Showing papers by "Bruce M. Spiegelman published in 2021"
01 Aug 2021
TL;DR: The authors showed that irisin, the cleaved and circulating form of the exercise-induced membrane protein FNDC5, is sufficient to confer the benefits of exercise on cognitive function.
Abstract: Identifying secreted mediators that drive the cognitive benefits of exercise holds great promise for the treatment of cognitive decline in ageing or Alzheimer's disease (AD). Here, we show that irisin, the cleaved and circulating form of the exercise-induced membrane protein FNDC5, is sufficient to confer the benefits of exercise on cognitive function. Genetic deletion of Fndc5/irisin (global Fndc5 knock-out (KO) mice; F5KO) impairs cognitive function in exercise, ageing and AD. Diminished pattern separation in F5KO mice can be rescued by delivering irisin directly into the dentate gyrus, suggesting that irisin is the active moiety. In F5KO mice, adult-born neurons in the dentate gyrus are morphologically, transcriptionally and functionally abnormal. Importantly, elevation of circulating irisin levels by peripheral delivery of irisin via adeno-associated viral overexpression in the liver results in enrichment of central irisin and is sufficient to improve both the cognitive deficit and neuropathology in AD mouse models. Irisin is a crucial regulator of the cognitive benefits of exercise and is a potential therapeutic agent for treating cognitive disorders including AD.
82 citations
TL;DR: In this article, the authors show that CKB is indispensable for thermogenesis resulting from the futile creatine cycle, during which it traffics to mitochondria using an internal mitochondrial targeting sequence, and that inactivation of CKB in mice diminishes thermogenic capacity, increases predisposition to obesity, and disrupts glucose homeostasis.
Abstract: Obesity increases the risk of mortality because of metabolic sequelae such as type 2 diabetes and cardiovascular disease1. Thermogenesis by adipocytes can counteract obesity and metabolic diseases2,3. In thermogenic fat, creatine liberates a molar excess of mitochondrial ADP—purportedly via a phosphorylation cycle4—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. Upon induction by thermogenic stimuli, creatine kinase B traffics to mitochondria to trigger the futile creatine cycle in thermogenic fat.
73 citations
TL;DR: In this paper, the authors provided direct evidence for the molecular basis of this futile creatine cycling activity in mice, which was based on the super-stoichiometric relationship between the amount of creatine added to mitochondria and the quantity of oxygen consumed.
Abstract: Adaptive thermogenesis has attracted much attention because of its ability to increase systemic energy expenditure and to counter obesity and diabetes1-3. Recent data have indicated that thermogenic fat cells use creatine to stimulate futile substrate cycling, dissipating chemical energy as heat4,5. This model was based on the super-stoichiometric relationship between the amount of creatine added to mitochondria and the quantity of oxygen consumed. Here we provide direct evidence for the molecular basis of this futile creatine cycling activity in mice. Thermogenic fat cells have robust phosphocreatine phosphatase activity, which is attributed to tissue-nonspecific alkaline phosphatase (TNAP). TNAP hydrolyses phosphocreatine to initiate a futile cycle of creatine dephosphorylation and phosphorylation. Unlike in other cells, TNAP in thermogenic fat cells is localized to the mitochondria, where futile creatine cycling occurs. 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, with no change in movement or feeding behaviour. These data illustrate the critical role of TNAP as a phosphocreatine phosphatase in the futile creatine cycle.
49 citations
TL;DR: In this article, the authors identify isthmin-1 (Ism1) as an adipokine and one that has a dual role in increasing adipose glucose uptake while suppressing hepatic lipid synthesis.
33 citations
TL;DR: In this article, the UCP1 C253 activation site was found to be a major regulator of acute thermogenesis and sex-dependent tissue inflammation in both males and females, but showed no measurable effect on fat accumulation in an obesogenic environment.
16 citations
01 Jan 2021
TL;DR: The results of a double-blind, randomized, placebo-controlled, cross-over trial (NCT04086381) as discussed by the authors showed that creatine monohydrate supplementation in young, healthy, lean, vegetarian adults does not enhance BAT activation after acute cold exposure.
Abstract: Creatine availability in adipose tissue has been shown to have profound effects on thermogenesis and energy balance in mice. However, whether dietary creatine supplementation affects brown adipose tissue (BAT) activation in humans is unclear. In the present study, we report the results of a double-blind, randomized, placebo-controlled, cross-over trial (NCT04086381) in which 14 young, healthy, vegetarian adults, who are characterized by low creatine levels, received 20 g of creatine monohydrate per day or placebo. Participants were eligible if they met the following criteria: male or female, white, aged 18–30 years, consuming a vegetarian diet (≥6 months) and body mass index 20–25 kg m−2. BAT activation after acute cold exposure was determined by calculating standard uptake values (SUVs) acquired by [18F]fluorodeoxyglucose positron emission tomography–magnetic resonance imaging. BAT volume (−31.32 (19.32) SUV (95% confidence interval (CI) −73.06, 10.42; P = 0.129)), SUVmean (−0.34 (0.29) SUV (95% CI −0.97, 0.28; P = 0.254)) and SUVmax (−2.49 (2.64) SUV (95% CI −8.20, 3.21; P = 0.362)) following acute cold exposure were similar between placebo and creatine supplementation. No side effects of creatine supplementation were reported; one participant experienced bowel complaints during placebo, which resolved without intervention. Our data show that creatine monohydrate supplementation in young, healthy, lean, vegetarian adults does not enhance BAT activation after acute cold exposure. Creatine availability is known to affect creatine-driven thermogenesis in mice. Here Connell et al. report data from a clinical trial in which daily creatine supplementation, perhaps surprisingly, did not alter thermogenesis in adults with otherwise low dietary creatine intake.
13 citations
Patent•
24 Mar 2021
TL;DR: In this article, compositions and methods for modulating thermogenesis and related activities by modulating PTH-related and EGF-related expression and activity are provided. And methods for preventing or treating metabolic disorders in a subject through modulation of PTH related and eGF related expression and activation.
Abstract: The present invention provides compositions and methods for modulating thermogenesis and related activities by modulating PTH-related and EGF-related expression and activity. Also provided are methods for preventing or treating metabolic disorders in a subject through modulation of PTH-related and EGF-related expression and activity.