Pegylated Fgf21 rapidly normalizes insulin-stimulated glucose utilization in diet-induced insulin resistant mice.

Fibroblast growth factor 21 (FGF21) is a novel hormone-like polypeptide that when administered exogenously, has been shown to have beneficial effects on food intake, body weight, and metabolism. The in vivo mechanisms of action for its positive metabolic effects remain to be fully elucidated. It has been shown that PEGylation of human FGF21 at specific and preferred sites confer superior metabolic pharmacology. We therefore hypothesized that low doses of PEGylated (30K PEG on position Q108) FGF21 (PEG30-Q108) would improve insulin action, independent of any effect on food intake or body weight. We identified a dose (0.25mg/kg) that had no effect on food intake or body weight, yet did show beneficial metabolic effects. Four groups of 12 weeks, high-fat fed, insulin resistant mice were studied: mice dosed subcutaneously once with vehicle or 0.25mg/kg of PEG30-Q108 24h before the experiment, or mice dosed 4 times over 2 weeks with vehicle or PEG30-Q108. Conscious, unrestrained mice were fasted for 5h and underwent a hyperinsulinemic-euglycemic clamp. Both PEG30-Q108 treatments significantly lowered fasting insulin compared to vehicle, with no difference in food intake or body weight. Insulin-stimulated whole body glucose utilization was normalized to that of lean mice with both PEG30-Q108 treatments compared to vehicle. This accounted for all of the enhanced insulin action, as there was no improvement in insulin's ability to suppress endogenous glucose production. In line with these findings, neither PEG30-Q108 treatment lowered hepatic triglycerides. These results demonstrate the profound ability of PEG30-Q108 to increase whole body insulin sensitivity.

Estrogen receptor (ER) subtype agonists alter monoamine levels in the female rat brain.

We assessed the effects of subtype-selective ER agonists on monoamine levels in discrete regions of the female rat brain. Ovariectomized (ovx) rats were treated for 4 days with vehicle, 17ß-estradiol (E; 0.05mg/kg), an ERß agonist (C19; 3mg/kg) or an ERα agonist (PPT; 3mg/kg) and samples from brain regions were assessed for monoamines and metabolites. We also assessed effects of ERß modulation on baseline and fenfluramine-induced release of monoamines in hippocampus using microdialysis. In the first study, E and the ERα agonist increased norepinephrine in cortex and all three ER ligands increased it in the ventral hippocampus. Changes in levels of the noradrenergic metabolite, MHPG and the dopaminergic metabolite, DOPAC were noted in brain areas of ER ligand-treated animals. E also increased levels of 5HIAA in three brain areas. In the microdialysis study, there were no differences among groups in baseline levels of monoamines. However, E and the ERß agonist increased levels of the dopaminergic metabolite, HVA following fenfluramine. In summary, activation of the two nuclear ERs with selective agonists affects monoamine and metabolite levels in discrete brain areas, a number of which are known to play key roles in cognitive and affective function.