Oral Presentation Australian Diabetes Society and the Australian Diabetes Educators Association Annual Scientific Meeting 2016

The free fatty acid receptor GPR84: a new player in glucose tolerance and mitochondrial function? (#67)

Magdalene K Montgomery 1 2 , Amanda E Brandon 3 , Liam O'Reilly 3 , Brenna Osborne 1 , Corrine E Fiveash 1 , Simon HJ Brown 4 , Nicola J Smith 5 , Todd W Mitchell 4 , Trevor J Biden 3 , Gregory J Cooney 3 6 , Nigel Turner 1
  1. Department of Pharmacology, University of New South Wales, Sydney, NSW, Australia
  2. Department of Physiology, Monash University, Clayton, VIC, Australia
  3. Diabetes and Metabolism Division, Garvan Institute of Medical Research, Sydney, NSW, Australia
  4. School of Health Sciences, University of Wollongong, Wollongong, NSW, Australia
  5. Molecular Cardiology Program, Victor Chang Cardiac Research Institute, Sydney, NSW, Australia
  6. Charles Perkins Centre, University of Sydney, Sydney, NSW, Australia

Introduction: Fatty acid receptors, including GPR40 and GPR120, have been recognized as important mediators of favourable effects on insulin secretion and glucose uptake. Here we describe a potential new player involved in the regulation of glucose tolerance and mitochondrial function, the G-protein coupled receptor GPR84. GPR84 is a medium-chain fatty acid (MCFA;C8-C14) receptor that was originally thought to be solely expressed in immune cells. However, our new data suggest that GPR84 is also abundantly expressed in skeletal muscle. We previously showed that mice fed a MCFA-diet (coconut oil-based) were partially protected from lipid-induced glucose intolerance, when compared to animals fed a lard-based high-fat diet (enriched in long-chain fatty acids).

Objective: This study aimed to determine if GPR84 was involved in potentiating these beneficial metabolic effects of MCFA.

Methods: GPR84 knockout (KO) and wild-type (WT) mice were fed a low-fat diet, a lard-based high-fat diet or a MCFA-enriched high-fat diet for 8 weeks, followed by determination of obesity, glucose tolerance, oxidative stress and mitochondrial metabolism.

Results: Both high-fat diets led to increased fat deposition that was independent of genotype. MCFA-fed WT mice showed protection from glucose intolerance compared to the lard-diet (as observed previously) but this protection was completely lost in KO mice. In addition, GPR84 KO mice fed the MCFA-diet exhibited substantial impairment in mitochondrial function in skeletal muscle. Mitochondrial respiration was decreased while oxidative stress was increased in muscle of MCFA-fed GPR84 KO mice. Interestingly, decreased mitochondrial respiration was observed despite an increase in overall mitochondrial content. This disconnect between increased mitochondrial content but decreased mitochondrial function is potentially due to defects in autophagic removal of mitochondria leading to accumulation of ‘defective’ mitochondria.

Conclusions: The results suggest that the MCFA receptor GPR84 plays an important role in glucose tolerance, potentially via the regulation of mitochondrial function in skeletal muscle.