Deletion of tumor necrosis factor-alpha receptor type 1 exacerbates insulin resistance and hepatic steatosis in aromatase knockout mice

作者：Toda Katsumi^*; Hayashi Yoshihiro; Saibara Toshiji

来源：Biochimica et Biophysica Acta-Molecular and Cell Biology of Lipids, 2010, 1801(6): 655-664.

DOI：10.1016/j.bbalip.2010.03.002

• Aromatase
• Estrogen
• Fatty acid
• Hepatic steatosis
• Insulin resistance
• Tumor necrosis factor-alpha receptor type 1

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.

• 出版日期2010-6