The complement system is an integral component of the innate immune response and plays a vital role in adaptive immunity. Activation of the system produces peptide fragments, such as C5a, that target G-protein coupled receptors expressed on immune-related cells, such as macrophages, that initiate pro-inflammatory responses. We have discovered that the C5a receptor 1 (C5aR1) is also expressed in skeletal muscle, a primary insulin target tissue. Sustained exposure of muscle cells to palmitate (PA), a saturated fatty acid, or C5aR1 activation is associated with impaired insulin sensitivity. We have studied the role that C5aR1 activation plays in in fatty-acid induced insulin resistance by exploring whether targeted receptor antagonism mitigates PA-induced mitochondrial dysfunction and insulin resistance. Mitochondrial health in rat skeletal muscle cells were examined by assessing mitochondrial morphology and mitophagy via microscopy, and cellular respiration using the XF24 seahorse flux analyser, following overnight incubation with PA in the absence/presence of C5aR1 antagonists. C5aR1, which was detected in mouse gastrocnemius muscle by immunoblot, increased in expression, in parallel with circulating levels of C5a, the peptide agonist for C5aR1, during a high-fat diet (HFD). PA treatment of rat L6 muscle cells suppresses insulin sensitivity as indicated by a reduction in PKB308 phosphorylation and glucose uptake. PA also reduced cellular mitochondrial respiration and promoted mitochondrial fragmentation and mitophagy. C5aR1 antagonism mitigated the PA dependent loss in insulin sensitivity, mitochondrial respiration and restrained mitochondrial fragmentation and the rates of mitophagy. Elevated C5aR1 activity, as might be observed during a HFD, may promote metabolic dysfunction in skeletal muscle, the antagonism of which could have therapeutic implications for mitigating HFD mediated insulin resistance.


D. S. Shah: None. A. D. Mcneilly: None. R. J. Mccrimmon: Advisory Panel; Sanofi, Speaker's Bureau; Novo Nordisk A/S. H. Hundal: None.


Diabetes UK

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