Combined α- and β-adrenergic receptor activation triggers thermogenesis by the futile creatine cycle.
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA854894 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR19918444_1.fastq.gz | Fastqsanger.gz | |||
| SRR19918444_2.fastq.gz | Fastqsanger.gz | |||
| SRR19918445_1.fastq.gz | Fastqsanger.gz | |||
| SRR19918445_2.fastq.gz | Fastqsanger.gz | |||
| SRR19918446_1.fastq.gz | Fastqsanger.gz |
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Project description:Noradrenaline regulates cold-stimulated adipocyte thermogenesis. Aside from cAMP signaling downstream of β-adrenergic receptor (βAR) activation, how noradrenaline promotes thermogenic output is still not fully understood. Here, we show that coordinated α1-adrenergic receptor (α1AR) and β3AR signaling induces the expression of thermogenic genes of the futile creatine cycle, and that EBFs, ERRs, and PGC1α are required for this response in vivo. Noradrenaline triggers physical and functional coupling between the α1AR subtype (ADRA1A) to Gαq to promote adipocyte thermogenesis in a manner that is dependent on the effector proteins of the futile creatine cycle, creatine kinase b (CKB) and tissue-nonspecific alkaline phosphatase (TNAP). Combined Gαq and Gαs signaling selectively in adipocytes promotes a continual rise in whole-body energy expenditure, and CKB is required for this effect. Thus, the ADRA1A-Gαq-futile creatine cycle axis is a key regulator of facultative and adaptive thermogenesis.
2022-09-08 | GSE207341 | GEO
Project description:Noradrenaline regulates cold-stimulated adipocyte thermogenesis. Aside from cAMP signaling downstream of β-adrenergic receptor (βAR) activation, how noradrenaline promotes thermogenic output is still not fully understood. Here, we show that coordinated α1-adrenergic receptor (α1AR) and β3AR signaling induces the expression of thermogenic genes of the futile creatine cycle, and that EBFs, ERRs, and PGC1α are required for this response in vivo. Noradrenaline triggers physical and functional coupling between the α1AR subtype (ADRA1A) to Gαq to promote adipocyte thermogenesis in a manner that is dependent on the effector proteins of the futile creatine cycle, creatine kinase b (CKB) and tissue-nonspecific alkaline phosphatase (TNAP). Combined Gαq and Gαs signaling selectively in adipocytes promotes a continual rise in whole-body energy expenditure, and CKB is required for this effect. Thus, the ADRA1A-Gαq-futile creatine cycle axis is a key regulator of facultative and adaptive thermogenesis.
2022-09-08 | GSE207340 | GEO
Project description:Combined α- and β-adrenergic receptor activation triggers thermogenesis by the futile creatine cycle.
| PRJNA854887 | ENA
Project description:Combined α- and β-adrenergic receptor activation triggers thermogenesis by the futile creatine cycle.
| PRJNA854893 | ENA
Project description:This SuperSeries is composed of the SubSeries listed below.
2022-09-08 | GSE207342 | GEO
Project description:Mice and other small mammals heavily rely on UCP1-mediated non-shivering thermogenesis in the cold, and thus the unexpected cold resistance of UCP1-knockout (UCP1KO) mice has always been and still is an unresolved mystery inextricably intertwined with alternative means of thermogenesis and futile substrate cycles. Several potentially thermogenic futile substrate cycles in adipose tissue of WT and UCP1KO mice have been reported in the literature. We hypothesized that isoproterenol treatment of brown adipocytes from UCP1KO mice would cause an immediate acceleration of futile substrate cycling, and entail a consecutive upregulation of the involved enzymes to recruit additional capacity. In this study, we analyzed changes in the proteome of wild type (WT) and UCP1KO adipocytes during acute adrenergic stimulation to detect characteristic molecular signatures, which allowed us to narrow down our search to potential candidates related to Ca2+ and lipid metabolism.
2022-04-25 | PXD025854 | Pride
Project description:Adaptive thermogenesis has attracted much attention because of its ability to raise systemic energy expenditure and counter obesity and diabetes. Recent data have indicated that thermogenic fat cells utilize creatine to stimulate futile substrate cycling, dissipating chemical energy as heat. This model was based on the super-stoichiometric relationship between creatine added to mitochondria and O2 consumed, and this project aims at providing direct evidence for the molecular basis of this futile creatine cycling activity. In this project, we found that thermogenic fat cells contain robust phosphocreatine hydrolase (PCr’ase) activity, attributable to tissue-nonspecific alkaline phosphatase (TNAP), which was identified by the quantitative mass spectrometric analysis of a purified mitochondrial protein fraction containing the PCr’ase activity. TNAP hydrolyzes phosphocreatine to initiate a futile cycle of creatine dephosphorylation and phosphorylation; it is localized to mitochondria of thermogenic fat cells, where the futile creatine cycling occurs. Furthermore, we demonstrated in this project the essential role of TNAP in activating the futile creatine cycling and increasing whole body energy expenditure using genetic and pharmacological approaches. We also found that the genetic depletion of TNAP in murine adipose tissue causes rapid-onset obesity, with no change in movement or feeding behavior of the animals. Using quantitative mass spectrometry, we showed that genetic depletion of TNAP causes an upregulation of UCP1, as well as other proteins involved in oxidative metabolism, to compensate for a dampened thermogenesis. In summary, the data we acquired in this project illustrate the critical role of TNAP as a phosphocreatine phosphatase in the futile creatine cycling and adipose thermogenesis.
2022-02-17 | PXD025032 | Pride
Project description:In obesity, misalignment of feeding time with the light/dark environment results in disruption of peripheral circadian clocks. Conversely, restricting feeding to the active period mitigates metabolic syndrome through mechanisms that remain unknown. Here we show that adipocyte thermogenesis is essential for the healthful metabolic response to time restricted feeding. Genetic enhancement of adipocyte thermogenesis through ablation of Zfp423 attenuates obesity caused by circadian mistimed high fat diet feeding through a mechanism involving creatine metabolism. Circadian control of adipocyte creatine metabolism underlies timing of diet-induced thermogenesis, and enhancement of adipocyte circadian rhythms through overexpression of the clock activator Bmal1 ameliorates metabolic complications during diet induced obesity. These findings establish creatine mediated diet-induced thermogenesis as a bioenergetic mechanism driving metabolic benefits during time-restricted feeding.
2022-10-24 | GSE181443 | GEO
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.
2024-01-10 | PXD047841 | Pride
Project description:Mitochondria are pivotal for cellular metabolism, serving as sources and targets of nutrient intermediates from converging metabolic pathways. Here, we demonstrate that insulin resistance leads to a marked alteration in the mitochondrial proteome of adipocytes. Analysis across multiple insulin resistance models revealed a consistent decrease in the level of the mitochondrial processing peptidase miPEP, suggesting a potential role for miPEP in the aetiology of insulin resistance. Adipocyte specific miPEP knockout mice demonstrated a strong phenotype marked by a browning-independent increment in energy expenditure, enhanced insulin sensitivity, and reduced adiposity, despite normal food intake and physical activity. These phenotypes vanished when mice were housed at thermoneutrality suggesting that miPEP deletion triggers a compensatory enhancement in thermogenesis protecting against metabolic dysfunction. Tissue specific analysis of miPEP deficient mice revealed a selective increment in muscle metabolism evidenced by increased basal and insulin induced glucose uptake and upregulation of the protein Fbp2, involved in energy wasting via futile cycling. These findings suggest that miPEP deletion initiates a compensatory increase in thermogenesis, acting as a protective mechanism against diet-induced insulin resistance.
2024-08-10 | PXD051606 | Pride