Showing papers by "Bruce M. Spiegelman published in 1998"

PPAR-gamma: adipogenic regulator and thiazolidinedione receptor.

Abstract: The past several years have seen an explosive increase in our understanding of the transcriptional basis of adipose cell differentiation. In particular, a key role has been illustrated for PPAR-gamma, a member of the nuclear hormone receptor superfamily. PPAR-gamma has also been recently identified as the major functional receptor for the thiazolidinedione class of insulin-sensitizing drugs. This review examines the evidence that has implicated this transcription factor in the processes of adipogenesis and systemic insulin action. In addition, several models are discussed that may explain how a single protein can be involved in these related but distinct physiological actions. I also point out several important areas where our knowledge is incomplete and more research is needed. Finally, I discuss how advances in our understanding of nuclear receptor function, particularly the docking of cofactors in a ligand-dependent fashion, should lead to improved drugs that utilize the PPAR-gamma system for the treatment of insulin resistance.

Differentiation and reversal of malignant changes in colon cancer through PPARgamma.

Abstract: PPARgamma is a nuclear receptor that has a dominant regulatory role in differentiation of cells of the adipose lineage, and has recently been shown to be expressed in the colon. We show here that PPARgamma is expressed at high levels in both well- and poorly-differentiated adenocarcinomas, in normal colonic mucosa and in human colon cancer cell lines. Ligand activation of this receptor in colon cancer cells causes a considerable reduction in linear and clonogenic growth, increased expression of carcinoembryonic antigen and the reversal of many gene expression events specifically associated with colon cancer. Transplantable tumors derived from human colon cancer cells show a significant reduction of growth when mice are treated with troglitazone, a PPARgamma ligand. These results indicate that the growth and differentiation of colon cancer cells can be modulated through PPARgamma.

Nutritional and insulin regulation of fatty acid synthetase and leptin gene expression through ADD1/SREBP1.

Abstract: The ability to regulate specific genes of energy metabolism in response to fasting and feeding is an important adaptation allowing survival of intermittent food supplies. However, little is known about transcription factors involved in such responses in higher organisms. We show here that gene expression in adipose tissue for adipocyte determination differentiation dependent factor (ADD) 1/sterol regulatory element binding protein (SREBP) 1, a basic-helix-loop-helix protein that has a dual DNA-binding specificity, is reduced dramatically upon fasting and elevated upon refeeding; this parallels closely the regulation of two adipose cell genes that are crucial in energy homeostasis, fatty acid synthetase (FAS) and leptin. This elevation of ADD1/SREBP1, leptin, and FAS that is induced by feeding in vivo is mimicked by exposure of cultured adipocytes to insulin, the classic hormone of the fed state. We also show that the promoters for both leptin and FAS are transactivated by ADD1/SREBP1. A mutation in the basic domain of ADD1/SREBP1 that allows E-box binding but destroys sterol regulatory element-1 binding prevents leptin gene transactivation but has no effect on the increase in FAS promoter function. Molecular dissection of the FAS promoter shows that most if not all of this action of ADD1/SREBP1 is through an E-box motif at -64 to -59, contained with a sequence identified previously as the major insulin response element of this gene. These results indicate that ADD1/SREBP1 is a key transcription factor linking changes in nutritional status and insulin levels to the expression of certain genes that regulate systemic energy metabolism.

ADD1/SREBP1 activates PPARγ through the production of endogenous ligand

Abstract: Adipose differentiation is an important part of the energy homeostasis system of higher organisms. Recent data have suggested that this process is controlled by an interplay of transcription factors including PPARγ, the C/EBPs, and ADD1/SREBP1. Although these factors interact functionally to initiate the program of differentiation, there are no data concerning specific mechanisms of interaction. We show here that the expression of ADD1/SREBP1 specifically increases the activity of PPARγ but not other isoforms, PPARα, or PPARδ. This activation occurs through the ligand-binding domain of PPARγ when it is fused to the DNA-binding domain of Gal4. The stimulation of PPARγ by ADD1/SREBP1 does not require coexpression in the same cells; supernatants from cultures that express ADD1/SREBP1 augment the transcriptional activity of PPARγ. Finally, we demonstrate directly that cells expressing ADD1/SREBP1 produce and secrete lipid molecule(s) that bind directly to PPARγ, displacing the binding of radioactive thiazolidinedione ligands. These data establish that ADD1/SREBP1 can control the production of endogenous ligand(s) for PPARγ and suggest a mechanism for coordinating the actions of these adipogenic factors.

TNF-alpha and insulin resistance: summary and future prospects.

Abstract: While the causes of obesity remain elusive, the relationship between obesity and insulin resistance is a well-established fact [1]. Insulin resistance is defined as a smaller than normal response to a certain dose of insulin, and contributes to several pathological problems of obese patients such as hyperlipidemia, arteriosclerosis and hypertension. Several pieces of evidence indicate that the cytokine tumor necrosis factor a (TNF-α) is an important player in the state of insulin resistance observed during obesity. In this review we will try to summarize what is known about the function of TNF-a in insulin resistance during obesity and how TNF-α interferes with insulin signaling.

A potential role for the nuclear factor of activated T cells family of transcriptional regulatory proteins in adipogenesis.

Abstract: NFAT (nuclear factor of activated T cells) is a family of transcription factors implicated in the control of cytokine and early immune response gene expression. Recent studies have pointed to a role for NFAT proteins in gene regulation outside of the immune system. Herein we demonstrate that NFAT proteins are present in 3T3-L1 adipocytes and, upon fat cell differentiation, bind to and transactivate the promoter of the adipocyte-specific gene aP2. Further, fat cell differentiation is inhibited by cyclosporin A, a drug shown to prevent NFAT nuclear localization and hence function. Thus, these data suggest a role for NFAT transcription factors in the regulation of the aP2 gene and in the process of adipocyte differentiation.

Differentiation enhancing factors and uses therefor

Abstract: The present invention relates to novel SH3 domain binding protein, referred to herein as a DEF polypeptides. The DEF polypeptides comprise several motifs including a src SH3 consensus binding sequence, four ankyrin repeats, one zinc finger domain and six copies of a proline-rich tandem repeat. DEF polypeptides may function as mediators of SH3 domain-dependent signal transduction pathways and, thus may mediate multiple signaling events such as cellular gene expression, cytoskeletal architecture, protein trafficking and endocytosis, cell adhesion, migration, proliferation and differentiation. Described herein are isolated and antisense nucleic acids molecules, recombinant expression vectors, host cells and non-human transgenic animals containing an insertion or a disruption of the DEF gene. Diagnostic, screening and therapeutic methods utilizing the compositions of the invention are also provided.

PGC-1, UN NOUVEAU COACTIVATEUR PPARη DE GRAISSES BRUNES

Abstract: La presente invention se rapporte a des molecules d'acides nucleiques isolees, appelees molecules d'acide nucleique PGC-1, qui codent des proteines pouvant moduler differentes activites liees aux adipocytes, par exemple, la thermogenese chez les adipocytes, notamment les adipocytes bruns, et l'adipogenese. L'invention concerne egalement des molecules antisens d'acide nucleique, des vecteurs d'expression recombinants renfermant des molecules d'acide nucleique PGC-1, des cellules hotes dans lesquelles on a introduit les vecteurs d'expression, ainsi que des animaux transgeniques dans lesquels on a introduit ou rompu un gene PGC-1. Par ailleurs, l'invention se rapporte a des proteines PGC-1 isolees, a des proteines de fusion, a des peptides antigeniques et a des anticorps anti-PGC-1, ainsi qu'a des procedes diagnostiques, therapeutiques et des procedes de selection utilisant les compositions de cette invention.