Showing papers by "Bruce M. Spiegelman published in 2022"
TL;DR: The peroxisome proliferator-activated receptor γ coactivator-1α (Ppargc1a) gene encodes several PGC-α isoforms that regulate mitochondrial bioenergetics and cellular adaptive processes as mentioned in this paper .
16 citations
TL;DR: It is shown that irisin prevents the accumulation of pathologic α-syn and neuronal cell death by enhancing endolysosomal degradation of pathological α- synuclein in PD.
Abstract: Significance Physical exercise is thought to have beneficial effects on the symptoms of Parkinson’s disease (PD). Irisin is an exercise-induced myokine released into the circulation. We therefore tested whether irisin itself could have a beneficial effect on pathologic α-synuclein (α-syn) accumulation and concomitant neurodegeneration in PD. Here, we show that irisin prevents the accumulation of pathologic α-syn and neuronal cell death by enhancing endolysosomal degradation of pathologic α-syn. Furthermore, elevation of blood irisin levels in mice prevented neurodegeneration and physiological deficits induced by injection α-syn preformed fibrils. These findings would seem to have translational promise as a disease-modifying therapy for treating PD and other neurodegenerative diseases involving pathologic α-syn.
10 citations
TL;DR: In this article , the authors performed deep quantitative proteomics of BAT across a cohort of 163 genetically defined diversity outbred mice, a model that parallels the genetic and phenotypic variation found in humans.
5 citations
01 Jan 2022
TL;DR: RahRahbani et al. as discussed by the authors proposed a model of a two-enzyme system, which they termed the futile Creatine Cycle, to support the thermogenic action of creatine, which can be monitored through the measurement of oxygen consumption under ADP-limiting conditions.
Abstract: Thermogenic adipose tissue plays a vital function in regulating whole-body energy expenditure and nutrient homeostasis due to its capacity to dissipate chemical energy as heat, in a process called non-shivering thermogenesis. A reduction of creatine levels in adipocytes impairs thermogenic capacity and promotes diet-induced obesityKazak et al, Cell 163, 643-55, 2015; Kazak et al, Cell Metab 26, 660-671.e3, 2017; Kazak et al, Nat Metab 1, 360-370, 2019). Mechanistically, thermogenic respiration can be promoted by the liberation of an excess quantity of ADP that is dependent on addition of creatine. A model of a two-enzyme system, which we term the Futile Creatine Cycle, has been posited to support this thermogenic action of creatine. Futile creatine cycling can be monitored in purified mitochondrial preparations wherein creatine-dependent liberation of ADP is monitored through the measurement of oxygen consumption under ADP-limiting conditions. The current model proposes that, in thermogenic fat cells, mitochondria-targeted creatine kinase B (CKB) uses mitochondrial-derived ATP to phosphorylate creatine (Rahbani JF, Nature 590, 480-485, 2021). The creatine kinase reaction generates phosphocreatine and ADP, and ADP stimulates respiration. Next, a pool of mitochondrial phosphocreatine is directly hydrolyzed by a phosphatase, to regenerate creatine. The liberated creatine can then engage mitochondrial CKB to trigger another round of this cycle to support ADP-dependent respiration. In this model, the coordinated action of creatine phosphorylation and phosphocreatine hydrolysis triggers a futile cycle that produces a molar excess of mitochondrial ADP to promote thermogenic respiration (Rahbani JF, Nature 590, 480-485, 2021; Kazak and Cohen, Nat Rev Endocrinol 16, 421-436, 2020). Here, we provide a detailed method to perform respiratory measurements on isolated mitochondria and calculate the stoichiometry of creatine-dependent ADP liberation. This method provides a direct measure of the futile creatine cycle.
3 citations
TL;DR: Drosophila UCP4b is induced by cold in a cell-intrinsic manner and protects against cold and obesity in fly models and is controlled by regulatory processes that are similar between DrosophILA and mammals.
Abstract: Regulation of energy metabolism and response to cold are intimately linked in mammals. Central to these two processes are the mitochondrial uncoupling proteins (UCPs), which by promoting proton leakage across the inner mitochondrial membrane lead to the generation of heat instead of ATP synthesis. In addition to heat generation, UCPs also influence energy storage and can protect against obesity and diabetes. Cold-blooded animals like flies also contain UCPs that protect from cold, however their regulations are poorly understood. We find that Drosophila UCP4b is induced by cold in a cell-intrinsic manner and protects against cold and obesity in fly models. Mechanistically, cold regulates UCP4b expression through calcium signaling and Spargel (Srl), the Drosophila ortholog of mammalian PGC1α. To the opposite, MAD, acting downstream of the BMP branch of the TGFβ signaling pathway, represses UCP4b expression independently of cold. Interestingly, the two mechanisms of UCP4b regulation are integrated as MAD binding to the UCP4b promoter is displaced by cold in a Srl-dependent manner. We discuss the similarities between the regulation of mammalian and Drosophila UCPs. Significance Mitochondrial uncoupling proteins (UCPs) that uncouple the mitochondrial respiration from ATP synthesis regulate energy metabolism, non-shivering thermogenesis, and redox balance in vertebrates and invertebrates. However, their regulation in Drosophila is poorly understood. We found that Drosophila uncoupling protein UCP4b is induced by cold in a cell-autonomous fashion. Conversely, MAD, acting downstream of BMP signaling, inhibits UCP4b expression. MAD is displaced from the upstream regions of the UCP4b gene by cold. UCP4b protects Drosophila against cold and diet-induced obesity. The regulation of UCP4b by cold and BMP signaling is reminiscent of the regulation of mammalian uncoupling protein UCP1. Altogether, we discovered an important regulator of Drosophila energy metabolism which is controlled by regulatory processes that are similar between Drosophila and mammals.
TL;DR: The critical role of TNAP as a phosphocreatine phosphatase in the futile creatine cycle is illustrated and finding the regulators of this process may provide important implications of the controlling of the futile Creatine cycling in thermic events.
Abstract: Adaptive thermogenesis has attracted much attention because of its ability to increase systemic energy expenditure and to counter obesity and diabetes. Thermogenic fat cells use creatine to stimulate futile substrate cycling, dissipating chemical energy as heat; but the molecular basis is unclear. Latest data show that thermogenic fat cells localize tissue‐nonspecific alkaline phosphatase (TNAP) to mitochondria to hydrolyze phosphocreatine, which initiates a futile cycle of creatine dephosphorylation and phosphorylation. TNAP expression is powerfully induced when mice are exposed to cold conditions, and its inhibition in isolated mitochondria leads to a loss of futile creatine cycling. In addition, genetic ablation of TNAP in adipocytes reduces whole‐body energy expenditure and leads to rapid‐onset obesity in mice. These data illustrate the critical role of TNAP as a phosphocreatine phosphatase in the futile creatine cycle. Lastly, TNAP is imported into mitochondria through an untypical pathway and finding the regulators of this process may provide important implications of the controlling of the futile creatine cycling in thermic events.