David Taylor1, Roberta A Gottlieb1. 1. The Cedars-Sinai Heart Institute, Barbra Streisand Women's Heart Center, Cedars-Sinai Medical Center, Los Angeles, California, USA.
Abstract
OBJECTIVE: Browning of white adipose tissue (WAT) promotes increased energy expenditure through the action of uncoupling protein 1 (UCP1) and is an attractive target to promote weight loss in obesity. Lowering of mitochondrial membrane potential by UCP1 is uniquely beneficial in this context; in other tissues, reduced membrane potential promotes mitochondrial clearance via mitophagy. It is unknown how parkin-mediated mitophagy is regulated in beige adipocytes. METHODS: The relationship between parkin expression and WAT browning was investigated in 3T3-L1 adipocytes and parkin-deficient male C57BL/6 mice in response to pharmacological browning stimuli. RESULTS: Rosiglitazone treatment in 3T3-L1 adipocytes promoted mitochondrial biogenesis, UCP1 expression, and mitochondrial uncoupling. Parkin expression was decreased and reduced mitochondrial-associated parkin, and p62 indicated a reduction in mitophagy activity. Parkin overexpression prevented mitochondrial remodeling in response to rosiglitazone. In CL 316,243-treated wild-type mice, decreased parkin expression was observed in subcutaneous inguinal WAT, where UCP1 was strongly induced. CL 316,243 treatment weakly induced UCP1 expression in the gonadal depot, where parkin expression was unchanged. In contrast, parkin-deficient mice exhibited robust UCP1 expression in gonadal WAT following CL 316,243 treatment. CONCLUSIONS: WAT browning was associated with a decrease in parkin-mediated mitophagy, and parkin expression antagonized browning of WAT.
OBJECTIVE: Browning of white adipose tissue (WAT) promotes increased energy expenditure through the action of uncoupling protein 1 (UCP1) and is an attractive target to promote weight loss in obesity. Lowering of mitochondrial membrane potential by UCP1 is uniquely beneficial in this context; in other tissues, reduced membrane potential promotes mitochondrial clearance via mitophagy. It is unknown how parkin-mediated mitophagy is regulated in beige adipocytes. METHODS: The relationship between parkin expression and WAT browning was investigated in 3T3-L1 adipocytes and parkin-deficient male C57BL/6 mice in response to pharmacological browning stimuli. RESULTS:Rosiglitazone treatment in 3T3-L1 adipocytes promoted mitochondrial biogenesis, UCP1 expression, and mitochondrial uncoupling. Parkin expression was decreased and reduced mitochondrial-associated parkin, and p62 indicated a reduction in mitophagy activity. Parkin overexpression prevented mitochondrial remodeling in response to rosiglitazone. In CL 316,243-treated wild-type mice, decreased parkin expression was observed in subcutaneous inguinal WAT, where UCP1 was strongly induced. CL 316,243 treatment weakly induced UCP1 expression in the gonadal depot, where parkin expression was unchanged. In contrast, parkin-deficientmice exhibited robust UCP1 expression in gonadal WAT following CL 316,243 treatment. CONCLUSIONS: WAT browning was associated with a decrease in parkin-mediated mitophagy, and parkin expression antagonized browning of WAT.
Authors: Kye-Young Kim; Mark V Stevens; M Hasina Akter; Sarah E Rusk; Robert J Huang; Alexandra Cohen; Audrey Noguchi; Danielle Springer; Alexander V Bocharov; Tomas L Eggerman; Der-Fen Suen; Richard J Youle; Marcelo Amar; Alan T Remaley; Michael N Sack Journal: J Clin Invest Date: 2011-08-25 Impact factor: 14.808
Authors: Davi M Lyra-Leite; Allen M Andres; Andrew P Petersen; Nethika R Ariyasinghe; Nathan Cho; Jezell A Lee; Roberta A Gottlieb; Megan L McCain Journal: Am J Physiol Heart Circ Physiol Date: 2017-07-21 Impact factor: 4.733
Authors: Raja Gopal Reddy Mooli; Dhanunjay Mukhi; Mikayla Watt; Lia Edmunds; Bingxian Xie; Joseph Capooci; Matthew Reslink; Chetachukwu Eze; Amanda Mills; Donna B Stolz; Michael Jurczak; Sadeesh K Ramakrishnan Journal: Metabolism Date: 2020-04-07 Impact factor: 8.694
Authors: Callie A S Corsa; Gemma L Pearson; Aaron Renberg; Matthew M Askar; Tracy Vozheiko; Ormond A MacDougald; Scott A Soleimanpour Journal: J Biol Chem Date: 2019-03-15 Impact factor: 5.157
Authors: Zhenqi Zhou; Timothy M Moore; Brian G Drew; Vicent Ribas; Jonathan Wanagat; Mete Civelek; Mayuko Segawa; Dane M Wolf; Frode Norheim; Marcus M Seldin; Alexander R Strumwasser; Kate A Whitney; Ellen Lester; Britany R Reddish; Laurent Vergnes; Karen Reue; Prashant Rajbhandari; Peter Tontonoz; Jason Lee; Sushil K Mahata; Sylvia C Hewitt; Orian Shirihai; Craig Gastonbury; Kerrin S Small; Markku Laakso; Jorgen Jensen; Sindre Lee; Christian A Drevon; Kenneth S Korach; Aldons J Lusis; Andrea L Hevener Journal: Sci Transl Med Date: 2020-08-05 Impact factor: 19.319
Authors: Roberta A Gottlieb; Helen S Goodridge; Annunziata N Crupi; Jordan S Nunnelee; David J Taylor; Amandine Thomas; Jean-Philippe Vit; Celine E Riera Journal: Aging (Albany NY) Date: 2018-11-18 Impact factor: 5.682