Estrogen : molecular mechanisms of antidiabetic action

Abstract

The pathogenesis of metabolic syndrome is multifactorial and hormones play an essential role in its development. Estrogen loss in postmenopausal women has been linked to several features of metabolic syndrome, while estrogen replacement therapy reverses these pathological and metabolic features. However, estrogen replacement therapy is associated with adverse effects including breast cancer and coagulopathy. Therefore, identification of the molecular mechanisms of estrogen’s beneficial effects would give the possibility to target them directly and to prevent the undesirable side effects. In this study, administration of 17β-estradiol (E2) in a perimenopausal mouse model maintained on a high fat diet (HFD) for 10 months results in improved glycemic control and body weight reduction, in association with multiple molecular mechanisms in the visceral adipose tissue (Paper 1) and liver (Paper 2) without suppression of inflammatory mediators in these organs (Paper 3).

In visceral adipose tissue, E2 administration results in an anti-obesogenic effect and a reduction of adipocyte size in parallel with molecular mechanisms, including the activation of the lipolytic enzyme pnpla2, the suppression of lipogenic gene expression possibly through downregulating the expression levels of the nuclear receptor nr2c2/tr4, and the induction of brown adipose tissue-specific gene expression via E2-dependent alterations in methylation levels (Paper 1). In liver, E2 treatment induces activation of hepatic AMPK, which results in the suppression of hepatic lipogenesis via inhibition of NR2C2/TR4, and in the inhibition of gluconeogenesis through suppression of transcript levels of the gluconeogenic g6pc; E2 treatment also normalizes hepatic triglycerides through the suppression of lipogenesis and the activation of triglyceride mobilization; the summative effect of these events results in improvements in hepatic insulin signaling (Paper 2).

E2 induces increased expression levels of pro-inflammatory mediators in the visceral adipose, which does not impact upon the positive actions of E2 on body weight, fasting blood glucose levels, and glycemic control (Paper 3). The reductions induced by E2 in the plasma levels of adiponectin, and in its mRNA levels in adipose tissue, could explain the continued elevated expression levels of these mediators. Tracing the events of metabolic pathogenesis due to ovariectomy-related estrogen loss in an ovariectomized mouse model shows that estrogen signaling appears to suppress features of hepatic insulin resistance resulting from short-term HFD exposure by opposing the continuous accumulation of hepatic triglycerides, and via reduced expression levels of gluconeogenic genes (Paper 4). Ovariectomy resulted in weight gain, elevation of fasting blood glucose levels, increased hepatic triglycerides and increases in expression levels of nr2r2/tr4 and the pro-inflammatory tlr2, independently of dietary intervention.

In conclusion, the current study highlights significant molecular mechanisms responsible for the effects of estrogen in relation to features of metabolic syndrome, giving the possibility to target them directly and to prevent the undesirable side effects of systemic E2 treatment.