Insulin resistance in the aromatase knockout mouse
Research project leader: Prof Evan Simpson, email: firstname.lastname@example.org
Sex hormones such as oestrogens and androgens are known to influence development of insulin resistance and adiposity, which contribute to many disease processes such as type 2 diabetes and the Metabolic Syndrome. Oestrogen (E2) and testosterone (T) are known to have bi-phasic effects on insulin resistance in a dose-dependent manner. To research the effects of sex hormones on insulin resistance we studied Aromatase knockout (ArKO) mice which are unable to convert androgens to oestrogens.
We are pursuing this work by conducting Glucose, Insulin and Pyruvate Tolerance tests. We are also studying the insulin signalling pathways in the muscle and liver of the ArKO mouse as well as by generating tissue-specific aromatase knock-ins in organs such as brain, muscle, adipose and liver on the genetic background of the ArKO mouse.
Sexually dimorphic differences were observed between the male and female ArKO mice. By 12 weeks old male ArKO mice present with hyperglycemia and significant glucose and pyruvate intolerance and signs of reduced insulin sensitivity. Similar phenotypes are present in 24 and 52 week old male ArKO mice. Upon oestrogen treatment, these phenotypes were corrected to WT levels. Only ArKO males develop hepatic steatosis which may be a contributing factor in the development of the insulin resistant state.
Female ArKO mice by 12 weeks of age show signs of hyperglycemia and glucose intolerance with trends continuing at 24 weeks. They also develop significant pyruvate intolerance and reduced insulin sensitivity.
Surprisingly, upon administration of 17β-estradiol to 12 and 24 week female ArKO mice, we observed no improvement of the insulin resistance phenotype.
We hypothesise that high oestrogen levels may have a negative effect on insulin sensitivity. An example of a physiological state in which estrogen levels are high is pregnancy.
The National Institutes of Health estimates that 7% of women develop gestational diabetes with 40% increased risk of developing type 2 diabetes later in life. We conclude that oestrogen may have biphasic effects on insulin sensitivity in female animals.
National Health and Medical Research Council
Victorian Breast Cancer Consortium
Carani C, Qin K, Simoni M, Faustini-Fustini M, Serpente S, Boyd J, Korach KS, Simpson ER. Effect of testosterone and estradiol in a man with aromatase deficiency. N Engl J Med 337(2)91-95 1997.
Jones MEE, AW Thorburn, KL Britt, KN Hewitt, NG Wreford, J Proietto, OK Oz, BJ Leury, KM Robertson, S Yao ER Simpson. Aromatase-deficient (ArKO) mice have a phenotype of increased adiposity. PNAS 97:12735-12740, 2000
McInnes KJ, Corbould A, Simpson ER, Jones ME. Regulation of AMPK and lipogenesis by androgens contributes to visceral obesity in an estrogen deficient state. Endocrinology 147: 5907-5913 (2006).