Molecular mechanisms of estrogen action in relation to metabolic disease

Estrogens have multiple effects on the body. Most studied are the effects on female reproduction. In this thesis, we have focused on the metabolic effects of estrogens. Estrogen treatment decreases adipose tissue mass and has anti-diabetic effects in humans and mice. Changes in food intake and voluntary activity occur upon estrogen treatment but are considered to be of minor importance for the observed effects. Studies on knockout mice have revealed a number of metabolic phenotypes such as obesity, glucose intolerance and insulin resistance as a consequence of disrupted signaling through one of the estrogen receptors (ER), ERalpha.

The aim of this thesis was to characterize the molecular mechanisms that mediate protective effects of estrogens against obesity and diabetes. We have used gene expression profiling to analyze changes in transcription after estrogen treatment in adipose tissue and liver, respectively. A number of target genes have been identified that could be possible mediators of the effects of estrogens on adiposity and glucose metabolism. In Paper I, we identified the nuclear receptor liver X receptor (LXRalpha) as an estrogen-regulated gene. The expression of LXRalpha and several of its target genes was decreased in mouse white adipose tissue following 10 h of estrogen treatment. One of the target genes, sterol regulatory element binding protein 1c (Srebp1c), is a master regulator of fatty acid synthesis. We also studied changes in gene expression in fat biopsies from postmenopausal women upon estrogen treatment for three months (Paper II). Several genes encoding enzymes in the fatty acid synthesis pathway were decreased by estrogen treatment in a subset of women. This was the first report showing estrogen regulation of stearoyl-CoA desaturase (Scd1), fatty acid synthase (Fas) and acetyl-CoA carboxylase alpha (Acc1) in human subcutaneous abdominal adipose tissue.

In Paper III, we investigated effects on estrogen administration on potential central and peripheral target tissues. Gene expression profiling revealed a small number of regulated genes in hypothalamus compared to white adipose tissue after three weeks of estrogen treatment. We focused on glutathione peroxidase (Gpx3) and cell death-inducing DNA fragmentation factor, alpha subunit-like effector A (Cidea) that were increased and decreased, respectively, in white adipose tissue upon estrogen treatment. Gpx3 protects against oxidative stress and its expression is low in obesity and high after weight loss. Obesity and diabetes are correlated to oxidative stress, which lead us to hypothezise that Gpx3 has a potential role in the effects of estrogen on adiposity. Cidea might have a role in the regulation of energy expenditure. In Paper IV, we confirmed that the anti-diabetic effects of estrogens are mediated via ERalpha. Diabetic ob/ob mice were treated with estrogen or the ERalpha-selective agonist PPT. Both compounds improve glucose tolerance, insulin sensitivity and the insulin response to glucose in vivo, with suggested action via the liver in this model. The mechanisms behind these effects are likely to be linked to an increased expression of signal transducer and activator of transcription 3 (Stat3) and a decreased expression of glucose-6-phosphatase (G6pc) as the regulation of these genes coincided with the observed phenotypes.

In conclusion, our studies, based around gene expression profiling, has contributed with a significant knowledge about the molecular mechanisms responsible for the effects of estrogen in relation to obesity and diabetes.

List of scientific papers

I. Lundholm L, Movérare S, Steffensen KR, Nilsson M, Otsuki M, Ohlsson C, Gustafsson JA, Dahlman-Wright K (2004). "Gene expression profiling identifies liver X receptor alpha as an estrogen-regulated gene in mouse adipose tissue." J Mol Endocrinol 32(3): 879-92.
https://pubmed.ncbi.nlm.nih.gov/15171719

II. Lundholm L, Zang H, Linden Hirschberg A, Gustafsson JÅ, Dahlman-Wright K (2007). "Key lipogenic gene expression can be decreased by estrogen in human adipose tissue." Fertil Steril. [Accepted]
https://pubmed.ncbi.nlm.nih.gov/18222430

III. Lundholm L, Otsuki M, Andersson S, Ohlsson C, Gustafsson JÅ, Dahlman-Wright K (2007). "Effects of estrogen on gene expression profiles in mouse hypothalamus and white adipose tissue; Target genes include GPX3 and CIDEA." J Endocrinol [Submitted]

IV. Bryzgalova G, Lundholm L, Gao H, Portwood N, Fält S, Berndt KD, Dicker A, Galuska D, Zierath JR, Gustafsson JÅ, Efendic S, Dahlman-Wright K, Khan A (2007). "The estrogen receptor alpha-selective agonist PPT improves glucose tolerance in ob/ob mice; potential molecular mechanisms." [Submitted]