Evidence that oestrogen receptor-α plays an important role in the regulation of glucose homeostasis in mice: insulin sensitivity in the liver

Bryzgalova, Galyna; Gao, Hui; Åhrén, Bo; Zierath, Juleen R.; Galuska, Dana; Steiler, Tatiana L.; Dahlman-Wright, Karin; Nilsson, Stefan; Gustafsson, Jan‐Åke; Efendić, Suad; Khan, Abdul Waheed

doi:10.1007/s00125-005-0105-3

Cited by 333 publications

(281 citation statements)

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“…ERα is highly expressed in reproductive organs and is indispensable for female reproductive functions (1). ERα is also present in most nonreproductive organs, where its role is currently object of intense investigation because of the large number of dysfunctions associated with the postmenopause and affecting the metabolic, cardiovascular, and immune systems (2)(3)(4)(5).…”

mentioning

confidence: 99%

Tetradian oscillation of estrogen receptor α is necessary to prevent liver lipid deposition

Villa

Torre²,

Stell³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

117

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In the liver of female mice, the transcriptional activity of estrogen receptor (ER) α oscillates in phase with the 4-d-long estrous cycle. Here systemic, genome-wide analysis demonstrates that ER tetradian oscillation is necessary to generate pulses of expression in genes for fatty acid and cholesterol synthesis. This ER-dependent metabolic programming changes with pregnancy and after cessation of ovarian function due to age or surgical menopause, suggesting that ER signaling is optimized to coordinate liver functions with the energetic requirements of each reproductive stage. Alterations of amplitude and frequency of the tetradian cycle, as observed after surgical menopause, age, or specific ablation of the hepatic Igf-1 gene, are associated with liver fat deposition. Appropriate hormone replacement therapy reinstating the oscillatory activity of liver ER prevents the effect of surgical menopause on fat deposition in liver.energy metabolism | estrogen action | steroid hormone physiology | selective estrogen receptor modulators E strogen receptor (ER) α (or ESR1 or NR3A) is a transcription factor regulated by estrogens and nonestrogenic substances. ERα is highly expressed in reproductive organs and is indispensable for female reproductive functions (1). ERα is also present in most nonreproductive organs, where its role is currently object of intense investigation because of the large number of dysfunctions associated with the postmenopause and affecting the metabolic, cardiovascular, and immune systems (2-5).Application of the ER responsive element (ERE)-Luc reporter mouse, a transgenic mouse in which the luciferase reporter is driven by a promoter carrying multiple ERE copies (6), identified the liver as the organ in which ERs are most transcriptionally active (7,8). Further studies demonstrated that hepatic ERα transcriptional activity oscillates with the estrous cycle (tetradian oscillation) and is regulated by several compounds, including growth factors and nutritional proteins (9). This latter mechanism is instrumental for the synthesis of the circulating insulin-like growth factor 1 (IGF-1) necessary for the progression of the estrous cycle (9).These studies pointed to the hepatic ERα as a sensor of nutrient availability and a switch able to block the reproductive cycle in the event of malnutrition. On the other hand, a large body of evidence indicates that ERs are important regulators of several aspects of liver energy metabolism. Phenotypic analysis of mutant mice, including ERα (ERKO), ERβ, and aromatase KO mice, demonstrated that ERs play a pivotal role in the regulation of many processes related to the control of energy homeostasis, including energy expenditure, insulin sensitivity, and fat distribution (1, 10-13). In addition, investigation of the genetic programs controlled by hepatic ERs performed by comparing the transcriptomes of vehicle-and 17β-estradiol (E 2 )-treated ovariectomized (ovx) mice (14) established the potential for ER to recognize and regulate the transcription of numerous genes in...

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mentioning

confidence: 99%

Tetradian oscillation of estrogen receptor α is necessary to prevent liver lipid deposition

Villa

Torre²,

Stell³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

117

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“…Actually, ERKO mice have severe hepatic insulin resistance as well as a concomitant alteration of glucose uptake by skeletal muscle (Bryzgalova et al, 2006). Additionally, estrogens control the distribution of body fat and adipose tissue metabolism, involving both ER and ER (Cooke et al, 2001;Couse & Korach, 1999;Naaz et al, 2002;Penza et al, 2006).…”

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confidence: 99%

The pancreatic β-cell as a target of estrogens and xenoestrogens: Implications for blood glucose homeostasis and diabetes

Nadal

Alonso-Magdalena

Soriano

et al. 2009

Molecular and Cellular Endocrinology

265

187

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. The pancreatic β-cell as a target of estrogens and xenoestrogens: Implications for blood glucose homeostasis and diabetes. Molecular and Cellular Endocrinology, Elsevier, 2009, 304 (1-2) Please cite this article as: Nadal, A., Alonso-Magdalena, P., Soriano, S., Quesada, I., Ropero, A.B., The pancreatic ␤-cell as a target of estrogens and xenoestrogens: Implications for blood glucose homeostasis and diabetes, Molecular and Cellular Endocrinology (2008), doi:10.1016/j.mce.2009 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. THE PANCREATIC -CELL AS A TARGET OF ESTROGENS AND XENOESTROGENS: IMPLICATIONS FOR BLOOD GLUCOSE HOMEOSTASIS AND DIABETESAngel Rosen & Spiegelman, 2006;Fritsche et al., 2008). During the fasting state, insulin remains at low levels because plasma glucose concentration is low. In this situation, the levels of the counter-regulatory hormones, glucagon, adrenaline and corticosteroids are increased to promote hepatic glucose production. In contrast, insulin, the only hormone in the body able to decrease blood glucose levels, is increased during the fed state. Insulin decreases blood glucose by promoting adipocyte and muscle glucose uptake, as well as by preventing the liver from producing glucose by suppressing glycogenolysis and gluconeogenesis (Fritsche et al., 2008). neurotransmitters, hormones and nutrients, among which glucose is the most important.Normally, in response to short glucose stimulation, insulin biosynthesis is regulated by the increased translation of the preproinsulin transcript. After a prolonged glucose exposure, however, it is regulated via the insulin gene transcription (Orland et al., 1985;Permutt & Rotwein, 1983;Poitout et al., 2006). Both transcriptional and translational regulation of insulin biosynthesis is essential to maintain the intracellular stores of insulin on a long term basis.The secretory response of -cells depends on their electrical activity. This consists of oscillations of the membrane potential that range from electrically silent periods to depolarised plateaus on which Ca 2+ -action potentials originate (Rorsman et al., 2000).The classical stimulus-secretion coupling that drives insulin release involves the closure of K ATP channels by increasing the intracellular ATP/ADP ratio (Ashcroft et al., 1984) and diadenosine polyphosphates concentration (DPs) (Ripoll et al., 1996) oscillatory pattern is originated (Nadal et al., 1999;Santos et al., 1991;Valdeolmillos et al., 1989), which triggers a pulsatile insulin secretion (Barbosa et al., 1998;Gilon et al., 1993;Dyachok et al., 2008). Estrogens, estrogen receptors and blood glucose homeostasisT...

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“…It has been shown to increase insulin sensitivity and suppress de novo lipogenesis in adipose tissue, the liver and skeletal muscle (Takeda et al 2003, D'Eon et al 2005, Nagira et al 2006, Macotela et al 2009). It also reportedly enhances cholesterol uptake and suppresses gluconeogenesis in the liver (Bryzgalova et al 2006). Furthermore, estrogen was shown to attenuate obesity-induced chronic inflammation in adipose tissue by repressing the inflammatory responses of macrophages (Ribas et al 2011).…”

Section: Introductionmentioning

confidence: 99%

Teneligliptin improves metabolic abnormalities in a mouse model of postmenopausal obesity

Sameshima

Wada

Ito

et al. 2015

Journal of Endocrinology

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A decrease in serum estrogen levels in menopause is closely associated with the development of visceral obesity and the onset of type 2 diabetes in women. In the present study, we demonstrated the therapeutic effects of the novel DPP4 inhibitor, teneligliptin, on the features of postmenopausal obesity in mice. In the control group, female C57BL/6 mice were sham-operated and maintained on a standard diet. In the postmenopausal obese group, ovariectomized (OVX) mice were maintained on a high-fat diet, and were referred to as OVX-HF. In the treated group, teneligliptin at 60 mg/kg per day was administrated to OVX-HF, and were referred to as Tene. After a 12-week food challenge, the metabolic phenotypes of these mice were analyzed. Body weight, fat accumulation, and glucose intolerance were greater in OVX-HF than in control, while these abnormalities were markedly improved without alterations in calorie intake in Tene. Teneligliptin effectively ameliorated the characteristics of metabolic abnormalities associated with postmenopausal obesity. Regarding chronic inflammation in visceral adipose tissue, the numbers of F4/80K M1-macrophages in flow cytometry, crown-like structure formation in immunohistochemistry, and proinflammatory cytokine expression were significantly attenuated in Tene. Hepatic steatosis was also markedly improved. Furthermore, decreased energy consumption in the dark and light phases, reduced locomotor activity in the dark phase, and lowered core body temperature in OVX-HF were ameliorated in Tene. Since obesity and reduced energy metabolism are a common physiology of menopause, teneligliptin appears to be beneficial as a treatment for type 2 diabetes in postmenopausal obesity. Key Words" dpp4 inhibitor " adipose tissue macrophage " energy expenditure " insulin resistance

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Evidence that oestrogen receptor-α plays an important role in the regulation of glucose homeostasis in mice: insulin sensitivity in the liver

Cited by 333 publications

References 50 publications

Tetradian oscillation of estrogen receptor α is necessary to prevent liver lipid deposition

Tetradian oscillation of estrogen receptor α is necessary to prevent liver lipid deposition

The pancreatic β-cell as a target of estrogens and xenoestrogens: Implications for blood glucose homeostasis and diabetes

Teneligliptin improves metabolic abnormalities in a mouse model of postmenopausal obesity

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