Abstract
The maintenance of glucose homeostasis within the body is crucial for constant and precise performance of energy balance and is sustained by a number of peripheral organs. Estrogens are known to play a role in the maintenance of glucose homeostasis. Aromatase knockout (ArKO) mice are estrogen-deficient and display symptoms of dysregulated glucose metabolism. We aim to investigate the effects of estrogen ablation and exogenous estrogen administration on glucose homeostasis regulation. Six month-old female wildtype, ArKO, and 17β-estradiol (E2) treated ArKO mice were subjected to whole body tolerance tests, serum examination of estrogen, glucose and insulin, ex-vivo muscle glucose uptake, and insulin signaling pathway analyses. Female ArKO mice display increased body weight, gonadal (omental) adiposity, hyperinsulinemia, and liver triglycerides, which were ameliorated upon estrogen treatment. Tolerance tests revealed that estrogen-deficient ArKO mice were pyruvate intolerant hence reflecting dysregulated hepatic gluconeogenesis. Analyses of skeletal muscle, liver, and adipose tissues supported a hepatic-based glucose dysregulation, with a down-regulation of Akt phosphorylation (a key insulin signaling pathway molecule) in the ArKO liver, which was improved with E2 treatment. Concurrently, estrogen treatment lowered ArKO serum leptin and adiponectin levels and increased inflammatory adipokines such as tumour necrosis factor alpha (TNFα) and interleukin 6 (IL6). Furthermore, estrogen deficiency resulted in the infiltration of CD45 macrophages into gonadal adipose tissues, which cannot be reversed by E2 treatment. This study describes the effects of estrogens on glucose homeostasis in female ArKO mice and highlights a primary phenotype of hepatic glucose dysregulation and a parallel estrogen modified adipokine profile.
Highlights
Glucose homeostasis is maintained throughout the body via essential cross talk between peripheral tissues
Untreated female Aromatase knockout (ArKO) mice were significantly heavier than WT controls (Table 1), and, their gonadal adipose tissue accumulation was higher (p
Female ArKO livers tended to be heavier than the WT livers (p = 0.053, Table 1) but no differences were seen in liver weights between ArKO+E2 and WT
Summary
Glucose homeostasis is maintained throughout the body via essential cross talk between peripheral tissues. Elevated blood glucose levels following energy intake stimulate the release of insulin from the pancreas which in-turn, stimulates glucose uptake into peripheral organs such as skeletal muscle and adipose tissue. The liver can produce glucose by glycogenolysis (i.e. the breaking down of glycogen) and by gluconeogenesis (i.e. the de novo synthesis of glucose from non-carbohydrate precursors such as lactate, pyruvate, glycerol and alanine). The former occurs more rapidly, beginning within two to three hours after a meal in humans, but the latter assumes a much greater importance with prolonged fasting [1,2]. Adipokines and free fatty acids (FFA) released from adipocytes can play a role in maintaining glucose homeostasis [3,6,7]
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