DiaComp Funded Abstracts
Program Application Abstract
Role of hepatic estrogen receptor a (Esr1) in the regulation of glucose and lipid metabolism
(Johns Hopkins University)
Summer Student Program
Estrogen action in the liver regulates metabolic function and may contribute in the control of energy homeostasis. Estrogen receptor alpha (Esr1) is the main estrogen receptor in the liver and several studies have suggested that Esr1 plays an important role in the regulation of metabolism in the liver. However, the mechanism by which estrogen functions in the liver is still unclear to date. Our study used both in vivo and ex vivo models to explore the role of Esr1 in the regulation of glucose and lipid metabolism in the liver of male mice. A male mouse model with specific liver Esr1 knockout (LERKO) was produced by injection of a CRE recombinase expressing AAV8 vector into the tail vein of male floxed Esr1 mice. While glucose and insulin tolerance were normal, we observed an increased in gluconeogenic activity in the LERKO mice compared to control. Messenger RNA (mRNA) levels of gluconeogenic genes such as Pck-1, G6p and Pgc-1a were increased in LERKO mice relative to controls. Using a primary hepatocyte culture model, we found that estrogen directly inhibits gluconeogenic gene mRNA levels through Esr1. To begin to assess lipogenic capacity of the liver, we measured expression of Fas and Acc and found an increase in the liver in LERKO compared to control mice. Accompanying these results, we found an increase in fatty acid deposits in the liver as measured with Oil Red O staining. Also, we observed an increase in hepatic triglyceride levels in the LERKO mice when compared to control. To further evaluate metabolic function, we used the CLAMS metabolic phenotyping system to measure basal metabolic rate, locomotor activity and feeding as well as to calculate the respiratory exchange rate (RER). We found that both basal metabolic rate and feeding were lower for the LERKO group than for controls. Also, the respiratory exchange rate was significantly lower in LERKO mice than in controls suggesting an increase in fat metabolism. This data suggests that E2/Esr1 signaling plays a critical role in hepatic glucose and lipid metabolism.
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