Oral Presentation Australian Diabetes Society and the Australian Diabetes Educators Association Annual Scientific Meeting 2017

An NMNAT1 over-expressing mouse model shows altered lipid profile in skeletal muscle, despite tissue specific improvements in glucose disposal (#172)

Brenna Osborne 1 , Sarah E Hancock 1 , Sanket Joshi 1 , Azrah F Samsudeen 1 , Corrine E Fiveash 1 , Amanda E Brandon 2 , Toshiyuki Araki 3 , Greg J Cooney 2 , Todd W Mitchell 4 , Nigel Turner 1
  1. Mitochondrial Bioenergetics, Department of Pharmacology, UNSW, Kensington, NSW, Australia
  2. Sydney Medical School, Charles Perkins Centre, Sydney, NSW, Australia
  3. Peripheral Nervous System Research, National Institute of Neuroscience, NCNP, Tokyo, Japan
  4. School of Medicine, University of Wollongong, Wollongong, NSW, Australia

Nicotinamide mononucleotide adenylyltransferases (NMNATs) are enzymes of the NAD+ salvage pathway that convert nicotinamide mononucleotide (NMN) into NAD+. The nuclear isoenzyme NMNAT1 is thought to control NAD+ salvage in the nuclear compartment and may have important roles in modulating the activity of key NAD+ consuming enzymes such as sirtuins and PARPs. Manipulation of NAD+ levels via administration of NAD-precursors has previously been shown to improve metabolic function1,2.

We have previously found that transgenic mice that globally overexpress NMNAT1 have a marked skeletal muscle phenotype, showing reduced skeletal muscle mass that is accompanied by a shift towards a more oxidative muscle phenotype. Importantly, when challenged with a high-fat diet (HFD) these mice also show improved glucose tolerance in a glucose tolerance test, and improved glucose-handling in their skeletal muscle when assessed by hyperinsulinemic-euglycaemic clamp. Intriguingly, this improvement in insulin action occurred despite marked increases in triglyceride accumulation in muscle from NMNAT1Tg mice.

To investigate the lipid profile of skeletal muscle in more detail, we performed lipidomic analysis of skeletal muscle from mice fed a chow or HFD for 8 weeks. This analysis revealed that the difference in triglyceride accumulation in NMNAT1Tg mice was due to significant changes in all detected species of triglyceride. Furthermore, there were also significant increases in C18:0 ceramide and several subspecies of diacylgycerols (DAGs), along with variable changes in a number of phospholipid species. Further investigation of how these changes in lipid metabolism contribute to the metabolic phenotype seen in this model will yield insights into the therapeutic benefits of boosting specific NAD+ pools within skeletal muscle.

1. Canto et al, (2012) Cell Metabolism 15(6): 838-847. 2. Yoshino et al, (2011) Cell Metabolism 14(4): 528-536.