The Role of Hepatic Estrogen Receptor Alpha in Control of Insulin Signaling Pathway and Glucose Homeostasis
Abstract
Estrogen has been reported to regulate various physiological processes such as cell growth,
reproduction, development, and differentiation. Estrogen has also been shown to be connected
with metabolic diseases by regulating glucose and lipid metabolism. The effects of estrogens are mediated mostly by estrogen receptors, estrogen receptor-ɑ (ERɑ) and estrogen receptor-ϐ (ERϐ). estrogens favor glucose homeostasis primarily through ERɑ, and ERɑ is the major ER isoform expressed in the liver. However, how ERɑ precisely regulates glucose metabolism in the liver remains unclear.
This study is aiming to explore the role of hepatic estrogen receptor alpha (ERɑ) in insulin
signaling pathway to regulate glucose homeostasis under both physiological and pathological conditions. To determine the specific role of ERɑ in the liver, we use Cre-loxP recombination system to generate liver-specific ERɑ knockout mice (ERɑLivKO). ERɑ flox mice (ERɑF∕F) were used
as control wild-type mice. These mice were fed with a high-fat diet (HFD) for 12 weeks at the
age of 5-6 weeks. Mice fed with a chow diet (CD) served as a control group. In the present studies, we found that in CD fed mice, hepatic ERɑ deletion led to impaired glucose tolerance and insulin signaling as evidenced by glucose tolerance tests and western blot in both male and female mice. In HFD fed group, HFD treatment impaired glucose homeostasis and induced inflammatory response as evidenced by glucose or pyruvate tolerance tests and quantification of gene expression. In HFD fed male mice, we did not observe significant differences in body weight, glucose tolerance, or mRNA expression of IRS between WT and ERɑLivKO mice. This may due to HFD treatment decreases ERɑ expression in WT male mice, loss of ERɑ protection in HFD fed male mice could be the reason. On the contrary, mice metabolic studies and histology studies showed hepatic ERɑ deficiency exacerbated insulin resistance and promoted lipid deposition in the liver from HFD fed female mice. In summary, we conclude that hepatic ERɑ plays an important role in mediating glucose and lipid homeostasis by participating in insulin signaling pathway under both healthy and pathological conditions.
Citation
Jiang, Wen (2021). The Role of Hepatic Estrogen Receptor Alpha in Control of Insulin Signaling Pathway and Glucose Homeostasis. Master's thesis, Texas A&M University. Available electronically from https : / /hdl .handle .net /1969 .1 /200672.