Hepatic Glucose Intolerance Precedes Hepatic Steatosis in the Male Aromatase Knockout (ArKO) Mouse

Sinderen, Michelle Leigh Van; Steinberg, Gregory R.; Jørgensen, Sebastian Beck; To, Sarah Quynh Giao; Knower, Kevin Christopher; Clyne, Colin; Honeyman, Jane; Chow, Jenny D.Y.; Herridge, Kerrie A.; Jones, Morris; Simpson, Evan R.; Boon, Wah Chin

doi:10.1371/journal.pone.0087230

Cited by 23 publications

(28 citation statements)

References 40 publications

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“…(Cooke et al, 2001) In a second model of male mice with aromatase deficiency, hyperglycemia was attributed specifically to hepatic insulin resistance and increased gluconeogenesis. (Van Sinderen et al, 2014) This liver phenotype again was reversed with exogenous estradiol. In female aromatase-deficient mice, adipose tissue exhibited increased expression of lipoprotein lipase (Lpl), consistent with increased fatty acid uptake, though this finding has not yet been corroborated in male mice.…”

Section: Genetic Mutations In Men and Micementioning

confidence: 92%

Estrogens and Body Weight Regulation in Men

Rubinow

2017

Advances in Experimental Medicine and Biology

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Our understanding of the metabolic roles of sex steroids in men has evolved substantially over recent decades. Whereas testosterone once was believed to contribute to metabolic risk in men, the importance of adequate androgen exposure for the maintenance of metabolic health has been demonstrated unequivocally. A growing body of evidence now also supports a critical role for estrogens in metabolic regulation in men. Recent data from clinical intervention studies indicate that estradiol may be a stronger determinant of adiposity than testosterone in men, and even short-term estradiol deprivation contributes to fat mass accrual. The following chapter will outline findings to date regarding the mechanisms whereby estrogens contribute to the regulation of body weight and adiposity in men. It will present emergent clinical data as well as preclinical findings that reveal mechanistic insights into estrogen-mediated regulation of body composition. Findings in both males and females will be reviewed, to draw comparisons and to highlight knowledge gaps regarding estrogen action specifically in males. Finally, the clinical relevance of estrogen exposure in men will be discussed, particularly in the context of a rising global prevalence of obesity and expanding clinical use of sex steroid-based therapies in men.

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Section: Genetic Mutations In Men and Micementioning

confidence: 92%

Estrogens and Body Weight Regulation in Men

Rubinow

2017

Advances in Experimental Medicine and Biology

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“…Nonetheless, loss of hematopoietic aromatase did not substantially affect adiposity in male mice. Similar body fat mass between WT(WT) and WT(ArKO) mice likely explains the comparable concentrations of circulating adipokines in both groups, in contrast to prior findings of elevated plasma leptin and reduced adiponectin concentrations in male mice with global aromatase deficiency [33]. One possible explanation for these overall null findings is that aromatase expression is high within adipose tissue, with aromatase activity in multiple cell types.…”

Section: Discussionmentioning

confidence: 67%

“…Further, WT(ArKO) mice did not develop time-dependent insulin resistance or hepatic steatosis, as has been observed in male mice with global aromatase deficiency and ascribed specifically to hepatic insulin resistance [27,33]. Thus, in male mice with global loss of aromatase activity, overt hyperglycemia was seen by 3 months of age in association with increased expression of gluconeogenic genes in liver and, subsequently, increased hepatic triglyceride accumulation [33]. The present study did not reveal any evidence of changes in hepatic energy metabolism or insulin sensitivity, in contrast to these models of global aromatase deficiency in male mice.…”

Section: Discussionmentioning

confidence: 72%

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Aromatase deficiency in hematopoietic cells improves glucose tolerance in male mice through skeletal muscle-specific effects

et al. 2020

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Estrogens are important for maintaining metabolic health in males. However, the key sources of local estrogen production for regulating energy metabolism have not been fully defined. Immune cells exhibit aromatase activity and are resident in metabolic tissues. To determine the relative contribution of immune cell-derived estrogens for metabolic health in males, C57BL6/J mice underwent bone marrow transplant with marrow from either wildtype (WT(WT)) or aromatase-deficient (WT(ArKO)) donors. Body weight, body composition, and glucose and insulin tolerance were assessed over 24 weeks with mice maintained on a regular chow diet. No differences were found in insulin sensitivity between groups, but WT (ArKO) mice were more glucose tolerant than WT(WT) mice 20 weeks after transplant, suggestive of enhanced glucose disposal (AUC glucose 6061±3349 in WT(WT) mice versus 3406

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“…He points to the necessity at elucidating the risk posed by mixtures of endocrine disruptors across the life span [47,48] …”

Section: Annotated References ( Of Special Interest;mentioning

confidence: 99%

Sex-specific metabolic alterations induced by environmental pollutants

Magueresse-Battistoni

Vidal

Naville

2018

Current Opinion in Toxicology

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Conflicts of interest: noneFunding: This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. 2 AbstractDiabetes and obesity are the biggest public health challenge and the current prevalence of these chronic diseases has reached epidemic proportions worldwide. Apart from genetic alterations and lifestyle, exposure to environmental chemicals has emerged as a new cause of metabolic diseases. Notably, several compounds that mimic or oppose hormone activity defined as endocrine disruptors (EDs), may exert metabolic disturbances through interfering with the regulatory roles of the sex steroids (among other hormones) in energy homeostasis.However, most studies to date have investigated the metabolic impact of EDs on males and there is a lack of information regarding the metabolic impact of endocrine disruptors in females. There is as well a paucity of data for both sexes related to the metabolic impact resulting from the exposure to a mixture of EDs which is a more realistic scenario than the exposure to chemicals individually. Hopefully, conducting studies on both sexes in situations of multi-exposure to chemicals will help at better understanding the sex-biased mechanisms linked to endocrine disruption that could be helpful to improve and personalize treatments of diseases for which obesity is a risk factor, such as the metabolic syndrome and the hormonodependent cancers. Bullet points:Energy homeostasis is a physiological function with strong sex-dimorphic outcomes Endocrine disruptors (EDs) are chemicals that interfere with any hormone action EDs may induce metabolic disturbances in a sex-specific wayThere is a lack of data on the metabolic impact of EDs in femalesThere is a lack of data on the metabolic impact of mixture of EDs in both sexes

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Hepatic Glucose Intolerance Precedes Hepatic Steatosis in the Male Aromatase Knockout (ArKO) Mouse

Cited by 23 publications

References 40 publications

Estrogens and Body Weight Regulation in Men

Estrogens and Body Weight Regulation in Men

Aromatase deficiency in hematopoietic cells improves glucose tolerance in male mice through skeletal muscle-specific effects

Sex-specific metabolic alterations induced by environmental pollutants

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