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Parkin controls brown adipose tissue plasticity in response to adaptive thermogenesis.

ABSTRACT: Parkin is an ubiquitin-E3 ligase that acts as a key component of the cellular machinery for mitophagy. We show here that Parkin expression is reciprocally regulated in brown adipose tissue in relation to thermogenic activity. Thermogenic stimuli repress Parkin gene expression via transcriptional mechanisms that are elicited by noradrenergic and PPAR?-mediated pathways that involve intracellular lipolysis in brown adipocytes. Parkin-KO mice show over-activated brown adipose tissue thermogenic activity and exhibit improved metabolic parameters, especially when fed a high-fat diet. Deacclimation, which is the return of a cold-adapted mouse to a thermoneutral temperature, dramatically induces mitophagy in brown adipocytes, with a concomitant induction of Parkin levels. We further reveal that Parkin-KO mice exhibit defects in the degradative processing of mitochondrial proteins in brown adipose tissue in response to deacclimation. These results suggest that the transcriptional control of Parkin in brown adipose tissue may contribute to modulating the mitochondrial mass and activity for adaptation to thermogenic requirements.

SUBMITTER: Cairo M

PROVIDER: S-EPMC6501052 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

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Parkin controls brown adipose tissue plasticity in response to adaptive thermogenesis.

Cairó Montserrat M Campderrós Laura L Gavaldà-Navarro Aleix A Cereijo Rubén R Delgado-Anglés Alejandro A Quesada-López Tania T Giralt Marta M Villarroya Joan J Villarroya Francesc F

EMBO reports 20190313 5

Parkin is an ubiquitin-E3 ligase that acts as a key component of the cellular machinery for mitophagy. We show here that Parkin expression is reciprocally regulated in brown adipose tissue in relation to thermogenic activity. Thermogenic stimuli repress Parkin gene expression via transcriptional mechanisms that are elicited by noradrenergic and PPARα-mediated pathways that involve intracellular lipolysis in brown adipocytes. Parkin-KO mice show over-activated brown adipose tissue thermogenic act ...[more]

PMID: 30867164

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Project description:ObjectiveBrown adipose tissue (BAT) is specialized in thermogenesis. The conversion of energy into heat in brown adipocytes proceeds via stimulation of ?-adrenergic receptor (?AR)-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.MethodsIn 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.ResultsIn brown adipocytes, Panx1 channel activity was induced either by apoptosis-dependent caspase activation or by ?3AR stimulation via a novel mechanism that involves G?? subunit binding to Panx1. Inactivation of Panx1 channels in cultured brown adipocytes resulted in inhibition of ?3AR-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 ?3AR 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.ConclusionsThese data demonstrate that G??-dependent Panx1 channel activation is involved in ?3AR-induced thermogenic regulation in brown adipocytes. Identification of Panx1 channels in BAT as novel thermo-regulatory elements downstream of ?3AR activation may have therapeutic implications.

Dataset Information

Parkin controls brown adipose tissue plasticity in response to adaptive thermogenesis.

Publications

Parkin controls brown adipose tissue plasticity in response to adaptive thermogenesis.

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