Influence of fenofibrate treatment on triacylglycerides, diacylglycerides and fatty acids in fructose fed rats.

Fenofibrate (FF) lowers plasma triglycerides via PPARα activation. Here, we analyzed lipidomic changes upon FF treatment of fructose fed rats. Three groups with 6 animals each were defined as control, fructose-fed and fructose-fed/FF treated. Male Wistar Unilever Rats were subjected to 10% fructose-feeding for 20 days. On day 14, fenofibrate treatment (100 mg/kg p.o.) was initiated and maintained for 7 days. Lipid species in serum were analyzed using mass spectrometry (ESI-MS/MS; LC-FT-MS, GC-MS) on days 0, 14 and 20 in all three groups. In addition, lipid levels in liver and intestine were determined. Short-chain TAGs increased in serum and liver upon fructose-feeding, while almost all TAG-species decreased under FF treatment. Long-chain unsaturated DAG-levels (36:1, 36:2, 36:4, 38:3, 38:4, 38:5) increased upon FF treatment in rat liver and decreased in rat serum. FAs, especially short-chain FAs (12:0, 14:0, 16:0) increased during fructose-challenge. VLDL secretion increased upon fructose-feeding and together with FA-levels decreased to control levels during FF treatment. Fructose challenge of de novo fatty acid synthesis through fatty acid synthase (FAS) may enhance the release of FAs ≤ 16:0 chain length, a process reversed by FF-mediated PPARα-activation.

Discovery and pharmacological characterization of a novel small molecule inhibitor of phosphatidylinositol-5-phosphate 4-kinase, type II, beta.

Phosphatidylinositol-5-phosphate 4-kinase, type II, beta (PIP5K2B) is linked to the pathogenesis of obesity, insulin resistance and diabetes. Here, we describe the identification of a novel pyrimidine-2,4-diamine PIP5K2B inhibitor, designated SAR088. The compound was identified by high-throughput screening and subsequently characterized in vitro and in vivo. SAR088 showed reasonable potency, selectivity and physicochemical properties in enzymatic and cellular assays. In vivo, SAR088 lowered blood glucose levels of obese and hyperglycemic male Zucker diabetic fatty rats treated for 3 weeks. Thus, SAR088 represents the first orally available and in vivo active PIP5K2B inhibitor and provides an excellent starting point for the development of potent and selective PIP5K2B inhibitors for the treatment of insulin resistance and diabetes.

Muscle-type specific intramyocellular and hepatic lipid metabolism during starvation in wistar rats.

The physiological dynamics of intramyocellular lipids (IMCLs) in different muscle types and of hepatocellular lipids (HepCLs) are still uncertain. The dynamics of IMCLs in the soleus, tibialis anterior, and extensor digitorum longus (EDL) muscles and HepCL during fed, 12- to 72-h starved, and refed conditions were measured in vivo by (1)H-magnetic resonance spectroscopy (MRS) in Wistar rats. Despite significant elevations of free fatty acids (FFAs) during starvation, HepCLs and IMCLs in soleus remained constant. In tibialis anterior and EDL, however, IMCLs increased significantly by 170 and 450% after 72 h of starvation, respectively. After refeeding, elevated IMCLs dropped immediately in both muscles. Total muscle long-chain acyl-CoAs (LCACoAs) remained constant during the study period. Hepatic palmitoleoyl-CoA (C16:1) decreased significantly during starvation while total hepatic LCACoAs increased significantly. Consistent with constant values for FFAs, HepCLs, IMCLs, and muscle LCACoAs from 12-72 h of starvation, insulin sensitivity did not change. We conclude that during starvation-induced adipocytic lipolysis, oxidative muscles dispose elevated FFAs by oxidation, while nonoxidative ones neutralize FFAs by reesterification. Both mechanisms might prevent impairment of insulin signaling by maintaining low levels of LCACoAs. Hepatic palmitoleoyl-CoA might have a special role in lipid metabolism due to its unique dynamic profile during starvation.