title: 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.affiliation: Institute for Diabetes and Obesity, Helmholtz Zentrum Muenchen and Department of Medicine, Technische Universität München, Munich, Germany.
authors.forename: Timo D
authors.initials: TD
authors.lastname: Müller
authors.forename: Sang Jun
authors.initials: SJ
authors.lastname: Lee
authors.forename: Martin
authors.initials: M
authors.lastname: Jastroch
authors.forename: Dhiraj
authors.initials: D
authors.lastname: Kabra
authors.forename: Kerstin
authors.initials: K
authors.lastname: Stemmer
authors.forename: Michaela
authors.initials: M
authors.lastname: Aichler
authors.forename: Bill
authors.initials: B
authors.lastname: Abplanalp
authors.forename: Gayathri
authors.initials: G
authors.lastname: Ananthakrishnan
authors.forename: Nakul
authors.initials: N
authors.lastname: Bhardwaj
authors.forename: Sheila
authors.initials: S
authors.lastname: Collins
authors.forename: Senad
authors.initials: S
authors.lastname: Divanovic
authors.forename: Max
authors.initials: M
authors.lastname: Endele
authors.forename: Brian
authors.initials: B
authors.lastname: Finan
authors.forename: Yuanqing
authors.initials: Y
authors.lastname: Gao
authors.forename: Kirk M
authors.initials: KM
authors.lastname: Habegger
authors.forename: Jazzmin
authors.initials: J
authors.lastname: Hembree
authors.forename: Kristy M
authors.initials: KM
authors.lastname: Heppner
authors.forename: Susanna
authors.initials: S
authors.lastname: Hofmann
authors.forename: Jenna
authors.initials: J
authors.lastname: Holland
authors.forename: Daniela
authors.initials: D
authors.lastname: Küchler
authors.forename: Maria
authors.initials: M
authors.lastname: Kutschke
authors.forename: Radha
authors.initials: R
authors.lastname: Krishna
authors.forename: Maarit
authors.initials: M
authors.lastname: Lehti
authors.forename: Rebecca
authors.initials: R
authors.lastname: Oelkrug
authors.forename: Nickki
authors.initials: N
authors.lastname: Ottaway
authors.forename: Diego
authors.initials: D
authors.lastname: Perez-Tilve
authors.forename: Christine
authors.initials: C
authors.lastname: Raver
authors.forename: Axel K
authors.initials: AK
authors.lastname: Walch
authors.forename: Sonja C
authors.initials: SC
authors.lastname: Schriever
authors.forename: John
authors.initials: J
authors.lastname: Speakman
authors.forename: Yu-Hua
authors.initials: YH
authors.lastname: Tseng
authors.forename: Maria
authors.initials: M
authors.lastname: Diaz-Meco
authors.forename: Paul T
authors.initials: PT
authors.lastname: Pfluger
authors.forename: Jorge
authors.initials: J
authors.lastname: Moscat
authors.forename: Matthias H
authors.initials: MH
authors.lastname: Tschöp
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D052437:Adipocytes, Brown / Q000166:cytology / Q000378:metabolism*; D002001:Adipose Tissue, Brown / Q000166:cytology / Q000378:metabolism*; D000818:Animals; D002478:Cells, Cultured; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism; D009928:Organ Specificity / Q000235:genetics; D000071456:Sequestosome-1 Protein; D022722:Thermogenesis / Q000502:physiology*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D006360:Heat-Shock Proteins; D024101:Mitochondrial Proteins; D000071456:Sequestosome-1 Protein; C101343:Sqstm1 protein, mouse; D014157:Transcription Factors; D048051:p38 Mitogen-Activated Protein Kinases