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

Control of energy homeostasis and metabolism: implications for oocyte quality and reproductive potential (#89)

Michael J Bertoldo 1
  1. Fertility and Research Centre, School of Women's and Children's Health, University of New South Wales, Sydney, NSW, Australia

It has long been known that energy homeostasis and metabolism play an integral role in regulating fertility. The AMP-activated protein kinase (AMPK) is an evolutionary conserved metabolic fuel gauge that senses changes in the AMP:ATP ratio. One response of AMPK activation is to increase the activity of nicotinamide adenine dinucleotide (NAD+). Through its ability to activate the Sirtuin family of transcription factors, NAD+ links cellular metabolism to changes in signalling and transcriptional events. It has now emerged that AMPK and NAD+ are crucial for the acquisition of oocyte developmental competence and preservation of reproductive potential. Using our novel global and oocyte-specific AMPK knockout mouse models, we firmly established a new role for AMPK-mediated actions in oocyte development and acquiring developmental competence. Furthermore, together with observational human studies and animal models, my results provide evidence for a role of AMPK in infertility associated with metabolic disease. Modulation of AMPK by metformin and exercise forms the cornerstone of clinical management of metabolic disorders and PCOS. Critically we have evidence to suggest that metformin can alter the chromatin status of gametes and reduce offspring fertility, and this requires further investigation. Following chemotherapy there is a precipitous decline in cellular NAD+ levels resulting in an inability of the cell to conduct processes that ensure its survival. There is emerging evidence that NAD+ therapies can protect and restore ovarian function against the damaging effects of chemotherapy, and we are currently deducing in detail methods to protect the ovary against chemotherapy, and means to enhance oocyte developmental competence by manipulating NAD+ metabolism. Together these findings illuminate the key roles of AMPK and NAD+ action in metabolic disease and chemoprotection in the ovary, as well as providing novel avenues of basic research for translation into the clinic.