Angiopoietin-like protein 4 is differentially regulated by glucocorticoids and insulin in vitro and in vivo in healthy humans.

OBJECTIVE: Angiopoietin-like protein 4 (Angptl4) is a circulating inhibitor of plasma triglyceride clearance via inhibition of lipoprotein lipase. The aim of the present study was to examine the regulation of Angptl4 by glucocorticoids and insulin in vivo in humans, since these factors regulate Angptl4 expression in vitro. RESEARCH DESIGN AND METHODS: In a randomized, placebo-controlled, double-blind, dose-response intervention study, 32 healthy males (age: 22 ± 3 years; BMI 22.4 ± 1.7 kg m⁻²) were allocated to prednisolone 30 mg once daily (n = 12), prednisolone 7.5 mg once daily (n = 12), or placebo (n = 8) for 2 weeks. Angptl4 levels and lipid metabolism were measured before and at 2 weeks of treatment, in the fasted state and during a 2-step hyperinsulinemic clamp. Additionally, human hepatoma cells were treated with dexamethasone and/or insulin. RESULTS: Compared to placebo, prednisolone treatment tended to lower fasting Angptl4 levels (P = 0.073), raised fasting insulin levels (P = 0.0004) and decreased fasting nonesterified fatty acid concentrations (NEFA) (P = 0.017). Insulin infusion reduced Angptl4 levels by 6 % (plasma insulin ~200 pmol/l, P = 0.006) and 22 % (plasma insulin ~600 pmol/l, P < 0.0001), which was attenuated by prednisolone treatment (P = 0.03). Prednisolone 7.5 mg and 30 mg dose-dependently decreased insulin-mediated suppression of lipolysis (by 11 ± 5 % and 34 ± 6 % respectively). Prednisolone 30 mg enhanced fasting triglyceride levels ( P = 0.028). Plasma Angptl4 was not related to prednisolone-induced changes in lipid metabolism. In human hepatoma cells, dexamethasone increased Angptl4 mRNA expression and protein secretion, whereas insulin had the opposite effect. CONCLUSIONS: Insulin lowers plasma Angptl4 levels in humans by lowering NEFA and by inhibiting Angptl4 expression and release. Glucocorticoids counteract insulin-mediated suppression of Angptl4.

Detecting population structure in a high gene-flow species, Atlantic herring (Clupea harengus): direct, simultaneous evaluation of neutral vs putatively selected loci.

In many marine fish species, genetic population structure is typically weak because populations are large, evolutionarily young and have a high potential for gene flow. We tested whether genetic markers influenced by natural selection are more efficient than the presumed neutral genetic markers to detect population structure in Atlantic herring (Clupea harengus), a migratory pelagic species with large effective population sizes. We compared the spatial and temporal patterns of divergence and statistical power of three traditional genetic marker types, microsatellites, allozymes and mitochondrial DNA, with one microsatellite locus, Cpa112, previously shown to be influenced by divergent selection associated with salinity, and one locus located in the major histocompatibility complex class IIA (MHC-IIA) gene, using the same individuals across analyses. Samples were collected in 2002 and 2003 at two locations in the North Sea, one location in the Skagerrak and one location in the low-saline Baltic Sea. Levels of divergence for putatively neutral markers were generally low, with the exception of single outlier locus/sample combinations; microsatellites were the most statistically powerful markers under neutral expectations. We found no evidence of selection acting on the MHC locus. Cpa112, however, was highly divergent in the Baltic samples. Simulations addressing the statistical power for detecting population divergence showed that when using Cpa112 alone, compared with using eight presumed neutral microsatellite loci, sample sizes could be reduced by up to a tenth while still retaining high statistical power. Our results show that the loci influenced by selection can serve as powerful markers for detecting population structure in high gene-flow marine fish species.