The identification of new pharmacological approaches to effectively prevent, treat, and cure the metabolic syndrome is of crucial importance. Excessive exposure to dietary lipids causes inflammatory responses, deranges the homeostasis of cellular metabolism, and is believed to constitute a key initiator of the metabolic syndrome. Mammalian Sirt1 is a protein deacetylase that has been involved in resveratrol-mediated protection from high-fat dietinduced metabolic damage, but direct proof for the implication of Sirt1 has remained elusive. Here, we report that mice with moderate overexpression of Sirt1 under the control of its natural promoter exhibit fat mass gain similar to wild-type controls when exposed to a high-fat diet. Higher energy expenditure appears to be compensated by a parallel increase in food intake. Interestingly, transgenic Sirt1 mice under a high-fat diet show lower lipidinduced inflammation along with better glucose tolerance, and are almost entirely protected from hepatic steatosis. We present data indicating that such beneficial effects of Sirt1 are due to at least two mechanisms: induction of antioxidant proteins MnSOD and Nrf1, possibly via stimulation of PGC1␣, and lower activation of proinflammatory cytokines, such as TNF␣ and IL-6, via downmodulation of NF B activity. Together, these results provide direct proof of the protective potential of Sirt1 against the metabolic consequences of chronic exposure to a high-fat diet.inflammation ͉ metabolism ͉ NF B ͉ sirtuins ͉ steatosis D riven by the need for potent and safe options to treat obesity, diabetes, and the metabolic syndrome, numerous efforts are currently underway to achieve a better understanding of the molecular networks controlling cellular glucose, lipid, and energy metabolism (1-3). It is generally accepted that gene-environment interactions (such as the effect of high-fat diets on the molecular pathways that maintain energy homeostasis) play a key role in the pathogenesis of the metabolic syndrome (4). Intriguingly, several reports recently showed that specific dietary fatty acids can directly activate Toll-like receptors, which are better known as components of the innate immune system recognizing bacteria-derived fatty acids (5-7). The resulting immune response promotes the systemic activation of proinflammatory pathways including NF B, TNF␣, or IL-6 (5, 6). This chain of events is believed to ultimately lead to insulin resistance, setting in motion the vicious cycle of the metabolic syndrome (8).Recently, a series of studies in several organisms revealed multiple important links of the Sirtuin family of proteins with energy metabolism and inflammation (9-11). Also known as silent information regulator 2 (Sir2)-related enzymes, the Sirtuins have been well conserved throughout evolution and represent a family of nicotinamide adenine dinucleotide-dependent enzymes that deacetylate residues of acetylated lysine. The mammalian sirtuins Sirt1-Sirt7 are implicated in a number of cellular and physiological functions including gene sil...

Transcriptional activation of target genes represents an important component of the tumour-suppressor function of p53 and provides a functional link between p53 and various growth-regulatory processes, including cell cycle progression (p21/WAF1), DNA repair (GADD45) and apoptosis (bax). Here we use a differential cloning approach to identify the gene encoding insulin-like growth factor binding protein 3 (IGF-BP3) as a novel p53-regulated target gene. Induction of IGF-BP3 gene expression by wild-type but not mutant p53 is associated with enhanced secretion of an active form of IGF-BP3 capable of inhibiting mitogenic signalling by the insulin-like growth factor IGF-1. Our results indicate that IGF-BP3 may link p53 to potential novel autocrine/paracrine signalling pathways and to processes regulated by or dependent on IGF(s), such as cellular growth, transformation and survival.

Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder characterized by increased incidence of benign and malignant tumors of neural crest origin. Mutations that activate the protooncogene ras, such as loss of Nf1, cooperate with inactivating mutations at the p53 tumor suppressor gene during malignant transformation. One hundred percent of mice harboring null Nf1 and p53 alleles in cis synergize to develop soft tissue sarcomas between 3 and 7 months of age. These sarcomas exhibit loss of heterozygosity at both gene loci and express phenotypic traits characteristic of neural crest derivatives and human NF1 malignancies.

Exposure of mammalian cells to hypoxia, radiation and certain chemotherapeutic agents promotes cell cycle arrest and/or apoptosis. Activation of p53 responsive genes is believed to play an important role in mediating such responses. In this study we identi®ed a novel gene, PA26, which maps to chromosome 6q21 and encodes at least three transcript isoforms, of which two are dierentially induced by genotoxic stress (UV, girradiation and cytotoxic drugs) in a p53-dependent manner. A functional p53-responsive element was identi®ed in the second intron of the PA26 gene, in consistence with a mechanism of transcriptional induction of the PA26 gene by p53. No clues to its functions were revealed by sequence analysis, although pronounced negative regulation by serum factors argues for a potential role of PA26 in growth regulation. Immunological analysis suggests that PA26 protein(s) is localized to the cell nucleus. Our results suggest that the PA26 gene is a novel p53 target gene with properties common to the GADD family of growth arrest and DNA damageinducible stress-response genes, and, thus, a potential novel regulator of cellular growth.