Molecular mechanisms of antidiabetic effects of estrogen
The role of estrogen in the development and regulation of female reproduction is well established. However, recent studies demonstrate that estrogen has a multiple effects on body functions. At present, it is becoming well recognized that one of the important roles of estrogen is the maintenance of glucose homeostasis.
The overall objective of this study was to investigate the molecular mechanisms that mediate the beneficial effects of estrogen on glucose tolerance (GT) and insulin sensitivity. Using estrogen receptor (ER) alpha knockout (ERKO) and ERbeta knockout (BERKO) mice we have shown that a lack of ERalpha, but not of ERbeta resulted in the development of glucose intolerance and insulin resistance in both female and male mice. Euglycaemic-hyperinsulinemic clamp with the determination of glucose turnover revealed that in ERKO mice impaired insulin sensitivity is due to pronounced hepatic insulin resistance. Gene expression profiling in ERKO mice demonstrated an increased expression of genes, involved in lipid biosynthesis in the liver, and the decreased expression of hepatic leptin receptor (Lepr), that could be potential mechanisms of hepatic insulin resistance in ERKO mice (Paper I).
To further develop this hypothesis we treated ob/ob mice with 17beta-estradiol (E2) for 30 days and found a significant improvement in GT and insulin sensitivity. Concordant with above findings these effects of E2 were accompanied by the downregulation of lipogenic genes and the increased hepatic expression of Lepr in liver. Microarray analyses revealed an increased hepatic mRNA expression of signal transducer and activator of transcription 3 (Stat3) after E2 treatment; we also showed that Stat3 is direct target gene of E2 in liver. Hence, the improvement in GT and insulin sensitivity in ob/ob mice after E2 treatment may result from stimulation of the hepatic expression of Stat3, leading to the downregulation of hepatic lipogenic genes (Paper II).
In Paper III, we demonstrated that similar to E2, the ERalpha-selective agonist propyl pyrazol triol (PPT) improved GT and insulin sensitivity in ob/ob mice. Thus, we confirmed that the antidiabetic effects of E2 are mediated via ERalpha-signaling. The lack of any effect of PPT treatment on glucose uptake by muscle and adipocytes indicates that its antidiabetic properties are mainly due to the improvement of hepatic insulin sensitivity. Increased hepatic expression of Stat3 and decreased hepatic expression of glucose-6-phosphatase (G6pc) could constitute one important mechanism behind the antidiabetic effects of E2 and PPT.
In Paper IV we have used high fat diet (HFD) fed mice, a model of obesity, glucose intolerance and insulin resistance to further elucidate the molecular mechanisms underlying the antidiabetic and weight-lowering effects of E2. C57BL mice were given HFD for up to 12 months and treated with E2 during last month of feeding. E2 administration resulted in decreased body weight and abdominal fat mass, and improvements in GT and insulin sensitivity. Mechanisms underlying these effects of E2 are linked to the downregulation of expression of sterol regulatory element binding protein 1c (Srebp1c) and its target lipogenic genes in white adipose tissue (WAT) and of stearoyl-CoA desaturase (Scd1) in the liver. Supression of hepatic G6pc could also play a crucial role in this context.
In conclusion, our data provide a deeper understanding of the molecular mechanisms behind the antidiabetic effects of E2. E2, acting via ERalpha exerts its beneficial effects on GT and insulin sensitivity mainly by regulating the expression of genes involved in the control of fatty acid synthesis and of G6pc expression, and also by modulating of adipokine signaling.
List of scientific papers
I. Bryzgalova G, Gao H, Ahren B, Zierath JR, Galuska D, Steiler TL, Dahlman-Wright K, Nilsson S, Gustafsson JA, Efendic S, Khan A (2006). Evidence that oestrogen receptor-alpha plays an important role in the regulation of glucose homeostasis in mice: insulin sensitivity in the liver. Diabetologia. 49(3): 588-97. Epub 2006 Feb 4
https://pubmed.ncbi.nlm.nih.gov/16463047
II. Gao H, Bryzgalova G, Hedman E, Khan A, Efendic S, Gustafsson JA, Dahlman-Wright K (2006). Long-term administration of estradiol decreases expression of hepatic lipogenic genes and improves insulin sensitivity in ob/ob mice: a possible mechanism is through direct regulation of signal transducer and activator of transcription 3. Mol Endocrinol. 20(6): 1287-99. Epub 2006 Apr 20
https://pubmed.ncbi.nlm.nih.gov/16627594
III. Lundholm L, Bryzgalova G, Gao H, Portwood N, Fält S, Berndt KD, Dicker A, Galuska D, Zierath JR, Gustafsson J-Å, Efendic S, Dahlman-Wright K, Khan A. (2008). The estrogen receptor alpha-selective agonist PPT improves glucose tolerance in ob/ob mice; potential molecular mechanisms. [Submitted]
IV. Bryzgalova G, Lundholm L, Portwood N, Gustafsson JA, Khan A, Efendic S, Dahlman-Wright K (2008). Mechanisms of antidiabetogenic and body weight-lowering effects of estrogen in high fat diet-fed mice. Am J Physiol Endocrinol Metab. Aug 12: Epub ahead of print
https://pubmed.ncbi.nlm.nih.gov/18697913
History
Defence date
2008-10-03Department
- Department of Molecular Medicine and Surgery
Publication year
2008Thesis type
- Doctoral thesis
ISBN
978-91-7409-098-7Number of supporting papers
4Language
- eng