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Adaptive thermogenesis in brown adipose tissue involves activation of pannexin-1 channels
- Source :
- Molecular Metabolism, Vol 44, Iss, Pp 101130-(2021), Molecular Metabolism
- Publication Year :
- 2021
- Publisher :
- Elsevier, 2021.
-
Abstract
- 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.<br />Highlights • Panx1 channel activation plays a critical role in thermogenic regulation in brown adipocytes. • Panx1 channel activity in brown adipocytes was induced by β3 adrenergic receptor stimulation. • Inactivation of Panx1 channels in cultured brown adipocytes resulted in defective cellular thermogenesis. • In mice, genetic deletion of Panx1 in all adipose tissue depots resulted in defective β3AR agonist- or cold-induced thermogenesis. • Panx1 deletion specifically in brown adipocytes reduced the capacity for adaptive thermogenesis and aggravated diet-induced obesity and insulin resistance in mice.
- Subjects :
- 0301 basic medicine
lcsh:Internal medicine
Adipose Tissue, White
Lipolysis
Glucose uptake
Adipose tissue
Nerve Tissue Proteins
030209 endocrinology & metabolism
White adipose tissue
adipocyte
Connexins
Mice
03 medical and health sciences
chemistry.chemical_compound
0302 clinical medicine
Adipose Tissue, Brown
Fluorodeoxyglucose F18
Adipocyte
Brown adipose tissue
medicine
Animals
Obesity
lcsh:RC31-1245
Molecular Biology
Pannexin channels
Mice, Knockout
Chemistry
brown adipose tissue
Thermogenesis
Cell Biology
Thermogenin
Cell biology
Cold Temperature
Adipocytes, Brown
030104 developmental biology
medicine.anatomical_structure
Original Article
Adiponectin
Insulin Resistance
Transcriptome
Signal Transduction
Subjects
Details
- Language :
- English
- ISSN :
- 22128778
- Volume :
- 44
- Database :
- OpenAIRE
- Journal :
- Molecular Metabolism
- Accession number :
- edsair.doi.dedup.....583445502d9ad837a62eb1dcce42ea6a