Impaired estrogens action is associated with features of the metabolic syndrome in animal models and humans. We sought to determine whether disruption of hepatic estrogens action in adult male mice could recapitulate aspects of the metabolic syndrome to understand the mechanistic basis for the phenotype. We found 17β-estradiol (E2) inhibited hepatic gluconeogenic genes such as phosphoenolpyruvate carboxykinase 1 (Pck-1) and glucose 6-phosphatase (G6Pase) and this effect was absent in mice lacking liver estrogen receptor α (Esr1) (LERKO mice). Male LERKO mice displayed elevated hepatic gluconeogenic activity and fasting hyperglycemia. We also observed increased liver lipid deposits and triglyceride levels in male LERKO mice, resulting from increased hepatic lipogenesis as reflected by increased mRNA levels of fatty acid synthase (Fas) and acetyl-CoA carboxylase (Acc1). ChIP assay demonstrated estradiol (E2) induced ESR1 binding to Pck-1, G6Pase, Fas and Acc1 promoters. Metabolic phenotyping demonstrated both basal metabolic rate and feeding were lower for the LERKO mice as compared to Controls. Furthermore, the respiratory exchange rate was significantly lower in LERKO mice than in Controls, suggesting an increase in lipid oxidation. Our data indicate that hepatic E2/ESR1 signaling plays a key role in the maintenance of gluconeogenesis and lipid metabolism in males.

BackgroundA sedentary lifestyle is an independent risk factor for cardiovascular disease and exercise has been shown to ameliorate this risk. Inactivity is associated with a loss of muscle mass, which is also reversed with isometric exercise training. The relationship between muscle mass and vascular function is poorly defined. The aims of the current study were to determine whether increasing muscle mass by genetic deletion of myostatin, a negative regulator of muscle growth, can influence vascular function in mesenteric arteries from obese db/db mice.Methods and ResultsMyostatin expression was elevated in skeletal muscle of obese mice and associated with reduced muscle mass (30% to 50%). Myostatin deletion increased muscle mass in lean (40% to 60%) and obese (80% to 115%) mice through increased muscle fiber size (P<0.05). Myostatin deletion decreased adipose tissue in lean mice, but not obese mice. Markers of insulin resistance and glucose tolerance were improved in obese myostatin knockout mice. Obese mice demonstrated an impaired endothelial vasodilation, compared to lean mice. This impairment was improved by superoxide dismutase mimic Tempol. Deletion of myostatin improved endothelial vasodilation in mesenteric arteries in obese, but not in lean, mice. This improvement was blunted by nitric oxide (NO) synthase inhibitor l‐NG‐nitroarginine methyl ester (l‐NAME). Prostacyclin (PGI2)‐ and endothelium‐derived hyperpolarizing factor (EDHF)‐mediated vasodilation were preserved in obese mice and unaffected by myostatin deletion. Reactive oxygen species) was elevated in the mesenteric endothelium of obese mice and down‐regulated by deletion of myostatin in obese mice. Impaired vasodilation in obese mice was improved by NADPH oxidase inhibitor (GKT136901). Treatment with sepiapterin, which increases levels of tetrahydrobiopterin, improved vasodilation in obese mice, an improvement blocked by l‐NAME.ConclusionsIncreasing muscle mass by genetic deletion of myostatin improves NO‐, but not PGI2‐ or EDHF‐mediated vasodilation in obese mice; this vasodilation improvement is mediated by down‐regulation of superoxide.

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