Sally Yu Shi1,2, Wei Zhang1,3, Cynthia T Luk1,2, Tharini Sivasubramaniyam1,2, Jara J Brunt1,2, Stephanie A Schroer1, Harsh R Desai1,4, Alexandra Majerski1, Minna Woo5,6,7. 1. Toronto General Research Institute, 101 College Street, MaRS Centre/TMDT, Toronto, ON, Canada, M5G 1L7. 2. Institute of Medical Science, University of Toronto, Toronto, ON, Canada. 3. Department of Endocrinology, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, China. 4. Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada. 5. Toronto General Research Institute, 101 College Street, MaRS Centre/TMDT, Toronto, ON, Canada, M5G 1L7. mwoo@uhnresearch.ca. 6. Institute of Medical Science, University of Toronto, Toronto, ON, Canada. mwoo@uhnresearch.ca. 7. Division of Endocrinology, Department of Medicine, Toronto General Hospital, University Health Network, University of Toronto, Toronto, ON, Canada. mwoo@uhnresearch.ca.
Abstract
AIMS/HYPOTHESIS: Non-shivering thermogenesis in adipose tissue can be activated by excessive energy intake or following cold exposure. The molecular mechanisms regulating this activation have not been fully elucidated. The Janus kinase (JAK) - signal transducer and activator of transcription (STAT) pathway mediates the signal transduction of numerous hormones and growth factors that regulate adipose tissue development and function, and may play a role in adaptive thermogenesis. METHODS: We analysed mRNA and protein levels of uncoupling protein 1 (UCP1) and JAK2 in different adipose depots in response to metabolic and thermal stress. The in vivo role of JAK2 in adaptive thermogenesis was examined using mice with adipocyte-specific Jak2 deficiency (A-Jak2 KO). RESULTS: We show in murine brown adipose tissue (BAT) that JAK2 is upregulated together with UCP1 in response to high-fat diet (HFD) feeding and cold exposure. In contrast to white adipose tissue, where JAK2 was dispensable for UCP1 induction, we identified an essential role for BAT JAK2 in diet- and cold-induced thermogenesis via mediating the thermogenic response to β-adrenergic stimulation. Accordingly, A-Jak2 KO mice were unable to upregulate BAT UCP1 following a HFD or after cold exposure. Therefore, A-Jak2 KO mice were cold intolerant and susceptible to HFD-induced obesity and diabetes. CONCLUSIONS/ INTERPRETATION: Taken together, our results suggest that JAK2 plays a critical role in BAT function and adaptive thermogenesis. Targeting the JAK-STAT pathway may be a novel therapeutic approach for the treatment of obesity and related metabolic disorders.
AIMS/HYPOTHESIS: Non-shivering thermogenesis in adipose tissue can be activated by excessive energy intake or following cold exposure. The molecular mechanisms regulating this activation have not been fully elucidated. The Janus kinase (JAK) - signal transducer and activator of transcription (STAT) pathway mediates the signal transduction of numerous hormones and growth factors that regulate adipose tissue development and function, and may play a role in adaptive thermogenesis. METHODS: We analysed mRNA and protein levels of uncoupling protein 1 (UCP1) and JAK2 in different adipose depots in response to metabolic and thermal stress. The in vivo role of JAK2 in adaptive thermogenesis was examined using mice with adipocyte-specific Jak2 deficiency (A-Jak2 KO). RESULTS: We show in murine brown adipose tissue (BAT) that JAK2 is upregulated together with UCP1 in response to high-fat diet (HFD) feeding and cold exposure. In contrast to white adipose tissue, where JAK2 was dispensable for UCP1 induction, we identified an essential role for BAT JAK2 in diet- and cold-induced thermogenesis via mediating the thermogenic response to β-adrenergic stimulation. Accordingly, A-Jak2 KO mice were unable to upregulate BAT UCP1 following a HFD or after cold exposure. Therefore, A-Jak2 KO mice were cold intolerant and susceptible to HFD-induced obesity and diabetes. CONCLUSIONS/ INTERPRETATION: Taken together, our results suggest that JAK2 plays a critical role in BAT function and adaptive thermogenesis. Targeting the JAK-STAT pathway may be a novel therapeutic approach for the treatment of obesity and related metabolic disorders.
Entities:
Keywords:
Adaptive thermogenesis; Brown adipose tissue; Diabetes; Glucose homeostasis; Janus kinase 2 (JAK2); Obesity; Uncoupling protein 1 (UCP1)
Authors: M B Marrero; B Schieffer; W G Paxton; L Heerdt; B C Berk; P Delafontaine; K E Bernstein Journal: Nature Date: 1995-05-18 Impact factor: 49.962
Authors: Eric S Bachman; Harveen Dhillon; Chen-Yu Zhang; Saverio Cinti; Antonio C Bianco; Brian K Kobilka; Bradford B Lowell Journal: Science Date: 2002-08-02 Impact factor: 47.728
Authors: Aaron M Cypess; Sanaz Lehman; Gethin Williams; Ilan Tal; Dean Rodman; Allison B Goldfine; Frank C Kuo; Edwin L Palmer; Yu-Hua Tseng; Alessandro Doria; Gerald M Kolodny; C Ronald Kahn Journal: N Engl J Med Date: 2009-04-09 Impact factor: 91.245
Authors: Marta Derecka; Agnieszka Gornicka; Sergei B Koralov; Karol Szczepanek; Magdalena Morgan; Vidisha Raje; Jennifer Sisler; Qifang Zhang; Dennis Otero; Joanna Cichy; Klaus Rajewsky; Kazuya Shimoda; Valeria Poli; Birgit Strobl; Sandra Pellegrini; Thurl E Harris; Patrick Seale; Aaron P Russell; Andrew J McAinch; Paul E O'Brien; Susanna R Keller; Colleen M Croniger; Tomasz Kordula; Andrew C Larner Journal: Cell Metab Date: 2012-12-05 Impact factor: 27.287
Authors: F Concha; G Prado; J Quezada; A Ramirez; N Bravo; C Flores; J J Herrera; N Lopez; D Uribe; L Duarte-Silva; P Lopez-Legarrea; Diego F Garcia-Diaz Journal: Rev Endocr Metab Disord Date: 2019-06 Impact factor: 6.514
Authors: Calvin C Chan; Michelle S M A Damen; Pablo C Alarcon; Joan Sanchez-Gurmaches; Senad Divanovic Journal: J Interferon Cytokine Res Date: 2019-03-28 Impact factor: 2.607
Authors: Harsh R Desai; Tharini Sivasubramaniyam; Xavier S Revelo; Stephanie A Schroer; Cynthia T Luk; Prashanth R Rikkala; Adam H Metherel; David W Dodington; Yoo Jin Park; Min Jeong Kim; Joshua A Rapps; Rickvinder Besla; Clinton S Robbins; Kay-Uwe Wagner; Richard P Bazinet; Daniel A Winer; Minna Woo Journal: Sci Rep Date: 2017-08-09 Impact factor: 4.379
Authors: Cynthia T Luk; Sally Yu Shi; Erica P Cai; Tharini Sivasubramaniyam; Mansa Krishnamurthy; Jara J Brunt; Stephanie A Schroer; Daniel A Winer; Minna Woo Journal: Nat Commun Date: 2017-02-06 Impact factor: 14.919
Authors: Doris Kaltenecker; Katrin Spirk; Frank Ruge; Florian Grebien; Marco Herling; Anne Rupprecht; Lukas Kenner; Elena E Pohl; Kristina M Mueller; Richard Moriggl Journal: Mol Metab Date: 2020-05-28 Impact factor: 7.422