sang Jun Lee, Martin Jastroch, Dhiraj Kabra, Kerstin Stemmer, Michaela Aichler, Bill Abplanalp, Gayathri Ananthakrishnan, Nakul Bhardwaj, Sheila Collins, Senad Divanovic, Max Endele, Brian Finan, Yuanqing Gao, Kirk M. Habegger, Jazzmin Hembree, Kristy M. Heppner, Susanna Hofmann, Jenna Holland, Daniela Küchler, Maria Kutschke, Radha Krishna, Maarit Lehti, Rebecca Oelkrug, Nickki Ottaway, Diego Perez-Tilve, Christine Raver, Axel K. Walch, Sonja C. Schriever, John Speakman, Yu-Hua Tseng, Maria Diaz-Meco, Paul T. Pfluger, Jorge Moscat, Matthias H. Tschöp

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Figure 4

Impaired mitochondrial function in BAT of chow-fed adipocyte-specific p62–/– mice.

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Impaired mitochondrial function in BAT of chow-fed adipocyte-specific p6...
H&E staining of BAT (A). Expression of genes related to inflammation (B) and macrophage infiltration (C) in BAT. Western blot analysis of Ppargc1a and Ucp1 (D) and ratio between levels of total and phosphorylated levels of p38α in BAT (E). Expression of genes related to thermogenesis (F). Western blot analysis of Ucp1, Lipe, and Creb in the inguinal WAT (G). Electron micrograph of brown adipocytes (H), Cox activity (I), and mRNA expression levels of genes related to mitochondrial electron transport (J) in BAT of adipocyte-specific p62–/– and WT mice. Cox4i2, COX subunit 4b. Measurement of gene expression was performed in n = 7–8 mice of each genotype. Cox activity and protein levels of p38α were assessed in n = 4 mice of each genotype. Scale bars: 25 μm (A); 1 μm (H, original magnification ×4,000); 200 nm (H; original magnification, ×25,000. Data represent mean ± SEM. *P < 0.05; **P < 0.01.