Showing papers by "Bruce M. Spiegelman published in 2016"
TL;DR: Mitochondrial ROS induction in brown adipose tissue is identified as a mechanism that supports UCP1-dependent thermogenesis and whole-body energy expenditure, which opens the way to improved therapeutic strategies for combating metabolic disorders.
Abstract: Brown and beige adipose tissues can dissipate chemical energy as heat through thermogenic respiration, which requires uncoupling protein 1 (UCP1). Thermogenesis from these adipocytes can combat obesity and diabetes, encouraging investigation of factors that control UCP1-dependent respiration in vivo. Here we show that acutely activated thermogenesis in brown adipose tissue is defined by a substantial increase in levels of mitochondrial reactive oxygen species (ROS). Remarkably, this process supports in vivo thermogenesis, as pharmacological depletion of mitochondrial ROS results in hypothermia upon cold exposure, and inhibits UCP1-dependent increases in whole-body energy expenditure. We further establish that thermogenic ROS alter the redox status of cysteine thiols in brown adipose tissue to drive increased respiration, and that Cys253 of UCP1 is a key target. UCP1 Cys253 is sulfenylated during thermogenesis, while mutation of this site desensitizes the purine-nucleotide-inhibited state of the carrier to adrenergic activation and uncoupling. These studies identify mitochondrial ROS induction in brown adipose tissue as a mechanism that supports UCP1-dependent thermogenesis and whole-body energy expenditure, which opens the way to improved therapeutic strategies for combating metabolic disorders.
318 citations
TL;DR: It is shown that PTH is involved in stimulating a thermogenic gene program in 5/6 nephrectomized mice that suffer from cachexia, and there exists an unexpected crosstalk mechanism between wasting of fat tissue and skeletal muscle.
216 citations
TL;DR: It is demonstrated that PM20D1 is a bidirectional enzyme in vitro, catalyzing both the condensation of fatty acids and amino acids to generate N-acyl amino acids and also the reverse hydrolytic reaction.
182 citations
TL;DR: This review is intended to serve as an introduction to adipose cell biology and to familiarize the reader with how these cell types play a role in metabolic disease and, perhaps, as targets for therapeutic development.
Abstract: The worldwide epidemic of obesity and type 2 diabetes has greatly increased interest in the biology and physiology of adipose tissues. Adipose (fat) cells are specialized for the storage of energy in the form of triglycerides, but research in the last few decades has shown that fat cells also play a critical role in sensing and responding to changes in systemic energy balance. White fat cells secrete important hormone-like molecules such as leptin, adiponectin, and adipsin to influence processes such as food intake, insulin sensitivity, and insulin secretion. Brown fat, on the other hand, dissipates chemical energy in the form of heat, thereby defending against hypothermia, obesity, and diabetes. It is now appreciated that there are two distinct types of thermogenic fat cells, termed brown and beige adipocytes. In addition to these distinct properties of fat cells, adipocytes exist within adipose tissue, where they are in dynamic communication with immune cells and closely influenced by innervation and blood supply. This review is intended to serve as an introduction to adipose cell biology and to familiarize the reader with how these cell types play a role in metabolic disease and, perhaps, as targets for therapeutic development.
147 citations
TL;DR: This work identifies Slit2, a 180 kDa member of the Slit extracellular protein family, as a PRDM16-regulated secreted factor from beige fat cells that has therapeutic potential for the treatment of obesity and related metabolic disorders.
120 citations
TL;DR: These findings establish a novel regulatory pathway connecting histone modification and hormone activation with mitochondrial oxidative capacity and whole-body energy homeostasis.
Abstract: Brown adipocytes display phenotypic plasticity, as they can switch between the active states of fatty acid oxidation and energy dissipation versus a more dormant state. Cold exposure or β-adrenergic stimulation favors the active thermogenic state, whereas sympathetic denervation or glucocorticoid administration promotes more lipid accumulation. Our understanding of the molecular mechanisms underlying these switches is incomplete. Here we found that LSD1 (lysine-specific demethylase 1), a histone demethylase, regulates brown adipocyte metabolism in two ways. On the one hand, LSD1 associates with PRDM16 to repress expression of white fat-selective genes. On the other hand, LSD1 represses HSD11B1 (hydroxysteroid 11-β-dehydrogenase isozyme 1), a key glucocorticoid-activating enzyme, independently from PRDM16. Adipose-specific ablation of LSD1 impaired mitochondrial fatty acid oxidation capacity of the brown adipose tissue, reduced whole-body energy expenditure, and increased fat deposition, which can be significantly alleviated by simultaneously deleting HSD11B1. These findings establish a novel regulatory pathway connecting histone modification and hormone activation with mitochondrial oxidative capacity and whole-body energy homeostasis.
68 citations
TL;DR: CITED4 is established as a regulator of mTOR signaling that is sufficient to induce physiologic hypertrophy at baseline and mitigate adverse ventricular remodeling after ischemic injury.
Abstract: The mechanisms by which exercise mediates its multiple cardiac benefits are only partly understood. Prior comprehensive analyses of the cardiac transcriptional components and microRNAs dynamically regulated by exercise suggest that the CBP/p300-interacting protein CITED4 is a downstream effector in both networks. While CITED4 has documented functional consequences in neonatal cardiomyocytes in vitro, nothing is known about its effects in the adult heart. To investigate the impact of cardiac CITED4 expression in adult animals, we generated transgenic mice with regulated, cardiomyocyte-specific CITED4 expression. Cardiac CITED4 expression in adult mice was sufficient to induce an increase in heart weight and cardiomyocyte size with normal systolic function, similar to the effects of endurance exercise training. After ischemia-reperfusion, CITED4 expression did not change initial infarct size but mediated substantial functional recovery while reducing ventricular dilation and fibrosis. Forced cardiac expression of CITED4 also induced robust activation of the mTORC1 pathway after ischemic injury. Moreover, pharmacological inhibition of mTORC1 abrogated CITED4's effects in vitro and in vivo. Together, these data establish CITED4 as a regulator of mTOR signaling that is sufficient to induce physiologic hypertrophy at baseline and mitigate adverse ventricular remodeling after ischemic injury.
61 citations
TL;DR: Tumor-derived PTHrP has emerged as a key molecule playing multiple roles in cachexia, from fat "browning" factor to potential therapeutic target.
Abstract: Cachexia, a progressive weight loss in cancer patients that results from tumor-induced energy wasting, is a serious problem that interferes with response to treatment and affects quality of life. Recent studies suggest that thermogenesis of adipose tissues is involved in energy wasting and also point to a link between the atrophy of fat and muscle. Tumor-derived PTHrP has emerged as a key molecule playing multiple roles in cachexia, from fat ‘browning' factor to potential therapeutic target.
59 citations
TL;DR: The attenuated expression of all four PGC-1α isoforms when EE is performed with blood flow restriction suggests this type of exercise provides an insufficient stimulus to activate the signaling pathways governing mitochondrial and angiogenesis responses observed with moderate- to high-intensity EE.
Abstract: Introduction: Exercise performed with blood flow restriction simultaneously enhances the acute responses to both myogenic and mitochondrial pathways with roles in training adaptation. We investigated isoform-specific gene expression of the peroxisome proliferator-activated receptor gamma (PPARG) coactivator 1 and selected target genes and proteins regulating skeletal muscle training adaptation.
Methods: 9 healthy, untrained males participated in a randomized, counter-balanced, cross-over design in which each subject completed a bout of low-intensity endurance exercise performed with blood flow restriction (15 min cycling at 40% of VO2peak, BFR-EE), endurance exercise (30 min cycling at 70% of VO2peak, EE) or resistance exercise (4 x 10 repetitions of leg press at 70% of 1-repetition maximum, RE) separated by at least one week recovery. A single resting muscle biopsy (vastus lateralis) was obtained two weeks before the first exercise trial (rest) and 3 h after each boat.
Results: Total PGC-1α mRNA abundance, along with all four isoforms, increased above rest with EE only (P<0.05) being higher than BFR-EE (P<0.05). PGC-1α1, 2 and 4 were higher after EE compared to RE (P<0.05). EE also increased VEGF, Hif-1α and MuRF-1 mRNA abundance above rest (P<0.05) while COXIV mRNA expression increased with EE compared to BFR-EE (P<0.05).
Conclusion: The attenuated expression of all four PGC- 1α isoforms when endurance exercise is performed with blood flow restriction suggests this type of exercise provides an insufficient stimulus to activate the signaling pathways governing mitochondrial and angiogenesis responses observed with moderate- to high intensity endurance exercise.
28 citations
TL;DR: It is reported that PGC-1α improves mitochondrial myopathy and that its overexpression can compensate for an OXPHOS defect and the first author sincerely apologizes to the scientific community.
12 citations
TL;DR: This corrects the article to say that the author of the paper was a post-graduate student at the Massachusetts Institute of Technology (MIT) when he wrote the paper, not a scientist.
Abstract: Nature 532, 112–116 (2016); doi:10.1038/nature17399 In this Letter, owing to a typographical error, Fig. 4h was erroneously referred to as Fig. 4j in the text and in the Fig. 4 legend. This error has been corrected online.
TL;DR: This is the first study to show that dasatinib regulates PGC-1α and causes glucose intolerance in obese mice, and this should be considered in the treatment of chronic myeloid leukemia.
Abstract: Dasatinib (Sprycel) is a tyrosine kinase inhibitor approved for treatment of chronic myeloid leukemia. In this study, we identify dasatinib as a potent inducer of Peroxisome proliferator-activated receptor gamma coactivator (PGC)-1α mRNA. Dasatinib increased PGC-1α mRNA expression up to 6-fold in 3T3-F442A adipocytes, primary adipocytes, and epididymal white adipose tissue from lean and diet-induced obese mice. Importantly, gene expression translated into increased PGC-1α protein content analyzed in melanoma cells and isolated mitochondria from adipocytes. However, dasatinib treatment had adverse effect on glucose tolerance in diet-induced obese and Ob/Ob mice. This correlated with increased hepatic PGC-1α expression and the gluconeogenesis genes phosphoenolpyruvate carboxykinase and glucose-6-phosphatase. In conclusion, we show that dasatinib is a potent inducer of PGC-1α mRNA and protein in adipose tissue. However, despite beneficial effects of increased PGC-1α content in adipose tissue, dasatinib significantly impaired glucose tolerance in obese but not lean mice. As far as we are aware, this is the first study to show that dasatinib regulates PGC-1α and causes glucose intolerance in obese mice. This should be considered in the treatment of chronic myeloid leukemia.
Patent•
15 Jul 2016
TL;DR: In this paper, the authors present methods for identifying, assessing, preventing, and treating metabolic disorders and modulating metabolic processes using Slit2, a tool for identifying and assessing metabolic disorders.
Abstract: The present invention relates to methods for identifying, assessing, preventing, and treating metabolic disorders and modulating metabolic processes using Slit2.
Patent•
28 Oct 2016TL;DR: In this article, the authors present methods for identifying, assessing, preventing, and treating metabolic disorders and modulating metabolic processes using PM20D1 and N- lipidated amino acids.
Abstract: The present invention relates to methods for identifying, assessing, preventing, and treating metabolic disorders and modulating metabolic processes using PM20D1 and N- lipidated amino acids.