Download PS 057 Fatty acids: long and short chain 678 The free fatty acid

PS 057 Fatty acids: long and short chain
678
The free fatty acid receptor GPR84: A new player in glucose tolerance and mitochondrial
function?
M.K. Montgomery1, A.E. Brandon2, L. O’Reilly2, B. Osborne3, C.E. Fiveash3, S.H. Brown4, N.J.
Smith5, T.W. Mitchell4, T.J. Biden2, G.J. Cooney2,6, N. Turner3;
1
Department of Physiology, Monash University, Clayton, 2Diabetes and Metabolism Division, Garvan
Institute of Medical Research, 3Department of Pharmacology, University of New South Wales,
Sydney, 4School of Health Sciences, University of Wollongong, 5Molecular Cardiology Program,
Victor Chang Cardiac Research Institute, 6Charles Perkins Centre, University of Sydney, Sydney,
Australia.
Background and aims: Free fatty acid receptors, such as GPR40 and GPR120, have been recognized
as important mediators of favourable metabolic effects on insulin secretion, inflammation 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 expressed only in immune cells. However,
our new data suggest that GPR84 is also abundantly expressed in skeletal muscle. We previously
showed that mice and rats fed a MCFA diet (based on coconut oil) were partially protected from lipidinduced glucose intolerance and insulin resistance, when compared to animals fed a lard-based highfat diet (enriched in long-chain fatty acids). This study aimed to determine if GPR84 was involved in
potentiating those beneficial metabolic effects.
Materials and methods: Global GPR84 knockout (KO) and wild type (WT) male mice were fed
either a low-fat control diet, a lard-based high-fat diet or a MCFA-enriched high-fat diet for 8 weeks.
Following the feeding period, various metabolic parameters were investigated including obesity,
glucose tolerance, oxidative stress and mitochondrial oxidative metabolism.
Results: The MCFA diet and lard diet led to increased fat deposition that was independent of
genotype. WT mice fed the MCFA diet showed protection from lipid-induced glucose intolerance
compared to the lard diet but this protection was completely lost in KO mice (iAUC WT: C
222.1±66.0, MCFA 345.3±36.6, lard 543.2±109.2; KO: C 266.3±27.7, MCFA 470.9±69.8, lard
406.7±86.2). In addition, GPR84 KO mice fed the MCFA diet exhibited a substantial impairment in
mitochondrial function in skeletal muscle. Mitochondrial respiration was decreased while
mitochondrial superoxide generation was increased in muscle of MCFA-fed KO mice (state 3
respiration with succinate: WT 127.4±33.7, KO 88.5±16.9 nmol/min/mg protein; superoxide
generation: WT 460.1±71.1, KO 638.5±99.8 pmol/min/mg protein). Higher superoxide generation in
MCFA-fed KO mice was accompanied by higher oxidative damage, suggesting an overall increase in
oxidative stress in muscle of MCFA-fed GPR84 KO mice. Interestingly, decreased mitochondrial
respiration was observed despite an increase in overall muscle mitochondrial content (determined as
protein content of the mitochondrial membrane protein VDAC, mitochondrial/nuclear DNA copy
number, and citrate synthase activity). The disconnect between an increase in mitochondrial content
but a decrease in mitochondrial function is potentially due to defects in autophagic removal of
mitochondria leading to accumulation of ‘defective’ mitochondria.
Conclusion: The results suggest that the MCFA receptor GPR84 plays an important role in glucose
tolerance, potentially via the regulation of mitochondrial health and function in skeletal muscle.
Supported by: National Health and Medical Research Council Australia
Disclosure: M.K. Montgomery: None.