of the metabolic syndrome, the exact mechanisms underlying the different comorbidities are not yet completely known. Recently, dietary fi bers have raised much interest, as they exert benefi cial effects on body weight, food intake, glucose homeostasis, and insulin sensitivity ( 2-4 ). Epidemiological studies show an association between a higher fi ber intake and a reduced risk of irritable bowel syndrome, infl ammatory bowel disease, cardiovascular disease, diabetes, and colon cancer ( 1 ).Humans lack the enzymes to degrade the bulk of dietary fi bers. Therefore these nondigestible carbohydrates pass the upper gastrointestinal tract unaffected and are fermented in the cecum and the large intestine by the anaerobic cecal and colonic microbiota. Fermentation results in multiple groups of metabolites [elegantly reviewed by Nicholson et al. ( 5 )] of which short-chain fatty acids (SCFAs) are the major group ( 6 ). To the microbial community SCFAs are a necessary waste product, required to balance redox equivalent production in the anaerobic environment of the gut ( 7 ). SCFAs are saturated aliphatic organic acids that consist of one to six carbons of which acetate (C2), propionate (C3), and butyrate (C4) are the most abundant ( у 95%) ( 8 ). Acetate, propionate, and butyrate are present in an approximate molar ratio of 60:20:20 in the colon and stool ( 9-11 ). Depending on the diet, the total concentration of SCFAs decreases from 70 to 140 mM in the proximal colon to 20 to 70 mM in the distal colon ( 12 ). A unique series of measurements in Abstract Short-chain fatty acids (SCFAs), the end products of fermentation of dietary fi bers by the anaerobic intestinal microbiota, have been shown to exert multiple benefi cial effects on mammalian energy metabolism. The mechanisms underlying these effects are the subject of intensive research and encompass the complex interplay between diet, gut microbiota, and host energy metabolism. This review summarizes the role of SCFAs in host energy metabolism, starting from the production by the gut microbiota to the uptake by the host and ending with the effects on host metabolism. There are interesting leads on the underlying molecular mechanisms, but there are also many apparently contradictory results . A coherent understanding of the multilevel network in which SCFAs exert their effects is hampered by the lack of quantitative data on actual fl uxes of SCFAs and metabolic processes regulated by SCFAs. In this review we address questions that, when answered, will bring us a great step forward in elucidating the role of SCFAs in mammalian energy metabolism. -den Besten, G., K. van Eunen, A. K. The decrease in physical exercise and increase in energy intake, especially seen in the Western world, disrupts the energy balance in humans and can lead to a complex of symptoms collectively denoted as the metabolic syndrome. The key characteristics of the metabolic syndrome are obesity, loss of glycemic control, dyslipidemia, and hypertension ( 1 ). Due to the complex multifactorial etiolog...

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.