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

Metabolic and reproductive abnormalities in mice with impaired skeletal-mTORC1 function mirror a dietary restriction phenotype (#82)

Pawanrat Tangseefa 1 2 , Sally K Martin 1 2 , Vicki Wilczek 1 2 , Paul Baldock 3 , Christopher G Proud 4 5 6 , Stephen Fitter 1 2 , Andrew CW Zannettino 1 2
  1. Adelaide Medical School, Faculty of Health and Medical Science, The University of Adelaide, Adelaide, SA 5005, Australia
  2. Cancer Theme, South Australian Health and Medical Research Institute, Adelaide, SA 5001, Australia
  3. Skeletal Metabolism Group, Garvan Institute of Medical Research, Sydney, NSW 2010, Australia
  4. Nutrition & Metabolism Theme, South Australian Health and Medical Research Institute, Adelaide, SA 5001, Australia
  5. School of Biological Science, Faculty of Science, The University of Adelaide, Adelaide, SA 5005, Australia
  6. Department of Biochemistry and Genetics, School of Medicine, Zhejiang University, Hangzhou 310058, People’s Republic of China

Dietary restriction (DR) improves whole-body metabolism, extends lifespan and reduces reproductive function. While the mechanisms leading to these profound physiological changes remain to be elucidated, suppression of mammalian target of rapamycin complex 1 (mTORC1) is thought to play a critical role. The skeleton has recently emerged as a critical endocrine tissue that regulates glucose and energy metabolism and male reproductive function, via release of the bone-specific hormone osteocalcin (OCN), suggesting that suppression of mTORC1 in the skeleton could play a crucial role in the physiological responses to DR.

To investigate the role of skeletal-mTORC1 in modulating glucose metabolism and male fertility, we generated mice in which raptor, an essential component of mTORC1, is specifically deleted in osteoblasts (RaptorOB-/-). RaptorOB-/- mice are significantly smaller than controls, are osteopenic, have increased bone marrow adipose tissue (MAT) and reduced serum OCN levels. Compared to controls, serum adiponectin levels are significantly elevated in RaptorOB-/- animals, while leptin levels are reduced. Serum triglyceride levels are also significantly reduced in RaptorOB-/-, while free fatty acid levels are elevated. Importantly, despite being hypoinsulinemic, RaptorOB-/- have significantly lower fasting glucose levels, suggestive of insulin hypersensitivity. Consistent with this, insulin and glucose tolerance tests have revealed that RaptorOB-/- mice have improved glucose tolerance, enhanced insulin sensitivity and elevated insulin secretion. Furthermore, the reproductive function of RaptorOB-/- mice is significantly impaired, as evidenced by reduced circulating testosterone levels and sperm counts. Collectively, our results demonstrate that physiological changes associated with DR (e.g. elevated MAT and circulating adiponectin levels, reduced leptin and triglyceride levels, improved glucose metabolism and impaired male reproductive function) are mirrored in RaptorOB-/-mice, which suggests that skeletal-mTORC1 signalling is critical in mediating cellular responses to DR. These data highlight an essential role for the skeleton in monitoring global nutritional status.