Deletion of tumor necrosis factor-alpha receptor type 1 exacerbates insulin resistance and hepatic steatosis in aromatase knockout mice.
The relevance of estrogen functions in lipid metabolism has been suggested in patients with estrogen-signaling deficiencies. Their importance was further implied by studies in estrogen-deficient mice (ArKO mice), which progressively developed hepatic steatosis. As circulating tumor necrosis factor (TNF)-alpha levels are known to positively correlate with disturbances in lipid metabolism, we investigated the impact of the loss of TNF-alpha signaling on carbohydrate and lipid metabolism in ArKO mice. Histological examinations of the livers of mice at 5 months of age revealed that ArKO male mice lacking the TNF-alpha receptor type 1 (TNFR1) gene (ArKO/TNFR1KO) or both the TNFR 1 and 2 genes (ArKO/TNFR1&2KO) developed more severe hepatic steatosis than ArKO or ArKO/TNFR2KO mice. Serum analyses demonstrated a clear increase in cholesterol and insulin levels in the ArKO/TNFR1KO mice compared with the ArKO mice. Glucose- and insulin-tolerance tests further revealed exacerbation of the systemic insulin resistant phenotype in the ArKO/TNFR1KO mice. Hepatic expression of lipogenic genes including fatty-acid synthase and stearoyl-Coenzyme A desaturase 1 were more markedly upregulated in the ArKO/TNFR1KO mice than the ArKO mice. These findings indicate that under estrogen-deficient physiological conditions, hepatic lipid metabolism would benefit from TNF-alpha mediated signaling via TNFR1.
Department of Biochemistry, Kochi University, School of Medicine, Nankoku, Kochi 783-8505, Japan. todak@kochi-u.ac.jp
Katsumi
K
Toda
Yoshihiro
Y
Hayashi
Toshiji
T
Saibara
D000818:Animals; D001141:Aromatase / Q000235:genetics / Q000502:physiology*; D001483:Base Sequence; D017931:DNA Primers; D005234:Fatty Liver / Q000503:physiopathology*; D007333:Insulin Resistance; D051379:Mice; D018345:Mice, Knockout; D012313:RNA / Q000235:genetics; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D017931:DNA Primers; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha; D012313:RNA; D001141:Aromatase