Showing papers by "Bruce M. Spiegelman published in 2002"

Transcriptional co-activator PGC-1α drives the formation of slow-twitch muscle fibres

Abstract: The biochemical basis for the regulation of fibre-type determination in skeletal muscle is not well understood In addition to the expression of particular myofibrillar proteins, type I (slow-twitch) fibres are much higher in mitochondrial content and are more dependent on oxidative metabolism than type II (fast-twitch) fibres We have previously identified a transcriptional co-activator, peroxisome-proliferator-activated receptor-gamma co-activator-1 (PGC-1 alpha), which is expressed in several tissues including brown fat and skeletal muscle, and that activates mitochondrial biogenesis and oxidative metabolism We show here that PGC-1 alpha is expressed preferentially in muscle enriched in type I fibres When PGC-1 alpha is expressed at physiological levels in transgenic mice driven by a muscle creatine kinase (MCK) promoter, a fibre type conversion is observed: muscles normally rich in type II fibres are redder and activate genes of mitochondrial oxidative metabolism Notably, putative type II muscles from PGC-1 alpha transgenic mice also express proteins characteristic of type I fibres, such as troponin I (slow) and myoglobin, and show a much greater resistance to electrically stimulated fatigue Using fibre-type-specific promoters, we show in cultured muscle cells that PGC-1 alpha activates transcription in cooperation with Mef2 proteins and serves as a target for calcineurin signalling, which has been implicated in slow fibre gene expression These data indicate that PGC-1 alpha is a principal factor regulating muscle fibre type determination

C/EBPalpha induces adipogenesis through PPARgamma: a unified pathway.

Abstract: PPARγ and C/EBPα are critical transcription factors in adipogenesis, but the precise role of these proteins has been difficult to ascertain because they positively regulate each other's expression. Questions remain about whether these factors operate independently in separate, parallel pathways of differentiation, or whether a single pathway exists. PPARγ can promote adipogenesis in C/EBPα-deficient cells, but the converse has not been tested. We have created an immortalized line of fibroblasts lacking PPARγ, which we use to show that C/EBPα has no ability to promote adipogenesis in the absence of PPARγ. These results indicate that C/EBPα and PPARγ participate in a single pathway of fat cell development with PPARγ being the proximal effector of adipogenesis.

Transcription coactivator TRAP220 is required for PPARγ2-stimulated adipogenesis

Abstract: The TRAP (thyroid hormone receptor-associated proteins) transcription coactivator complex (also known as Mediator) was first isolated as a group of proteins that facilitate the function of the thyroid hormone receptor1. This complex interacts physically with several nuclear receptors through the TRAP220 subunit, and with diverse activators through other subunits2. TRAP220 has been reported to show ligand-enhanced interaction with peroxisome proliferator-activated receptor γ2 (PPARγ2)3,4, a nuclear receptor essential for adipogenesis5,6,7,8. Here we show that Trap220-/- fibroblasts are refractory to PPARγ2-stimulated adipogenesis, but not to MyoD-stimulated myogenesis, and do not express adipogenesis markers or PPARγ2 target genes. These defects can be restored by expression of exogenous TRAP220. Further indicative of a direct role for TRAP220 in PPARγ2 function via the TRAP complex, TRAP functions directly as a transcriptional coactivator for PPARγ2 in a purified in vitro system and interacts with PPARγ2 in a ligand- and TRAP220-dependent manner. These data indicate that TRAP220 acts, via the TRAP complex, as a PPARγ2-selective coactivator and, accordingly, that it is specific for one fibroblast differentiation pathway (adipogenesis) relative to another (myogenesis).

APC-dependent suppression of colon carcinogenesis by PPARγ

Abstract: Activation of PPARγ by synthetic ligands, such as thiazolidinediones, stimulates adipogenesis and improves insulin sensitivity. Although thiazolidinediones represent a major therapy for type 2 diabetes, conflicting studies showing that these agents can increase or decrease colonic tumors in mice have raised concerns about the role of PPARγ in colon cancer. To analyze critically the role of this receptor, we have used mice heterozygous for Pparγ with both chemical and genetic models of this malignancy. Heterozygous loss of PPARγ causes an increase in β-catenin levels and a greater incidence of colon cancer when animals are treated with azoxymethane. However, mice with preexisting damage to Apc, a regulator of β-catenin, develop tumors in a manner insensitive to the status of PPARγ. These data show that PPARγ can suppress β-catenin levels and colon carcinogenesis but only before damage to the APC/β-catenin pathway. This finding suggests a potentially important use for PPARγ ligands as chemopreventative agents in colon cancer.

C/EBP induces adipogenesis through PPAR: a unified pathway

Abstract: PPAR and C/EBP are critical transcription factors inadipogenesis, but the precise role of these proteins hasbeen difficult to ascertain because they positively regu-late each other’s expression. Questions remain aboutwhether these factors operate independently in separate,parallel pathways of differentiation, or whether a singlepathway exists. PPAR can promote adipogenesis inC/EBP

A Phase Ii Study of Troglitazone, an Activator of the Pparγ Receptor, in Patients with Chemotherapy-resistant Metastatic Colorectal Cancer

Abstract: PURPOSE Troglitazone, a potent activator of the peroxisome proliferator-activated receptor-γ, induces tumor differentiation in human lipo-sarcomas and causes regression of tumors that are derived from human colon cancer cells in nude mice. We therefore assessed the efficacy of troglitazone in the treatment of metastatic colon cancer in humans. METHODS Twenty-five patients with metastatic colorectal cancer were treated with oral troglitazone. Patients were followed up for evidence of toxicity, tumor response, and survival. RESULTS The treatment was well tolerated: no grade 3/4 treatment-related toxicities were observed. However, no objective tumor responses were noted, and all 25 patients had progressive disease as their best response to therapy. The median progression-free survival time was only 1.6 months, and the median survival time was 3.9 months. DISCUSSION Troglitazone is not an active agent for the treatment of metastatic colorectal cancer.

c-Fos Deficiency Inhibits Induction of mRNA for Some, but Not All, Neurotransmitter Biosynthetic Enzymes by Immobilization Stress

Abstract: Recent studies indicated that c-Fos protein may be mediating stress-elicited transcriptional activation of genes involved in neurotransmitter biosynthesis. However, direct evidence for c-Fos mediating these changes in gene expression has been lacking. Mice with disrupted c-fos gene (+/− or −/− genotypes) were used to examine the effect of immobilization stress on a group of stress-responsive genes. In male adrenals, c-Fos was found not essential for stress-elicited activation of expression of tyrosine hydroxylase, dopamine β-hydroxylase (DBH), phenylethanolamine N-methyltransferase, or neuropeptide Y. In females, immobilization failed to induce adrenal DBH in the c-Fos-deficient mice. In brainstem, c-Fos was indispensable for elevation of DBH mRNA in both genders. The gene, gender, and tissue specificity in the requirement for c-Fos points to diversity in adaptation mechanisms to stress.

PGC-1β, A NOVEL PGC-1 HOMOLOGUE AND USES THEREFOR

Abstract: The invention provides isolated nucleic acid molecules, designated PGC-1β nucleic acid molecules, which encode novel PGC-1 related coactivator molecules. The invention also provides antisense nucleic acid molecules, recombinant expression vectors containing PGC-1β nucleic acid molecules, host cells into which the expression vectors have been introduced, and nonhuman transgenic animals in which a PGC-1β gene has been introduced or disrupted. The invention still further provides isolated PGC-1β proteins, fusion proteins, antigenic peptides and anti-PGC-1β antibodies. Diagnostic and therapeutic methods utilizing compositions of the invention are also provided.

Novel pgc-1 isoforms and uses therefor

Abstract: The invention provides isolated nucleic acid molecules, designated PGC-1b and PGC-1c nucleic acid molecules, which encode novel isoforms of PGC-1 family members. The invention also provides antisense nucleic acid molecules, recombinant expression vectors containing PGC-1 nucleic acid molecules, host cells into which the expression vectors have been introduced, and nonhuman transgenic animals in which a PGC-1 gene has been introduced or disrupted. The invention still further provides isolated PGC-1 proteins, fusion proteins, antigenic peptides and anti-PGC-1 antibodies. Diagnostic methods utilizing compositions of the invention are also provided.

Methods and compositions for modulating gluconeogenesis using PGC-1

Abstract: The invention provides novel methods and compositions for modulating gluconeogenesis through modulation of PGC-1 activity or expression. Also provided are methods for identifying compounds that modulate gluconeogenesis through modulation of PGC-1 activity or expression, as well as methods for identifying compounds that modulate the interaction of PGC-1 with PGC-1 target molecules. Further provided are methods for treating disorders characterized by aberrant gluconeogenesis.

PGC-1 isoforms and uses therefor

Abstract: The invention provides isolated nucleic acid molecules, designated PGC-1 b and PGC-1 c nucleic acid molecules, which encode novel isoforms of PGC-1 family members. The invention also provides antisense nucleic acid molecules, recombinant expression vectors containing PGC-1 nucleic acid molecules, host cells into which the expression vectors have been introduced, and nonhuman transgenic animals in which a PGC-1 gene has been introduced or disrupted. The invention still further provides isolated PGC-1 proteins, fusion proteins, antigenic peptides and anti-PGC-1 antibodies. Diagnostic methods utilizing compositions of the invention are also provided.