Showing papers by "Bruce M. Spiegelman published in 2012"

A PGC1-α-dependent myokine that drives brown-fat-like development of white fat and thermogenesis

Abstract: Exercise benefits a variety of organ systems in mammals, and some of the best-recognized effects of exercise on muscle are mediated by the transcriptional co-activator PPAR-γ co-activator-1 α (PGC1-α). Here we show in mouse that PGC1-α expression in muscle stimulates an increase in expression of FNDC5, a membrane protein that is cleaved and secreted as a newly identified hormone, irisin. Irisin acts on white adipose cells in culture and in vivo to stimulate UCP1 expression and a broad program of brown-fat-like development. Irisin is induced with exercise in mice and humans, and mildly increased irisin levels in the blood cause an increase in energy expenditure in mice with no changes in movement or food intake. This results in improvements in obesity and glucose homeostasis. Irisin could be therapeutic for human metabolic disease and other disorders that are improved with exercise.

FGF21 regulates PGC-1α and browning of white adipose tissues in adaptive thermogenesis

Abstract: Certain white adipose tissue (WAT) depots are readily able to convert to a "brown-like" state with prolonged cold exposure or exposure to β-adrenergic compounds. This process is characterized by the appearance of pockets of uncoupling protein 1 (UCP1)-positive, multilocular adipocytes and serves to increase the thermogenic capacity of the organism. We show here that fibroblast growth factor 21 (FGF21) plays a physiologic role in this thermogenic recruitment of WATs. In fact, mice deficient in FGF21 display an impaired ability to adapt to chronic cold exposure, with diminished browning of WAT. Adipose-derived FGF21 acts in an autocrine/paracrine manner to increase expression of UCP1 and other thermogenic genes in fat tissues. FGF21 regulates this process, at least in part, by enhancing adipose tissue PGC-1α protein levels independently of mRNA expression. We conclude that FGF21 acts to activate and expand the thermogenic machinery in vivo to provide a robust defense against hypothermia.

Development of insulin resistance in mice lacking PGC-1α in adipose tissues

Abstract: Reduced peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) expression and mitochondrial dysfunction in adipose tissue have been associated with obesity and insulin resistance. Whether this association is causally involved in the development of insulin resistance or is only a consequence of this condition has not been clearly determined. Here we studied the effects of adipose-specific deficiency of PGC-1α on systemic glucose homeostasis. Loss of PGC-1α in white fat resulted in reduced expression of the thermogenic and mitochondrial genes in mice housed at ambient temperature, whereas gene expression patterns in brown fat were not altered. When challenged with a high-fat diet, insulin resistance was observed in the mutant mice, characterized by reduced suppression of hepatic glucose output. Resistance to insulin was also associated with an increase in circulating lipids, along with a decrease in the expression of genes regulating lipid metabolism and fatty acid uptake in adipose tissues. Taken together, these data demonstrate a critical role for adipose PGC-1α in the regulation of glucose homeostasis and a potentially causal involvement in the development of insulin resistance.

A novel therapeutic approach to treating obesity through modulation of TGFβ signaling.

Abstract: Obesity results from disproportionately high energy intake relative to energy expenditure. Many therapeutic strategies have focused on the intake side of the equation, including pharmaceutical targeting of appetite and digestion. An alternative approach is to increase energy expenditure through physical activity or adaptive thermogenesis. A pharmacological way to increase muscle mass and hence exercise capacity is through inhibition of the activin receptor type IIB (ActRIIB). Muscle mass and strength is regulated, at least in part, by growth factors that signal via ActRIIB. Administration of a soluble ActRIIB protein comprised of a form of the extracellular domain of ActRIIB fused to a human Fc (ActRIIB-Fc) results in a substantial muscle mass increase in normal mice. However, ActRIIB is also present on and mediates the action of growth factors in adipose tissue, although the function of this system is poorly understood. In the current study, we report the effect of ActRIIB-Fc to suppress diet-induced obesity and linked metabolic dysfunctions in mice fed a high-fat diet. ActRIIB-Fc induced a brown fat-like thermogenic gene program in epididymal white fat, as shown by robustly increased expression of the thermogenic genes uncoupling protein 1 and peroxisomal proliferator-activated receptor-γ coactivator 1α. Finally, we identified multiple ligands capable of reducing thermogenesis that represent likely target ligands for the ActRIIB-Fc effects on the white fat depots. These data demonstrate that novel therapeutic ActRIIB-Fc improves obesity and obesity-linked metabolic disease by both increasing skeletal muscle mass and by inducing a gene program of thermogenesis in the white adipose tissues.

A Chemical Screen Probing the Relationship between Mitochondrial Content and Cell Size

Abstract: The cellular content of mitochondria changes dynamically during development and in response to external stimuli, but the underlying mechanisms remain obscure. To systematically identify molecular probes and pathways that control mitochondrial abundance, we developed a high-throughput imaging assay that tracks both the per cell mitochondrial content and the cell size in confluent human umbilical vein endothelial cells. We screened 28,786 small molecules and observed that hundreds of small molecules are capable of increasing or decreasing the cellular content of mitochondria in a manner proportionate to cell size, revealing stereotyped control of these parameters. However, only a handful of compounds dissociate this relationship. We focus on one such compound, BRD6897, and demonstrate through secondary assays that it increases the cellular content of mitochondria as evidenced by fluorescence microscopy, mitochondrial protein content, and respiration, even after rigorous correction for cell size, cell volume, or total protein content. BRD6897 increases uncoupled respiration 1.6-fold in two different, non-dividing cell types. Based on electron microscopy, BRD6897 does not alter the percent of cytoplasmic area occupied by mitochondria, but instead, induces a striking increase in the electron density of existing mitochondria. The mechanism is independent of known transcriptional programs and is likely to be related to a blockade in the turnover of mitochondrial proteins. At present the molecular target of BRD6897 remains to be elucidated, but if identified, could reveal an important additional mechanism that governs mitochondrial biogenesis and turnover.

Compositions and methods for brown fat induction and activity using fndc5

Abstract: The invention provides compositions and methods for brown fat induction and activity through modulation of Fndc5 activity and/or expression. Also provided are methods for preventing or treating metabolic disorders in a subject through modulation of Fndc5 activity and/or expression. Further provided are methods for identifying compounds that are capable of modulating Fndc5 activity and/or expression.

Irisin and the therapeutic benefits of exercise

Abstract: We are experiencing a worldwide epidemic of obesity and type II diabetes. Our group has been interested in the development of both white and brown fat, particularly at the level of gene transcription. PGC1α was first described as a coactivator of PPARγ in the control of brown fat-mediated thermogenesis. More recent work has shown that PGC1α controls much of an exercise program in skeletal muscle. We have now found that PGC1α expression and exercise control the expression of Fndc5, a membrane protein of skeletal muscle. Fndc5 is proteolysed to give rise to a new secreted protein of 112 amino acids that we have called irisin. Irisin circulates in both muse and man, and even mild elevations of irisin activates the browning of white fat, causing increased energy expenditure and reducing obesity. Irisin administration via adenoviral vectors also greatly improves glucose homeostasis in high-fat fed mice. Most recently we have identified cell surface binding of irisin that is likely to represent a cell surface receptor. These data indicate that irisin is a protein regulated in muscle by exercise that gives some of the benefits of exercise on energy homeostasis and metabolic disease.

Boström et al. reply

Abstract: Replying to J. A. Timmons, K. Baar, P. K. Davidsen & P. J. Atherton , 10.1038/nature11364 (2012)

Se-Jin Lee, myostatin discoverer, elected to the National Academy of Science

Abstract: Se-Jin Lee was elected member to the National Academy of Sciences on 28 April 2012. Dr Lee is responsible for the discovery of myostatin, a critical regulator of skeletal muscle mass and function. He also determined the primary binding receptor for myostatin, and has characterized additional transforming growth factor–β family members acting in this pathway.

Compositions et procédés pour induction et activité de tissu adipeux brun à l'aide de fndc5

Abstract: L'invention concerne des compositions et des procedes pour l'induction et l'activite de tissu adipeux brun par l'intermediaire d'une modulation de l'activite et/ou de l'expression de Fndc5. L'invention concerne egalement des methodes de prevention ou de traitement de troubles metaboliques chez un sujet par l'intermediaire d'une modulation de l'activite et/ou de l'expression de Fndc5. L'invention concerne en outre des procedes d'identification de composes qui sont capables de moduler l'activite et/ou l'expression de Fndc5.