New thesis on Estrogen : molecular mechanisms of antidiabetic action
Saad Al-Qahtani from the group Signal Transduction will defend his thesis "Estrogen : molecular mechanisms of antidiabetic action" on December 20, 2016. Main supervisor is Neil Portwood.
What´s the main focus of your thesis?
Estrogens as hormonal replacement therapy are associated with positive metabolic effects. However, estrogens are reported to have severe adverse actions including breast cancer and coagulopathy. Therefore, it was the main focus of this thesis to elucidate the molecular mechanisms behind the beneficial metabolic effects of estrogen to direct them directly and to prevent undesirable side effects of systemic therapy.
Which are the most important results?
In visceral adipose tissue, estrogen 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 estrogen-dependent alterations in methylation levels (Paper 1).
In liver tissue, estrogen 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; estrogen 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).
Estrogen induces increased expression levels of pro-inflammatory mediators in the visceral adipose, which does not impact upon the positive actions of estrogen on body weight, fasting blood glucose levels, and glycemic control (Paper 3). The reductions induced by estrogen 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.
How can this new knowledge contribute to the improvement of people’s health?
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 estrogen treatment.
What are your future ambitions?
I will continue my clinical profession as a medical diagnostic pathologist in parallel with research. My interest in research will be mainly molecular pathogenesis of metabolic and neoplastic diseases to provide diagnostic and therapeutic tools which would help in improvement and advancement of healthcare.
December 20, 2016 at 09:30, venue: Skandiasalen Q1:01 Astrid Lindgrens Barnsjukhus, Karolinska University Hospital, Solna, more information in the calendar.