We investigated the effects of eicosapentaenoic acid (EPA) on prevention (P) and reversal (R) of high saturated-fat (HF) diet-induced obesity and glucose-insulin homeostasis. Male C57BL/6J mice were fed low-fat (LF; 10% energy from fat), HF (45% energy from fat), or a HF-EPA-P (45% energy from fat; 36 g/kg EPA) diet for 11 wk. A 4th group was initially fed HF for 6 wk followed by the HF-EPA-R diet for 5 wk. As expected, mice fed the HF diet developed obesity and glucose intolerance. In contrast, mice fed the HF-EPA-P diet maintained normal glucose tolerance despite weight gain compared with the LF group. Whereas the HF group developed hyperglycemia and hyperinsulinemia, both HF-EPA groups (P and R) exhibited normal glycemia and insulinemia. Further, plasma adiponectin concentration was lower in the HF group but was comparable in the LF and HF-EPA groups, suggesting a role of EPA in preventing and improving insulin resistance induced by HF feeding. Further analysis of adipose tissue adipokine levels and proteomic studies in cultured adipocytes indicated that dietary EPA supplementation of HF diets was associated with reduced adipose inflammation and lipogenesis and elevated markers of fatty acid oxidation. In C57BL/6J mice, EPA minimized saturated fat-induced insulin resistance and this is in part mediated by its effects on fatty acid oxidation and inflammation.

BackgroundEpidemiologic data suggest that diets rich in nuts have beneficial health effects, including reducing total and cause-specific mortality from cancer and heart disease. Although there is accumulating preclinical evidence that walnuts beneficially affect the gastrointestinal microbiota and gut and metabolic health, these relations have not been investigated in humans.ObjectiveWe aimed to assess the impact of walnut consumption on the human gastrointestinal microbiota and metabolic markers of health.MethodsA controlled-feeding, randomized crossover study was undertaken in healthy men and women [n = 18; mean age = 53.1 y; body mass index (kg/m2): 28.8]. Study participants received isocaloric diets containing 0 or 42 g walnuts/d for two 3-wk periods, with a 1-wk washout between diet periods. Fecal and blood samples were collected at baseline and at the end of each period to assess secondary outcomes of the study, including effects of walnut consumption on fecal microbiota and bile acids and metabolic markers of health.ResultsCompared with after the control period, walnut consumption resulted in a 49–160% higher relative abundance of Faecalibacterium, Clostridium, Dialister, and Roseburia and 16–38% lower relative abundances of Ruminococcus, Dorea, Oscillospira, and Bifidobacterium (P < 0.05). Fecal secondary bile acids, deoxycholic acid and lithocholic acid, were 25% and 45% lower, respectively, after the walnut treatment compared with the control treatment (P < 0.05). Serum LDL cholesterol and the noncholesterol sterol campesterol concentrations were 7% and 6% lower, respectively, after walnut consumption compared with after the control treatment (P < 0.01).ConclusionWalnut consumption affected the composition and function of the human gastrointestinal microbiota, increasing the relative abundances of Firmicutes species in butyrate-producing Clostridium clusters XIVa and IV, including Faecalibacterium and Roseburia, and reducing microbially derived, proinflammatory secondary bile acids and LDL cholesterol. These results suggest that the gastrointestinal microbiota may contribute to the underlying mechanisms of the beneficial health effects of walnut consumption. This trial was registered at www.clinicaltrials.gov as NCT01832909.

Background Alirocumab, a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 (PCSK9), lowers plasma low density lipoprotein cholesterol (LDL-C) and apolipoprotein B100 (apoB). Although studies in mice and cells have identified increased hepatic LDL receptors as the basis for LDL lowering by PCSK9 inhibitors, there have been no human studies characterizing the effects of PCSK9 inhibitors on lipoprotein metabolism. In particular, it is not known if inhibition of PCSK9 has any effects on very low density lipoprotein (VLDL) or intermediate density lipoprotein (IDL) metabolism. Inhibition of PCSK9 also results in reductions of plasma Lp(a) levels. The regulation of plasma Lp(a) levels, including the role of LDL receptors (LDLRs) in the clearance of Lp(a), is poorly defined, and there have been no mechanistic studies of the Lp(a) lowering by alirocumab in humans. Methods Eighteen (10F, 8M) participants completed a placebo-controlled, two-period study. They received 2 doses of placebo, 2 weeks apart, followed by 5 doses of 150 mg of alirocumab, 2 weeks apart. At the end of each period, fractional clearance rates (FCR) and production rates (PR) of apoB and apo(a) were determined. In 10 participants, postprandial triglycerides (TG) and apoB48 levels were measured. Results Alirocumab reduced ultracentrifugally isolated LDL-C by 55.1%, LDL-apoB by 56.3%, and plasma Lp(a) by 18.7%. The fall in LDL-apoB was due to an 80.4% increase in LDL-apoB FCR and a 23.9% reduction in LDL-apoB PR. The latter was associated with a 46.1% increase in IDL-apoB FCR coupled with a 27.2% decrease in conversion of IDL to LDL. The FCR of apo(a) tended to increase (24.6%) without any change in apo(a) PR. Alirocumab had no effects on FCRs or PRs of VLDL-apoB and VLDL-TG, or on postprandial plasma TG or apoB48 concentrations. Conclusions Alirocumab decreased LDL-C and LDL-apoB by increasing IDL- and LDL-apoB FCRs, and decreasing LDL-apoB PR. These results are consistent with increases in LDLRs available to clear IDL and LDL from blood during PCSK9 inhibition. The possible increase in apo(a) FCR during alirocumab treatment suggests that increased LDLRs may also play a role in the reduction of plasma Lp(a). Clinical Trials Registration Clinical trials.gov # NCT01959971