Estrogen signaling in metabolic disease : a functional genomics approach
Author: Gao, Hui
Date: 2006-12-15
Location: Sal 9Q Månen, Alfred Nobels allé 8, Huddinge
Time: 09.00
Department: Biovetenskaper och näringslära / Biosciences and Nutrition
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Thesis (4.189Mb)
Abstract
Estrogens have traditionally been associated with female reproduction. More and more evidence has also linked estrogens to maintenance of glucose homeostasis and normal heart function. Most of the known effects of estrogen are mediated via a direct interaction of estrogen with estrogen receptors (ERs), ERɑ and ERβ, which regulate the expression of specific sets of genes. Advances in whole genome sequence determination for various species and the development of high throughput techniques, such as gene expression profiling and genome wide identification of DNA-binding sites for specific transcription factors (Chromatin immunoprecipitation (ChIP) combined with microarray, ChIP-on-chip), allow for the first time a comprehensive characterization of ER target genes and associated cis-regulatory ER DNA-binding sites.
The aim of this thesis was to improve our understanding of the molecular events involved in mediating the effects of estrogen on glucose homeostasis and heart function. To this end, we have investigated the mechanisms behind the effects of estrogen on glucose homeostasis using ERɑ knockout (ERKO) and ERβ knockout (BERKO) mice. The absence of ERɑ, but not ERβ, resulted in glucose intolerance and insulin resistance in both female and male mice. This was shown to be due to profound hepatic insulin resistance in ERKO mice. Gene expression profiling revealed upregulation of lipogenic genes in livers of ERKO mice and we hypothesized that this is a reason for the observed insulin resistance (Paper I).
To further explore this finding, we treated ob/ob mice, a rodent model for obesity and type II diabetes, with estradiol and found markedly improved glucose tolerance and insulin response to glucose. Gene expression profiling revealed that hepatic lipogenic genes were decreased in ob/ob mouse livers after estradiol treatment. These studies support the studies in Paper I in suggesting a link between the insulin sensitizing effects of estrogen and decreased expression of lipogenic genes in the liver. We demonstrated that Stat3 is a direct target gene of ERɑ in mouse liver and hypothesized that estrogenic modulation of lipid metabolism in the liver, leading to improved glucose tolerance, is mediated by Stat3 (Paper II).
To link estrogen induced changes in gene expression profiles to DNA-binding by ERs, we established genome-wide analysis of promoter occupancy by ERɑ for mouse liver tissue. This analysis confirmed binding of ERɑ to promoter regions of known estrogen target genes. We showed that the estrogen response element (ERE) is the one of the most common motifs present in promoters where have recruitment of ERɑ Genes linked to the identified ERɑ binding sites included important cellular signaling molecules such as Stat3 and several genes involved in glucose and lipid metabolism (Paper III).
We also employed gene expression profiling to study the molecular mechanism of estrogen action in mouse heart. Overall very few genes were regulated in the heart compared to the liver. However, we identified Ptgds as an ERβ specific target gene in mouse heart and identified the response element that mediates this selective activation (Paper IV). Interestingly, the promoter of Ptgds was occupied by ERɑ and regulated by an ERɑ selective ligand in mouse liver (Paper III).
The ER selectivity of Ptgds expression might provide a model to study the molecular basis for receptor selectivity in different tissues. In summary, a functional genomics approach provides a powerful new perspective on estrogen action in different tissues and has the potential to transform traditional research approaches to become more productive and efficient.
The aim of this thesis was to improve our understanding of the molecular events involved in mediating the effects of estrogen on glucose homeostasis and heart function. To this end, we have investigated the mechanisms behind the effects of estrogen on glucose homeostasis using ERɑ knockout (ERKO) and ERβ knockout (BERKO) mice. The absence of ERɑ, but not ERβ, resulted in glucose intolerance and insulin resistance in both female and male mice. This was shown to be due to profound hepatic insulin resistance in ERKO mice. Gene expression profiling revealed upregulation of lipogenic genes in livers of ERKO mice and we hypothesized that this is a reason for the observed insulin resistance (Paper I).
To further explore this finding, we treated ob/ob mice, a rodent model for obesity and type II diabetes, with estradiol and found markedly improved glucose tolerance and insulin response to glucose. Gene expression profiling revealed that hepatic lipogenic genes were decreased in ob/ob mouse livers after estradiol treatment. These studies support the studies in Paper I in suggesting a link between the insulin sensitizing effects of estrogen and decreased expression of lipogenic genes in the liver. We demonstrated that Stat3 is a direct target gene of ERɑ in mouse liver and hypothesized that estrogenic modulation of lipid metabolism in the liver, leading to improved glucose tolerance, is mediated by Stat3 (Paper II).
To link estrogen induced changes in gene expression profiles to DNA-binding by ERs, we established genome-wide analysis of promoter occupancy by ERɑ for mouse liver tissue. This analysis confirmed binding of ERɑ to promoter regions of known estrogen target genes. We showed that the estrogen response element (ERE) is the one of the most common motifs present in promoters where have recruitment of ERɑ Genes linked to the identified ERɑ binding sites included important cellular signaling molecules such as Stat3 and several genes involved in glucose and lipid metabolism (Paper III).
We also employed gene expression profiling to study the molecular mechanism of estrogen action in mouse heart. Overall very few genes were regulated in the heart compared to the liver. However, we identified Ptgds as an ERβ specific target gene in mouse heart and identified the response element that mediates this selective activation (Paper IV). Interestingly, the promoter of Ptgds was occupied by ERɑ and regulated by an ERɑ selective ligand in mouse liver (Paper III).
The ER selectivity of Ptgds expression might provide a model to study the molecular basis for receptor selectivity in different tissues. In summary, a functional genomics approach provides a powerful new perspective on estrogen action in different tissues and has the potential to transform traditional research approaches to become more productive and efficient.
List of 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.
Pubmed
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.
Pubmed
III. Gao H, Fält S, Gustafsson JÅ. Dahlman-Wright K (2006). Genome-wide identification of estogen receptor alpha binding sites in mouse liver. [Manuscript]
IV. Otsuki M, Gao H, Dahlman-Wright K, Ohlsson C, Eguchi N, Urade Y, Gustafsson JA (2003). Specific regulation of lipocalin-type prostaglandin D synthase in mouse heart by estrogen receptor beta. Mol Endocrinol. 17(9): 1844-55.
Pubmed
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.
Pubmed
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.
Pubmed
III. Gao H, Fält S, Gustafsson JÅ. Dahlman-Wright K (2006). Genome-wide identification of estogen receptor alpha binding sites in mouse liver. [Manuscript]
IV. Otsuki M, Gao H, Dahlman-Wright K, Ohlsson C, Eguchi N, Urade Y, Gustafsson JA (2003). Specific regulation of lipocalin-type prostaglandin D synthase in mouse heart by estrogen receptor beta. Mol Endocrinol. 17(9): 1844-55.
Pubmed
Issue date: 2006-11-24
Rights:
Publication year: 2006
ISBN: 91-7140-974-2
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