As NAD(+) is a rate-limiting cosubstrate for the sirtuin enzymes, its modulation is emerging as a valuable tool to regulate sirtuin function and, consequently, oxidative metabolism. In line with this premise, decreased activity of PARP-1 or CD38-both NAD(+) consumers-increases NAD(+) bioavailability, resulting in SIRT1 activation and protection against metabolic disease. Here we evaluated whether similar effects could be achieved by increasing the supply of nicotinamide riboside (NR), a recently described natural NAD(+) precursor with the ability to increase NAD(+) levels, Sir2-dependent gene silencing, and replicative life span in yeast. We show that NR supplementation in mammalian cells and mouse tissues increases NAD(+) levels and activates SIRT1 and SIRT3, culminating in enhanced oxidative metabolism and protection against high-fat diet-induced metabolic abnormalities. Consequently, our results indicate that the natural vitamin NR could be used as a nutritional supplement to ameliorate metabolic and age-related disorders characterized by defective mitochondrial function.
Short-chain fatty acids (SCFAs) are the main products of dietary fiber fermentation and are believed to drive the fiber-related prevention of the metabolic syndrome. Here we show that dietary SCFAs induce a peroxisome proliferator–activated receptor-γ (PPARγ)–dependent switch from lipid synthesis to utilization. Dietary SCFA supplementation prevented and reversed high-fat diet–induced metabolic abnormalities in mice by decreasing PPARγ expression and activity. This increased the expression of mitochondrial uncoupling protein 2 and raised the AMP-to-ATP ratio, thereby stimulating oxidative metabolism in liver and adipose tissue via AMPK. The SCFA-induced reduction in body weight and stimulation of insulin sensitivity were absent in mice with adipose-specific disruption of PPARγ. Similarly, SCFA-induced reduction of hepatic steatosis was absent in mice lacking hepatic PPARγ. These results demonstrate that adipose and hepatic PPARγ are critical mediators of the beneficial effects of SCFAs on the metabolic syndrome, with clearly distinct and complementary roles. Our findings indicate that SCFAs may be used therapeutically as cheap and selective PPARγ modulators.
The G protein-coupled receptor TGR5 has been identified as an important component of the bile acid signaling network, and its activation has been linked to enhanced energy expenditure and improved glycemic control. Here, we demonstrate that activation of TGR5 in macrophages by 6α-ethyl-23(S)-methylcholic acid (6-EMCA, INT-777), a semisynthetic BA, inhibits proinflammatory cytokine production, an effect mediated by TGR5-induced cAMP signaling and subsequent NF-κB inhibition. TGR5 activation attenuated atherosclerosis in Ldlr(-/-)Tgr5(+/+) mice but not in Ldlr(-/-)Tgr5(-/-) double-knockout mice. The inhibition of lesion formation was associated with decreased intraplaque inflammation and less plaque macrophage content. Furthermore, Ldlr(-/-) animals transplanted with Tgr5(-/-) bone marrow did not show an inhibition of atherosclerosis by INT-777, further establishing an important role of leukocytes in INT-777-mediated inhibition of vascular lesion formation. Taken together, these data attribute a significant immune modulating function to TGR5 activation in the prevention of atherosclerosis, an important facet of the metabolic syndrome.
A growing body of evidence indicates that peroxisome proliferator-activated receptor ␣ (PPAR␣) not merely serves as a transcriptional regulator of fatty acid catabolism but also exerts a much broader role in hepatic lipid metabolism. We determined adaptations in hepatic lipid metabolism and related aspects of carbohydrate metabolism upon treatment of C57Bl/6 mice with the PPAR␣ agonist fenofibrate. Stable isotope procedures were applied to assess hepatic fatty acid synthesis, fatty acid elongation, and carbohydrate metabolism. Fenofibrate treatment strongly induced hepatic de novo lipogenesis and chain elongation (؎300, 150, and 600% for C16:0, C18:0, and C18:1 synthesis, respectively) in parallel with an increased expression of lipogenic genes. The lipogenic induction in fenofibrate-treated mice was found to depend on sterol regulatory element-binding protein 1c (SREBP-1c) but not carbohydrate response element-binding protein (ChREBP). Fenofibrate treatment resulted in a reduced contribution of glycolysis to acetylCoA production, whereas the cycling of glucose 6-phosphate through the pentose phosphate pathway presumably was enhanced. Altogether, our data indicate that -oxidation and lipogenesis are induced simultaneously upon fenofibrate treatment. These observations may reflect a physiological mechanism by which PPAR␣ and SREBP-1c collectively ensure proper handling of fatty acids to protect the liver against cytotoxic damage.Fatty acids are cytotoxic molecules. Both their oxidation and storage as triglycerides (TGs) 2 may be important in protecting the liver against lipotoxicity. Recently it was postulated that an increased conversion of saturated fatty acids into monounsaturated fatty acids (MUFAs) stimulates storage as TG and prevents non-esterified fatty acid (NEFA)-induced hepatocellular apoptosis (1). However, the mechanisms underlying this lipogenic response have remained enigmatic. Peroxisome proliferator-activated receptors (PPARs) represent likely candidates to mediate this response because these nuclear receptors act as cellular fatty acid sensors.PPAR␣ induces the remodeling of hepatic lipid metabolism under conditions of increased fatty acid influx such as fasting and high fat feeding (2-4). Upon activation, PPAR␣ induces the expression of a multitude of genes encoding proteins involved in peripheral lipid mobilization and fatty acid oxidation (2, 3, 5-7). In addition PPAR␣ plays a role in hepatic lipid droplet formation (8, 9) and mediates adaptive responses to prevent oxidative stress and the accumulation of cytotoxic NEFAs (10). For example, PPAR␣ promotes the degradation of lipid-derived inflammatory mediators (11) and induces mitochondrial uncoupling as well as antioxidant systems to protect against oxidative damage associated with (incomplete) -oxidation (12-18). As a consequence, PPAR␣ activity protects against hepatic inflammation in mice (19 -22).Fibrates are pharmacological PPAR␣ agonists that are used clinically to treat dyslipidemia (23). Interestingly, PPAR␣ agonist treatment has al...
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