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Noradrenaline (NA) regulates cold-stimulated adipocyte thermogenesis 1 . 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 α 1 -adrenergic receptor (AR) and β 3 -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 α 1 -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., (© 2022. The Author(s).)

Obesity increases the risk of mortality because of metabolic sequelae such as type 2 diabetes and cardiovascular disease 1 . Thermogenesis by adipocytes can counteract obesity and metabolic diseases 2,3 . In thermogenic fat, creatine liberates a molar excess of mitochondrial ADP-purportedly via a phosphorylation cycle 4 -to drive thermogenic respiration. However, the proteins that control this futile creatine cycle are unknown. Here we show that creatine kinase B (CKB) is indispensable for thermogenesis resulting from the futile creatine cycle, during which it traffics to mitochondria using an internal mitochondrial targeting sequence. CKB is powerfully induced by thermogenic stimuli in both mouse and human adipocytes. Adipocyte-selective inactivation of Ckb in mice diminishes thermogenic capacity, increases predisposition to obesity, and disrupts glucose homeostasis. CKB is therefore a key effector of the futile creatine cycle.

Adipocyte biology has been intensely researched in recent years due to the emergence of obesity as a serious global health concern and because of the realization that adipose tissue is more than simply a cell type that stores and releases lipids. The plasticity of adipose tissues, to rapidly adapt to altered physiological states of energy demand, is under neuronal and endocrine control. The capacity for white adipocytes to store chemical energy in lipid droplets is key for protecting other organs from the toxic effects of ectopic lipid deposition. In contrast, thermogenic (brown and beige) adipocytes combust macronutrients to generate heat. The thermogenic activity of adipocytes allows them to protect themselves and other tissues from lipid overaccumulation. Advances in brown fat biology have uncovered key molecular players involved in adipocyte determination, differentiation, and thermogenic activation. It is now, well appreciated that three distinct adipocyte types exist: white, beige, and brown. Moreover, functional differences are present within adipocyte subtypes located in anatomically distinct locations. Adding to this complexity is the recent realization from single-cell sequencing studies that adipocyte progenitors are also heterogeneous. Understanding the molecular details of how to increase the number of thermogenic fat cells and their activation may delineate some of the pathophysiological basis of obesity and obesity-related diseases. Here, we review recent advances that have extended our understanding of the central role that adipose tissue plays in energy balance and the mechanisms that control their amount and function., (© 2020 Federation of European Biochemical Societies.)

Obesity results from energy imbalance, when energy intake exceeds energy expenditure. Brown adipose tissue (BAT) drives non-shivering thermogenesis which represents a powerful mechanism of enhancing the energy expenditure side of the energy balance equation. The best understood thermogenic system in BAT that evolved to protect the body from hypothermia is based on the uncoupling of protonmotive force from oxidative phosphorylation through the actions of uncoupling protein 1 (UCP1), a key regulator of cold-mediated thermogenesis. Similarly, energy expenditure is triggered in response to caloric excess, and animals with reduced thermogenic fat function can succumb to diet-induced obesity. Thus, it was surprising when inactivation of Ucp1 did not potentiate diet-induced obesity. In recent years, it has become clear that multiple thermogenic mechanisms exist, based on ATP sinks centered on creatine, lipid, or calcium cycling, along with Fatty acid-mediated UCP1-independent leak pathways driven by the ADP/ATP carrier (AAC). With a key difference between cold- and diet-induced thermogenesis being the dynamic changes in purine nucleotide (primarily ATP) levels, ATP-dependent thermogenic pathways may play a key role in diet-induced thermogenesis. Additionally, the ubiquitous expression of AAC may facilitate increased energy expenditure in many cell types, in the face of over feeding. Interest in UCP1-independent energy expenditure has begun to showcase the therapeutic potential that lies in refining our understanding of the diversity of biochemical pathways controlling thermogenic respiration., (© 2020 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.)

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.

That uncoupling protein 1 (UCP1) is the sole mediator of adipocyte thermogenesis is a conventional viewpoint that has primarily been inferred from the attenuation of the thermogenic output of mice genetically lacking Ucp1 from birth (germline Ucp1 −/−). However, germline Ucp1 −/− mice harbor secondary changes within brown adipose tissue. To mitigate these potentially confounding ancillary changes, we constructed mice with inducible adipocyte-selective Ucp1 disruption. We find that, although germline Ucp1 −/− mice succumb to cold-induced hypothermia with complete penetrance, most mice with the 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. Following UCP1 deletion or UCP1/CKB co-deletion from mature adipocytes, moderate cold exposure triggers the regeneration of mature brown adipocytes that coordinately restore UCP1 and CKB expression. Our findings suggest that thermogenic adipocytes utilize non-paralogous protein redundancy—through UCP1 and CKB—to promote cold-induced energy dissipation. [Display omitted] • Inducible adipocyte-specific Ucp1 deletion evades secondary changes beyond UCP1 • Individually, UCP1 and CKB are dispensable for cold-stimulated thermogenesis • UCP1 and CKB co-deletion causes hypothermia with near-full penetrance • Quantitative contribution of UCP1-independent adipocyte thermogenesis is defined Rahbani and Bunk et al. reveal that thermogenic adipocytes utilize UCP1 and CKB in parallel to support whole-body thermogenic demand in response to acute cold exposure. [ABSTRACT FROM AUTHOR]