Oral Presentation The Joint Annual Scientific Meetings of the Endocrine Society of Australia and the Society for Reproductive Biology 2017

The hormone nuclear receptor eralpha and its role in mitochondrial health and metabolism (#130)

Brian Drew 1
  1. Baker Heart and Diabetes Institute, Prahran, VIC, Australia

Impaired action of the nuclear hormone receptor, estrogen receptor alpha (ERα), promotes obesity and metabolic dysfunction in humans and rodents. Moreover, human GWAS studies have revealed that both men and women with mutations in ERα have a higher incidence of obesity, glucose intolerance and type 2 diabetes. These findings suggest that ERα plays a role in regulating metabolic pathways in both a ligand dependent and independent manner. Thus, our group is interested in understanding the mechanistic and tissue specific underpinnings of these observations. Using several approaches including tissue specific KO models, mouse genetic panels and human tissue samples, we have established that loss of ERα activity in skeletal muscle recapitulates the significant glucose intolerance, insulin resistance and increased adiposity observed in global ERα-KO mice, where liver and adipose specific deletion does not. Moreover, this phenotype is characterised by marked alterations in mitochondrial morphology, overproduction of reactive oxygen species, and impairment in basal and stress-induced mitochondrial (mt) fission dynamics in both male and female mice. Furthermore, although muscle mtDNA abundance was similar between genotypes, ERα deficiency diminished mtDNA turnover via impairments in mitochondrial fission and mitophagy. These findings are consistent with ERα assuming a preservation role in mitochondrial health, revealing a potential link between this nuclear receptor and a role in protecting mitochondria in preparation for their exclusive maternal inheritance.