Dataset Information

ADRA1A-Gα_q signalling potentiates adipocyte thermogenesis through CKB and TNAP.

ABSTRACT: Noradrenaline (NA) regulates cold-stimulated adipocyte thermogenesis¹. Aside from cAMP signalling downstream of β-adrenergic receptor activation, how NA promotes thermogenic output is still not fully understood. Here, we show that coordinated α₁-adrenergic receptor (AR) and β₃-AR signalling induces the expression of thermogenic genes of the futile creatine cycle^2,3, and that early B cell factors, oestrogen-related receptors and PGC1α are required for this response in vivo. NA triggers physical and functional coupling between the α₁-AR subtype (ADRA1A) and Gα_q to promote adipocyte thermogenesis in a manner that is dependent on the effector proteins of the futile creatine cycle, creatine kinase B and tissue-non-specific alkaline phosphatase. Combined Gα_q and Gα_s signalling selectively in adipocytes promotes a continual rise in whole-body energy expenditure, and creatine kinase B is required for this effect. Thus, the ADRA1A-Gα_q-futile creatine cycle axis is a key regulator of facultative and adaptive thermogenesis.

SUBMITTER: Rahbani JF

PROVIDER: S-EPMC9684074 | biostudies-literature | 2022 Nov

REPOSITORIES: biostudies-literature

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ADRA1A-Gαq signalling potentiates adipocyte thermogenesis through CKB and TNAP.

Rahbani Janane F JF Scholtes Charlotte C Lagarde Damien M DM Hussain Mohammed F MF Roesler Anna A Dykstra Christien B CB Bunk Jakub J Samborska Bozena B O'Brien Shannon L SL Tripp Emma E Pacis Alain A Angueira Anthony R AR Johansen Olivia S OS Cinkornpumin Jessica J Hossain Ishtiaque I Lynes Matthew D MD Zhang Yang Y White Andrew P AP Pastor William A WA Chondronikola Maria M Sidossis Labros L Klein Samuel S Kralli Anastasia A Cypess Aaron M AM Pedersen Steen B SB Jessen Niels N Tseng Yu-Hua YH Gerhart-Hines Zachary Z Seale Patrick P Calebiro Davide D Giguère Vincent V Kazak Lawrence L

Nature metabolism 20221107 11

Noradrenaline (NA) regulates cold-stimulated adipocyte thermogenesis1. Aside from cAMP signalling downstream of β-adrenergic receptor activation, how NA promotes thermogenic output is still not fully understood. Here, we show that coordinated α1-adrenergic receptor (AR) and β3-AR signalling induces the expression of thermogenic genes of the futile creatine cycle2,3, and that early B cell factors, oestrogen-related receptors and PGC1α are required for t ...[more]

PMID: 36344764

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Project description:Non-shivering thermogenesis in adipocytes is mediated by brown adipose tissue, purportedly through the sole action of uncoupling protein 1 (UCP1). The physiological relevance of UCP1-dependent thermogenesis has primarily been inferred from the attenuation of thermogenic output of mice genetically lacking Ucp1 from birth (germline Ucp1-/-). However, germline Ucp1-/- mice harbor secondary changes within brown adipose tissue beyond UCP1, such as reduced electron transport chain abundance. We show here that these secondary changes also encompass reduced expression of genes regulating fuel liberation, changes that would attenuate the capacity of any thermogenic pathway. Therefore, the quantitative contribution of UCP1-dependent and -independent thermogenesis is not fully understood. To mitigate the potentially confounding ancillary changes to brown adipose tissue of germline Ucp1-/- mice, we constructed mice with inducible adipocyte-selective disruption of Ucp1. We find that, while germline Ucp1-/- mice succumb to cold-induced hypothermia with complete penetrance, most mice with inducible deletion of Ucp1 maintain homeothermy in the cold. However, inducible adipocyte-selective co-deletion of Ucp1 and creatine kinase B (Ckb, an effector of UCP1-independent thermogenesis) exacerbates cold-intolerance, indicative of a negative genetic interaction and thus a parallel thermogenic function. We find no evidence for impairments in insulation or non-shivering thermogenesis in skeletal muscle that would drive this phenotype. Furthermore, following UCP1 deletion or UCP1/CKB co-deletion from mature adipocytes, moderate cold exposure triggers the regeneration of mature adipocytes that coordinately restore UCP1 and CKB to brown adipose tissue, providing further evidence of their parallel thermogenic relationship. Our findings suggest that thermogenic adipocytes utilize non-paralogous protein redundancy – through UCP1 and CKB – to promote cold-induced energy dissipation.

Dataset Information

ADRA1A-Gα_q signalling potentiates adipocyte thermogenesis through CKB and TNAP.

Publications

ADRA1A-Gα<sub>q</sub> signalling potentiates adipocyte thermogenesis through CKB and TNAP.

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