ADRA1A–Gαq 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 cycle2,3, 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 Gαq 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 Gαq and Gαs 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–Gαq–futile creatine cycle axis is a key regulator of facultative and adaptive thermogenesis.

Altered astrocytic and microglial homeostasis characterizes a decreased proinflammatory state in bipolar disorder

“…Calcium and cAMP signalling are important second messengers of signals involved in glucose and glycogen homeostasis and of lactate production and both these second messengers are modulated by adrenergic signalling. Our results show that the gene coding for the adrenergic α1 receptor ( ADRA1A ) was upregulated in BD, along with the downstream thermogenesis pathway genes ( SMARCD3, ADCY2, ARID1A, ADCY8, PRKG1, MAP3K5, SMARCA4, FGFR1 ) 74 . However, genes implicated in the mobilisation and the increase of calcium and calcium signalling were downregulated ( PPP3CA, GNA14, PPP3CC, STIM2, ITPR2, PLCG1, CALM2, SLC8A1 ), including the GWAS gene CACNB2 , which also codes for a subunit of a voltage-gated calcium channel 39 .…”

Promoting metabolic inefficiency for metabolic disease

“…In recent years, the idea that thermogenesis occurs through futile cycles that accelerate ATP turnover has gained attention. 48 , 60 , 61 , 62 , 63 , 64 , 65 , 66 BAT harvested during physiological activation of thermogenesis (cold exposure) indicates that thermogenic adipocytes maintain a high phosphorylation potential, 67 and that the calculated adenylate energy charge 68 is maintained around 0.8, which is within the normal physiological range displayed by a wide variety of eukaryotes and prokaryotes. 69 These data indicate that ATP-producing reactions are in balance with major ATP-consuming reactions during adipocyte thermogenesis.…”

Mechanism of action of the bile acid receptor TGR5 in obesity

“…However, the detailed mechanism of TGR5–CKMT2, which induces thermogenesis, has not been fully studied. The latest research shows that tissue-nonspecific alkaline phosphatase (TNAP) initiates the FCC in thermogenic adipocytes 121 and that TNAP, CK and G-protein-coupled receptors have certain connections 122 , which represent a hypothesis to be confirmed, that is, there may be upstream and downstream regulation between TNAP, CK and TGR5.…”