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...

GLP-1 receptor (GLP-1R) is widely located throughout the brain, but the precise molecular mechanisms mediating the actions of GLP-1 and its long-acting analogs on adipose tissue as well as the brain areas responsible for these interactions remain largely unknown. We found that central injection of a clinically used GLP-1R agonist, liraglutide, in mice stimulates brown adipose tissue (BAT) thermogenesis and adipocyte browning independent of nutrient intake. The mechanism controlling these actions is located in the hypothalamic ventromedial nucleus (VMH), and the activation of AMPK in this area is sufficient to blunt both central liraglutide-induced thermogenesis and adipocyte browning. The decreased body weight caused by the central injection of liraglutide in other hypothalamic sites was sufficiently explained by the suppression of food intake. In a longitudinal study involving obese type 2 diabetic patients treated for 1 year with GLP-1R agonists, both exenatide and liraglutide increased energy expenditure. Although the results do not exclude the possibility that extrahypothalamic areas are also modulating the effects of GLP-1R agonists, the data indicate that long-acting GLP-1R agonists influence body weight by regulating either food intake or energy expenditure through various hypothalamic sites and that these mechanisms might be clinically relevant.

Genetic overexpression of protein deacetylase Sir2 increases longevity in a variety of lower organisms, and this has prompted interest in the effects of its closest mammalian homologue, Sirt1, on ageing and cancer. We have generated transgenic mice moderately overexpressing Sirt1 under its own regulatory elements (Sirt1-tg). Old Sirt1-tg mice present lower levels of DNA damage, decreased expression of the ageing-associated gene p16 Ink4a , a better general health and fewer spontaneous carcinomas and sarcomas. These effects, however, were not suffi ciently potent to affect longevity. To further extend these observations, we developed a metabolic syndrome-associated liver cancer model in which wild-type mice develop multiple carcinomas. Sirt1-tg mice show a reduced susceptibility to liver cancer and exhibit improved hepatic protection from both DNA damage and metabolic damage. Together, these results provide direct proof of the anti-ageing activity of Sirt1 in mammals and of its tumour suppression activity in ageing-and metabolic syndrome-associated cancer.