Adaptive thermogenesis in brown adipose tissue involves activation of pannexin-1 channels
Objective: Brown adipose tissue (BAT) is specialized in thermogenesis. The conversion of energy into heat in brown adipocytes proceeds via stimulation of β-adrenergic receptor (βAR)-dependent signaling and activation of mitochondrial uncoupling protein 1 (UCP1). We have previously demonstrated a fun...
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| Format: | Article |
| Language: | English |
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Elsevier
2021-02-01
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| Series: | Molecular Metabolism |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2212877820302040 |
| _version_ | 1818394060061147136 |
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| author | Subramanian Senthivinayagam Vlad Serbulea Clint M. Upchurch Renata Polanowska-Grabowska Suresh K. Mendu Srabani Sahu Prathiba Jayaguru Kevin W. Aylor Mahendra D. Chordia Limor Steinberg Nathaniel Oberholtzer Seichii Uchiyama Noriko Inada Ulrike M. Lorenz Thurl E. Harris Susanna R. Keller Akshaya K. Meher Alexandra Kadl Bimal N. Desai Bijoy K. Kundu Norbert Leitinger |
| author_facet | Subramanian Senthivinayagam Vlad Serbulea Clint M. Upchurch Renata Polanowska-Grabowska Suresh K. Mendu Srabani Sahu Prathiba Jayaguru Kevin W. Aylor Mahendra D. Chordia Limor Steinberg Nathaniel Oberholtzer Seichii Uchiyama Noriko Inada Ulrike M. Lorenz Thurl E. Harris Susanna R. Keller Akshaya K. Meher Alexandra Kadl Bimal N. Desai Bijoy K. Kundu Norbert Leitinger |
| author_sort | Subramanian Senthivinayagam |
| collection | DOAJ |
| description | Objective: Brown adipose tissue (BAT) is specialized in thermogenesis. The conversion of energy into heat in brown adipocytes proceeds via stimulation of β-adrenergic receptor (βAR)-dependent signaling and activation of mitochondrial uncoupling protein 1 (UCP1). We have previously demonstrated a functional role for pannexin-1 (Panx1) channels in white adipose tissue; however, it is not known whether Panx1 channels play a role in the regulation of brown adipocyte function. Here, we tested the hypothesis that Panx1 channels are involved in brown adipocyte activation and thermogenesis. Methods: In an immortalized brown pre-adipocytes cell line, Panx1 currents were measured using patch-clamp electrophysiology. Flow cytometry was used for assessment of dye uptake and luminescence assays for adenosine triphosphate (ATP) release, and cellular temperature measurement was performed using a ratiometric fluorescence thermometer. We used RNA interference and expression plasmids to manipulate expression of wild-type and mutant Panx1. We used previously described adipocyte-specific Panx1 knockout mice (Panx1Adip-/-) and generated brown adipocyte-specific Panx1 knockout mice (Panx1BAT-/-) to study pharmacological or cold-induced thermogenesis. Glucose uptake into brown adipose tissue was quantified by positron emission tomography (PET) analysis of 18F-fluorodeoxyglucose (18F-FDG) content. BAT temperature was measured using an implantable telemetric temperature probe. Results: In brown adipocytes, Panx1 channel activity was induced either by apoptosis-dependent caspase activation or by β3AR stimulation via a novel mechanism that involves Gβγ subunit binding to Panx1. Inactivation of Panx1 channels in cultured brown adipocytes resulted in inhibition of β3AR-induced lipolysis, UCP-1 expression, and cellular thermogenesis. In mice, adiponectin-Cre-dependent genetic deletion of Panx1 in all adipose tissue depots resulted in defective β3AR agonist- or cold-induced thermogenesis in BAT and suppressed beigeing of white adipose tissue. UCP1-Cre-dependent Panx1 deletion specifically in brown adipocytes reduced the capacity for adaptive thermogenesis without affecting beigeing of white adipose tissue and aggravated diet-induced obesity and insulin resistance. Conclusions: These data demonstrate that Gβγ-dependent Panx1 channel activation is involved in β3AR-induced thermogenic regulation in brown adipocytes. Identification of Panx1 channels in BAT as novel thermo-regulatory elements downstream of β3AR activation may have therapeutic implications. |
| first_indexed | 2024-12-14T05:55:12Z |
| format | Article |
| id | doaj.art-3bac5da2881d485a8632564ecf041a48 |
| institution | Directory Open Access Journal |
| issn | 2212-8778 |
| language | English |
| last_indexed | 2024-12-14T05:55:12Z |
| publishDate | 2021-02-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Metabolism |
| spelling | doaj.art-3bac5da2881d485a8632564ecf041a482022-12-21T23:14:36ZengElsevierMolecular Metabolism2212-87782021-02-0144101130Adaptive thermogenesis in brown adipose tissue involves activation of pannexin-1 channelsSubramanian Senthivinayagam0Vlad Serbulea1Clint M. Upchurch2Renata Polanowska-Grabowska3Suresh K. Mendu4Srabani Sahu5Prathiba Jayaguru6Kevin W. Aylor7Mahendra D. Chordia8Limor Steinberg9Nathaniel Oberholtzer10Seichii Uchiyama11Noriko Inada12Ulrike M. Lorenz13Thurl E. Harris14Susanna R. Keller15Akshaya K. Meher16Alexandra Kadl17Bimal N. Desai18Bijoy K. Kundu19Norbert Leitinger20Department of Pharmacology, University of Virginia School of Medicine, Charlottesville, VA, 22908, USADepartment of Pharmacology, University of Virginia School of Medicine, Charlottesville, VA, 22908, USADepartment of Pharmacology, University of Virginia School of Medicine, Charlottesville, VA, 22908, USADepartment of Pharmacology, University of Virginia School of Medicine, Charlottesville, VA, 22908, USADepartment of Pharmacology, University of Virginia School of Medicine, Charlottesville, VA, 22908, USADepartment of Pharmacology, University of Virginia School of Medicine, Charlottesville, VA, 22908, USADivision of Pulmonary and Critical Care Medicine, Department of Medicine, University of Virginia, Charlottesville, VA, 22908, USADivision of Endocrinology and Metabolism, Department of Medicine, University of Virginia, Charlottesville, VA, 22908, USADepartment of Radiology and Medical Imaging, University of Virginia School of Medicine, Charlottesville, VA, 22908, USADepartment of Pharmacology, University of Virginia School of Medicine, Charlottesville, VA, 22908, USADepartment of Pharmacology, University of Virginia School of Medicine, Charlottesville, VA, 22908, USAGraduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, JapanGraduate School of Life and Environmental Sciences, Osaka Prefecture University, Osaka, JapanDepartment of Microbiology, Immunology and Cancer Biology, Center for Cell Clearance, the Beirne B. Carter Center for Immunology Research, USADepartment of Pharmacology, University of Virginia School of Medicine, Charlottesville, VA, 22908, USADivision of Endocrinology and Metabolism, Department of Medicine, University of Virginia, Charlottesville, VA, 22908, USADepartment of Pharmacology, University of Virginia School of Medicine, Charlottesville, VA, 22908, USADivision of Pulmonary and Critical Care Medicine, Department of Medicine, University of Virginia, Charlottesville, VA, 22908, USADepartment of Pharmacology, University of Virginia School of Medicine, Charlottesville, VA, 22908, USADepartment of Radiology and Medical Imaging, University of Virginia School of Medicine, Charlottesville, VA, 22908, USA; Department of Biomedical Engineering, University of Virginia School of Medicine, Charlottesville, VA, 22908, USADepartment of Pharmacology, University of Virginia School of Medicine, Charlottesville, VA, 22908, USA; Robert M Berne Cardiovascular Research Center, University of Virginia, Charlottesville, VA, 22908, USA; Corresponding author. Department of Pharmacology, University of Virginia, 1340 Jefferson Park Ave, Charlottesville, VA, 22911, USA.Objective: Brown adipose tissue (BAT) is specialized in thermogenesis. The conversion of energy into heat in brown adipocytes proceeds via stimulation of β-adrenergic receptor (βAR)-dependent signaling and activation of mitochondrial uncoupling protein 1 (UCP1). We have previously demonstrated a functional role for pannexin-1 (Panx1) channels in white adipose tissue; however, it is not known whether Panx1 channels play a role in the regulation of brown adipocyte function. Here, we tested the hypothesis that Panx1 channels are involved in brown adipocyte activation and thermogenesis. Methods: In an immortalized brown pre-adipocytes cell line, Panx1 currents were measured using patch-clamp electrophysiology. Flow cytometry was used for assessment of dye uptake and luminescence assays for adenosine triphosphate (ATP) release, and cellular temperature measurement was performed using a ratiometric fluorescence thermometer. We used RNA interference and expression plasmids to manipulate expression of wild-type and mutant Panx1. We used previously described adipocyte-specific Panx1 knockout mice (Panx1Adip-/-) and generated brown adipocyte-specific Panx1 knockout mice (Panx1BAT-/-) to study pharmacological or cold-induced thermogenesis. Glucose uptake into brown adipose tissue was quantified by positron emission tomography (PET) analysis of 18F-fluorodeoxyglucose (18F-FDG) content. BAT temperature was measured using an implantable telemetric temperature probe. Results: In brown adipocytes, Panx1 channel activity was induced either by apoptosis-dependent caspase activation or by β3AR stimulation via a novel mechanism that involves Gβγ subunit binding to Panx1. Inactivation of Panx1 channels in cultured brown adipocytes resulted in inhibition of β3AR-induced lipolysis, UCP-1 expression, and cellular thermogenesis. In mice, adiponectin-Cre-dependent genetic deletion of Panx1 in all adipose tissue depots resulted in defective β3AR agonist- or cold-induced thermogenesis in BAT and suppressed beigeing of white adipose tissue. UCP1-Cre-dependent Panx1 deletion specifically in brown adipocytes reduced the capacity for adaptive thermogenesis without affecting beigeing of white adipose tissue and aggravated diet-induced obesity and insulin resistance. Conclusions: These data demonstrate that Gβγ-dependent Panx1 channel activation is involved in β3AR-induced thermogenic regulation in brown adipocytes. Identification of Panx1 channels in BAT as novel thermo-regulatory elements downstream of β3AR activation may have therapeutic implications.http://www.sciencedirect.com/science/article/pii/S2212877820302040adipocytebrown adipose tissueThermogenesisPannexin channels |
| spellingShingle | Subramanian Senthivinayagam Vlad Serbulea Clint M. Upchurch Renata Polanowska-Grabowska Suresh K. Mendu Srabani Sahu Prathiba Jayaguru Kevin W. Aylor Mahendra D. Chordia Limor Steinberg Nathaniel Oberholtzer Seichii Uchiyama Noriko Inada Ulrike M. Lorenz Thurl E. Harris Susanna R. Keller Akshaya K. Meher Alexandra Kadl Bimal N. Desai Bijoy K. Kundu Norbert Leitinger Adaptive thermogenesis in brown adipose tissue involves activation of pannexin-1 channels Molecular Metabolism adipocyte brown adipose tissue Thermogenesis Pannexin channels |
| title | Adaptive thermogenesis in brown adipose tissue involves activation of pannexin-1 channels |
| title_full | Adaptive thermogenesis in brown adipose tissue involves activation of pannexin-1 channels |
| title_fullStr | Adaptive thermogenesis in brown adipose tissue involves activation of pannexin-1 channels |
| title_full_unstemmed | Adaptive thermogenesis in brown adipose tissue involves activation of pannexin-1 channels |
| title_short | Adaptive thermogenesis in brown adipose tissue involves activation of pannexin-1 channels |
| title_sort | adaptive thermogenesis in brown adipose tissue involves activation of pannexin 1 channels |
| topic | adipocyte brown adipose tissue Thermogenesis Pannexin channels |
| url | http://www.sciencedirect.com/science/article/pii/S2212877820302040 |
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