Combined α- and β-adrenergic receptor activation triggers thermogenesis by the futile creatine cycle

Abstract

Noradrenaline is the primary physiological regulator of adipocyte thermogenesis in response to decreased environmental temperature1. However, the molecular factors and effector pathways that lie downstream of noradrenaline-stimulated thermogenesis are still not fully understood but are purportedly driven by cAMP downstream of β-adrenergic receptor (βAR) activation. Furthermore, while the transcriptional mechanisms regulating Ucp1 are well-characterized2, the transcriptional regulation of UCP1-independent thermogenesis is largely unknown. Here, we show that brown adipose tissue (BAT) is primed to respond to environmental cold by triggering coordinated α-adrenergic receptor (αAR) and βAR signaling to induce the expression of thermogenic genes of the futile creatine cycle3,4. Using fat-specific loss-of-function models, we reveal that EBFs, ERRs, and PGC1α are required for the cold-stimulated transcriptional induction of the futile creatine cycle in vivo. Through the application of chemogenetics, we demonstrate that combined fat-selective Gαs (activated by βARs) and Gαq (activated by αARs) signaling elevates whole-body energy expenditure to a greater extent than either signaling pathway alone in a manner that is dependent on the key effector protein of the futile creatine cycle, CKB3. Moreover, genetic and pharmacological studies reveal that CKB is necessary for nearly all of the α1AR-stimulated component of brown adipocyte-intrinsic respiration and is thus critical for the full activation of noradrenaline-stimulated thermogenesis. Thus, the futile creatine cycle is integrated into facultative and adaptive thermogenesis through coordinated α1AR and β3AR signaling.

Thermogenic Modulation of Adipose Depots: A Perspective on Possible Therapeutic Intervention with Early Cardiorenal Complications of Metabolic Impairment

“…In this framework, continuous alternating creatine phosphorylation and dephosphorylation proceed to dissipate energy as heat in adipocytes (Kazak et al, 2015). This process is triggered by a coordinated activation of α1-and β3 adrenergic receptors induced by thermogenic stimulation, followed by Gαs and Gαq signaling, respectively (Kazak et al, 2022;Rahbani et al, 2021;Sun et al, 2021).…”

Adipose tissue mitochondrial dysfunction and cardiometabolic diseases: On the search for novel molecular targets

“…Creatine futile cycling represents the most prominent and wellcharacterized alternative thermogenic pathway in adipocytes [104]. Creatine futile cycling, that is the phosphorylation of creatine by creatine kinase B (CKB) in the mitochondrial matrix and the subsequent hydrolysis of phosphocreatine by tissue non-specific alkaline phosphatase (TNAP) prior to its shuttling outside the mitochondria, occurs following thermogenic stimulation-induced coordinated activation of α1and β3 adrenergic receptors, and downstream of Gαs and Gαq signaling, respectively [105][106][107]. Mitochondrial patch clamp experiments revealed the occurrence of futile creatine cycling in UCP1-positive and UCP1-negative beige adipocytes [108].…”