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.

Acetate, propionate, and butyrate are the main short-chain fatty acids (SCFAs) that arise from the fermentation of fibers by the colonic microbiota. While many studies focus on the regulatory role of SCFAs, their quantitative role as a catabolic or anabolic substrate for the host has received relatively little attention. To investigate this aspect, we infused conscious mice with physiological quantities of stable isotopes [1-(13)C]acetate, [2-(13)C]propionate, or [2,4-(13)C2]butyrate directly in the cecum, which is the natural production site in mice, and analyzed their interconversion by the microbiota as well as their metabolism by the host. Cecal interconversion, pointing to microbial cross-feeding, was high between acetate and butyrate, low between butyrate and propionate, and almost absent between acetate and propionate. As much as 62% of infused propionate was used in whole body glucose production, in line with its role as gluconeogenic substrate. Conversely, glucose synthesis from propionate accounted for 69% of total glucose production. The synthesis of palmitate and cholesterol in the liver was high from cecal acetate (2.8 and 0.7%, respectively) and butyrate (2.7 and 0.9%, respectively) as substrates, but low or absent from propionate (0.6 and 0.0%, respectively). Label incorporation due to chain elongation of stearate was approximately eightfold higher than de novo synthesis of stearate. Microarray data suggested that SCFAs exert a mild regulatory effect on the expression of genes involved in hepatic metabolic pathways during the 6-h infusion period. Altogether, gut-derived acetate, propionate, and butyrate play important roles as substrates for glucose, cholesterol, and lipid metabolism.

FGF1 is an autocrine/paracrine regulator whose binding to heparan sulfate proteoglycans effectively precludes its circulation 1,2. Though known as a mitogenic factor, FGF1 knockout mice develop insulin resistance when stressed by a high fat diet, suggesting a potential role in nutrient homeostasis 3,4. Here we show that parenteral delivery of a single dose of recombinant FGF1 (rFGF1) results in potent, insulin-dependent glucose lowering in diabetic mice that is dose-dependent, but does not lead to hypoglycemia. Chronic pharmacological rFGF1 treatment increases insulin-dependent glucose uptake in skeletal muscle and suppresses hepatic glucose production to achieve whole-body insulin sensitization. The sustained glucose lowering and insulin sensitization attributed to rFGF1 are not accompanied by the side effects of weight gain, liver steatosis and bone loss associated with current insulin sensitizing therapies. Furthermore, we demonstrate that the glucose lowering activity of FGF1 can be dissociated from its mitogenic activity and is mediated predominantly via FGF receptor 1 (FGFR1) signaling. In summary, we have uncovered an unexpected, neomorphic insulin sensitizing action for exogenous non-mitogenic human FGF1 with therapeutic potential for treatment of insulin resistance and type 2 diabetes.