Loss of Estrogen Receptor α Signaling Leads to Insulin Resistance and Obesity in Young and Adult Female Mice

Manrique, Camila; Lastra, Guido; Habibi, Javad; Mugerfeld, Irina; Garro, Mona; Sowers, James R.

doi:10.1159/000339563

Cited by 62 publications

(41 citation statements)

References 61 publications

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“…Premenopausal women have a lower prevalence of obesity and type 2 diabetes mellitus as compared to age-matched men, while the prevalence of T2DM in postmenopausal women was significantly increased than premenopausal women. Estrogen participates in the modulation of insulin sensitivity, energy balance, and body composition [23,24]. The lack of a robust phenotype in female mice in this study may also be related to the differences of sexual hormones between them.…”

Section: Discussionmentioning

confidence: 80%

Deficiency of IRTKS as an adaptor of insulin receptor leads to insulin resistance

et al. 2013

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IRTKS encodes a member of the IRSp53/MIM homology domain family, which has been shown to play an important role in the formation of plasma membrane protrusions. Although the phosphorylation of IRTKS occurs in response to insulin stimulation, the role of this protein in insulin signaling remains unknown. Here we show that IRTKS-deficient mice exhibit insulin resistance, including hyperglycemia, hyperinsulinemia, glucose intolerance, decreased insulin sensitivity, and increased hepatic glucose production. The administration of ectopic IRTKS can ameliorate the insulin resistance of IRTKS-deficient and diabetic mice. In parallel, the expression level of IRTKS was significantly decreased in diabetic mouse model. Furthermore, DNA hypermethylation of the IRTKS promoter was also observed in these subjects. We also show that IRTKS, as an adaptor of the insulin receptor (IR), modulates IR-IRS1-PI3K-AKT signaling via regulating the phosphorylation of IR. These findings add new insights into our understanding of insulin signaling and resistance.

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Section: Discussionmentioning

confidence: 80%

Deficiency of IRTKS as an adaptor of insulin receptor leads to insulin resistance

et al. 2013

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“…Additionally, research in men with estrogen resistance due to a mutation in ER suggests that E2 alters carbohydrate and lipid metabolism (Smith et al 1994). Studies using rodent models have further elucidated the relationship between E2 and insulin sensitivity (Tremblay et al 2001, Ribas et al 2010, Gorres et al 2011, Manrique et al 2012. ERαKO mice have decreased whole body glucose tolerance compared to wild-type mice, but the role of the adipose tissue ERα remains to be discerned (Ribas et al 2010, Manrique et al 2012.…”

Section: Insulin Sensitivitymentioning

confidence: 99%

“…Studies using rodent models have further elucidated the relationship between E2 and insulin sensitivity (Tremblay et al 2001, Ribas et al 2010, Gorres et al 2011, Manrique et al 2012. ERαKO mice have decreased whole body glucose tolerance compared to wild-type mice, but the role of the adipose tissue ERα remains to be discerned (Ribas et al 2010, Manrique et al 2012. Interestingly, when female mice are OVX or sham treated and then high fat fed, GLUT4 and ESR1 proteins decrease in visceral WAT of both treatment groups (Gorres et al 2011).…”

Section: Insulin Sensitivitymentioning

confidence: 99%

The role of sex steroids in white adipose tissue adipocyte function

Newell-Fugate

2017

Reproduction

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Abstractwith the increasing knowledge that gender influences normal physiology, much biomedical research has begun to focus on the differential effects of sex on tissue function. Sexual dimorphism in mammals is due to the combined effects of both genetic and hormonal factors. Hormonal factors are mutable particularly in females in whom the estrous cycle dominates the hormonal milieu. Given the severity of the obesity epidemic and the fact that there are differences in the obesity rates in men and women, the role of sex in white adipose tissue function is being recognized as increasingly important. Although sex differences in white adipose tissue distribution are well established, the mechanisms affecting differential function of adipocytes within white adipose tissue in males and females remain largely understudied and poorly understood. One of the largest differences in the endocrine environment in males and females is the concentration of circulating androgens and estrogens. This review examines the effects of androgens and estrogens on lipolysis/lipogenesis, adipocyte differentiation, insulin sensitivity and adipokine production in adipocytes from white adipose tissue with a specific emphasis on the sexual dimorphism of adipocyte function in white adipose tissue during both health and disease.Reproduction (2017) 153 R133-R149

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“…Laboratory-based studies demonstrate that male mice are more prone to developing chemical-or high-fat dietinduced diabetes (30,36) and that diabetic symptoms improve after administration of E 2 (30). Female mice and rats have been shown to develop insulin resistance or glucose intolerance following exogenous T administration (23,30), ovariectomy (35,36), or knockout/inhibition of E 2 receptors such as ER␣ (24,35,39,40). In human-based studies, a decrease in E 2 levels in women, or polymorphisms in its receptor ER␣ in men have been associated with increased risk of diabetes onset (1,26).…”

mentioning

confidence: 99%

Chronic rapamycin treatment causes diabetes in male mice

Schindler

Partap

Patchen

et al. 2014

American Journal of Physiology-Regulatory, Integrative and Comp

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Current evidence indicates that the mammalian target of rapamycin inhibitor rapamycin both increases longevity and, seemingly contradictorily, impairs glucose homeostasis. Most studies exploring the dimensions of this paradox have been based on rapamycin treatment in mice for up to 20 wk. We sought to better understand the metabolic effects of oral rapamycin over a substantially longer period of time in HET3 mice. We observed that treatment with rapamycin for 52 wk induced diabetes in male mice, characterized by hyperglycemia, significant urine glucose levels, and severe glucose and pyruvate intolerance. Glucose intolerance occurred in male mice by 4 wk on rapamycin and could be only partially reversed with cessation of rapamycin treatment. Female mice developed moderate glucose intolerance over 1 yr of rapamycin treatment, but not diabetes. The role of sex hormones in the differential development of diabetic symptoms in male and female mice was further explored. HET3 mice treated with rapamycin for 52 wk were gonadectomized and monitored over 10 wk. Castrated male mice remained glucose intolerant, while ovariectomized females developed significant glucose intolerance over the same time period. Subsequent replacement of 17β-estradiol (E2) in ovariectomized females promoted a recovery of glucose tolerance over a 4-wk period, suggesting the protective role of E2 against rapamycin-induced diabetes. These results indicate that 1) oral rapamycin treatment causes diabetes in male mice, 2) the diabetes is partially reversible with cessation of treatment, and 3) E2 plays a protective role against the development of rapamycin-induced diabetes.

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Loss of Estrogen Receptor α Signaling Leads to Insulin Resistance and Obesity in Young and Adult Female Mice

Cited by 62 publications

References 61 publications

Deficiency of IRTKS as an adaptor of insulin receptor leads to insulin resistance

Deficiency of IRTKS as an adaptor of insulin receptor leads to insulin resistance

The role of sex steroids in white adipose tissue adipocyte function

Chronic rapamycin treatment causes diabetes in male mice

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