Abstract
An increasing body of evidence now links estrogenic signalling with the metabolic syndrome (MS). Despite the beneficial estrogenic effects in reversing some of the MS symptoms, the underlying mechanisms remain largely undiscovered. We have previously shown that total estrogen receptor alpha (ERα) knockout (KO) mice exhibit hepatic insulin resistance. To determine whether liver-selective ablation of ERα recapitulates metabolic phenotypes of ERKO mice we generated a liver-selective ERαKO mouse model, LERKO. We demonstrate that LERKO mice have efficient reduction of ERα selectively within the liver. However, LERKO and wild type control mice do not differ in body weight, and have a comparable hormone profile as well as insulin and glucose response, even when challenged with a high fat diet. Furthermore, LERKO mice display very minor changes in their hepatic transcript profile. Collectively, our findings indicate that hepatic ERα action may not be the responsible factor for the previously identified hepatic insulin resistance in ERαKO mice.
Highlights
The metabolic syndrome (MS) refers to a group of interrelated metabolic abnormalities including insulin resistance, increased body weight and abdominal fat accumulation, mild dyslipidemia and hypertension [1,2,3,4]
Successful liver-selective down-regulation of estrogen receptor alpha (ERa) was confirmed by evaluating the mRNA levels of ERa in muscle, liver, white adipose tissue (WAT), kidney, and uterus of LERKO and CT mice (Figure 1A)
ERa protein levels were assessed by immunostaining, which indicated that ERa was predominantly localised in the hepatocyte nucleus, and was of weaker intensity in LERKO compared to CT animals (Figure 2)
Summary
The metabolic syndrome (MS) refers to a group of interrelated metabolic abnormalities including insulin resistance, increased body weight and abdominal fat accumulation, mild dyslipidemia and hypertension [1,2,3,4]. The beneficial effect of estrogen in relation to normalising body weight and glucose homeostasis is further evidenced in ob/ob and high fat diet (HFD) fed mice, models of obesity and T2D. In both models, estrogen treatment improves glucose tolerance and insulin sensitivity [4,19,20], in addition to having a weight lowering effect in HFD-fed mice [20]. Estrogen treatment improves glucose tolerance and insulin sensitivity [4,19,20], in addition to having a weight lowering effect in HFD-fed mice [20] These studies firmly establish a role for estrogenic signalling in the development of MS. This makes it difficult to correlate the sequences of events and tissue-specific contributions of the underlying estrogenic mechanisms to the observed phenotypes
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