Diabetes and obesity are two metabolic diseases characterized by insulin resistance and a low-grade inflammation. Seeking an inflammatory factor causative of the onset of insulin resistance, obesity, and diabetes, we have identified bacterial lipopolysaccharide (LPS) as a triggering factor. We found that normal endotoxemia increased or decreased during the fed or fasted state, respectively, on a nutritional basis and that a 4-week high-fat diet chronically increased plasma LPS concentration two to three times, a threshold that we have defined as metabolic endotoxemia. Importantly, a high-fat diet increased the proportion of an LPScontaining microbiota in the gut. When metabolic endotoxemia was induced for 4 weeks in mice through continuous subcutaneous infusion of LPS, fasted glycemia and insulinemia and whole-body, liver, and adipose tissue weight gain were increased to a similar extent as in highfat-fed mice. In addition, adipose tissue F4/80-positive cells and markers of inflammation, and liver triglyceride content, were increased. Furthermore, liver, but not wholebody, insulin resistance was detected in LPS-infused mice. CD14 mutant mice resisted most of the LPS and high-fat diet-induced features of metabolic diseases. This new finding demonstrates that metabolic endotoxemia dysregulates the inflammatory tone and triggers body weight gain and diabetes. We conclude that the LPS/CD14 system sets the tone of insulin sensitivity and the onset of diabetes and obesity. Lowering plasma LPS concentration could be a potent strategy for the control of metabolic diseases. Diabetes 56: [1761][1762][1763][1764][1765][1766][1767][1768][1769][1770][1771][1772] 2007 T he outbreak of a fat-enriched diet in Western countries is becoming a problem of the utmost importance. Obesity is the result of a complex interaction between genetic and environmental factors. Among the latter, changes in eating habits to increase fat intake are involved in the increased occurrence of metabolic diseases, such as obesity and diabetes, which are bearing features of the metabolic syndrome. The major metabolic consequence of a high-fat diet is that insulin action and the regulatory mechanisms of body weight are impaired through a well-described lipotoxic effect (1). In addition, it has been recently determined that obesity and insulin resistance are associated with lowgrade chronic systemic inflammation (2). In models of diet-induced and genetic obesity, the adipose tissue presents increased expression and content of proinflammatory cytokines such as tumor necrosis factor (TNF)-␣ (3,4), interleukin (IL)-1 (3,4), and IL-6 (4). This cytokine production is then deleterious for muscle insulin action; for example, TNF-␣ has been shown to cause insulin resistance by increasing serine phosphorylation on insulin receptor substrate-1 (5), leading to its inactivation. The consequent insulin resistance will favor hyperinsulinemia and excessive hepatic and adipose tissue lipid storage. However, while extensive research is dedicated to the effects of an in...

Metformin is a widely used antidiabetic agent, which regulates glucose homeostasis through inhibition of liver glucose production and an increase in muscle glucose uptake. Recent studies suggest that metformin may reduce the risk of cancer, but its mode of action in cancer remains not elucidated. We investigated the effect of metformin on human prostate cancer cell proliferation in vitro and in vivo. Metformin inhibited the proliferation of DU145, PC-3 and LNCaP cancer cells with a 50% decrease of cell viability and had a modest effect on normal prostate epithelial cell line P69. Metformin did not induce apoptosis but blocked cell cycle in G 0 /G 1 . This blockade was accompanied by a strong decrease of cyclin D1 protein level, pRb phosphorylation and an increase in p27 kip protein expression. Metformin activated the AMP kinase pathway, a fuel sensor signaling pathway. However, inhibition of the AMPK pathway using siRNA against the two catalytic subunits of AMPK did not prevent the antiproliferative effect of metformin in prostate cancer cells. Importantly, oral and intraperitoneal treatment with metformin led to a 50 and 35% reduction of tumor growth, respectively, in mice bearing xenografts of LNCaP. Similar, to the in vitro study, metformin led to a strong reduction of cyclin D1 protein level in tumors providing evidence for a mechanism that may contribute to the antineoplastic effects of metformin suggested by recent epidemiological studies.

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Metformin is a widely prescribed antidiabetic drug associated with a reduced risk of cancer. Many studies show that metformin inhibits cancer cell viability through the inhibition of mTOR. We recently showed that antiproliferative action of metformin in prostate cancer cell lines is not mediated by AMP-activated protein kinase (AMPK). We identified REDD1 (also known as DDIT4 and RTP801), a negative regulator of mTOR, as a new molecular target of metformin. We show that metformin increases REDD1 expression in a p53-dependent manner. REDD1 invalidation, using siRNA or REDD1 À/À cells, abrogates metformin inhibition of mTOR. Importantly, inhibition of REDD1 reverses metformin-induced cell-cycle arrest and significantly protects from the deleterious effects of metformin on cell transformation. Finally, we show the contribution of p53 in mediating metformin action in prostate cancer cells. These results highlight the p53/REDD1 axis as a new molecular target in anticancer therapy in response to metformin treatment. Cancer Res; 71(13); 4366-72. '2011 AACR.