Oral Presentation ANZOS-OSSANZ-AOCO Joint Annual Scientific Meeting 2017

Metabolic and reproductive abnormalities in mice with impaired skeletal-mTORC1 function mirror a dietary restriction phenotype (#135)

Pawanrat Tangseefa 1 2 , Sally K Martin 1 2 , Stephen Fitter 1 2 , Christopher G Proud 3 4 , 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. School of Biological Science, Faculty of Science, The University of Adelaide, Adelaide, SA 5005, Australia
  4. Nutrition & Metabolism Theme, South Australian Health and Medical Research Institute, Adelaide, SA 5001, Australia

Dietary restriction (DR) improves whole-body metabolism, extends lifespan while reducing reproductive function. The mechanisms leading to these profound physiological changes remain to be elucidated, however, 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 effects of suppressing skeletal‑mTORC1 function on metabolism and male fertility, we generated mice in which raptor, an essential component of mTORC1, is deleted in osteoblasts (RaptorOB-/-). RaptorOB-/- mice are significantly smaller than controls and have increased bone marrow adipose tissue (MAT), and low bone mass that is associated with 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-/-mice, while free fatty acid levels are elevated. Importantly, despite being hypoinsulinemic, RaptorOB-/- mice have significantly lower fasting glucose levels, suggestive of insulin hypersensitivity. Consistent with this, insulin and glucose tolerance tests revealed that RaptorOB-/- mice have enhanced glucose tolerance, insulin sensitivity and insulin secretion. Furthermore, the reproductive function of RaptorOB-/ mice is significantly impaired as evidenced by reduced circulating testosterone levels and sperm counts. Our results demonstrate that physiological changes associated with DR (elevated MAT and circulating adiponectin levels, reduced leptin and triglyceride levels, improved glucose metabolism and impaired male reproductive function) are mirrored in RaptorOB-/-mice, suggesting that skeletal-mTORC1 signalling is critical in the cellular responses to DR and highlights the essential role of skeleton in monitoring global nutritional status.

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