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Lipid signalling dynamics of palmitate-induced endoplasmic reticulum stress in skeletal muscle



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McNally, Ben 


Approximately 340 million people worldwide have Type 2 Diabetes Mellitus (T2DM), making identification of the aetiological processes underlying this disease imperative. Endoplasmic reticulum (ER) stress has emerged as a potential mechanism driving the pathogenesis of obesity and T2DM. Palmitate, the predominant saturated fatty acid elevated in the blood plasma of obese individuals, induces ER stress and insulin resistance in skeletal muscle. However, the interaction between ER stress, lipid metabolism and T2DM remains poorly understood. This thesis uses lipidomic tools to investigate skeletal muscle ER stress in cell culture and animal models. Chronic palmitate treatment of both mouse C2C12 and human primary myotubes induced ER stress, concurrent with the cytosolic phospholipase A2-dependent release of polyunsaturated fatty acids (PUFAs) from phosphatidylcholines (PCs). This phenotype was also observed in skeletal muscle from mouse models of diet-induced obesity and T2DM patients. Palmitate-stimulated catabolism of PUFA-containing PCs was concomitant with increases in bioactive eicosanoid secretion, which was shown to be important in the control of ER stress, inflammatory signalling and macrophage activation. This provides a novel link between palmitate and the control of ER stress and inflammation in metabolic disease. Previous work has suggested that the propagation of ER stress signalling between cells may result from the secretion of a, as yet undefined, cell non-autonomous signal. In this thesis, long-chain ceramides (40:1 and 42:1) were identified as signals transmitting the induction of ER stress between myotubes via exosome-mediated transport. Long-chain ceramide concentrations were increased in skeletal muscle and blood plasma from in vivo models of obesity and were elevated in the muscle of T2DM patients. Muscle synthesis of long chain ceramides in response to palmitate was found to occur via the de novo pathway and was linked to ER stress by Perk, an important unfolded protein response kinase. This work identifies ceramides as cell non-autonomous signals that propagate ER stress activation following exposure to palmitate, providing a novel mechanism for stress signalling in obesity and insulin resistance.





Griffin, Julian
Roberts, Lee


Lipidomics, ER stress, Ceramide, Eicosanoid, Skeletal muscle, Insulin resistance, Type 2 Diabetes, Metabolism


Doctor of Philosophy (PhD)

Awarding Institution

University of Cambridge