Tidswell, Robert; (2023) Investigation of thermogenic mechanisms in adipose tissue during recovery from sepsis. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Background – Sepsis is defined as a dysregulated host response to infection resulting in organ dysfunction and, in some cases, death. Temperature impacts outcomes from sepsis – patients with fever are more likely to survive. However, in the recovery phase, thermogenesis may be detrimental. Survivors frequently develop cachexia and sepsis-induced myopathy which impairs recovery and increases long term mortality. In conditions akin to sepsis, including burn injury and cancer-associated cachexia, this has been attributed to catabolism driven by hypermetabolism due to a process called ‘browning’. Browning describes the switch of energy-storing white adipose tissue to a thermogenic energy-burning brown adipose tissue-like phenotype. Identification and prevention of browning in sepsis may improve outcomes. Hypothesis – In survivors of sepsis, browning of white adipose tissue occurs and drives cachexia and myopathy. Methods – Experimental sepsis was induced in rats using intraperitoneal zymosan. Body mass, muscle mass and myofibre cross sectional area were used to assess cachexia and myopathy. Expression of thermogenic browning mechanisms were studied in epididymal and retroperitoneal adipose tissue (eWAT and rpWAT, respectively) using thermal imaging, respirometry, RNA-sequencing and Western blot. Mitochondrial function and tissue morphology was interrogated by multiphoton imaging in live rpWAT explants. Results – Rats with zymosan peritonitis developed a sepsis-like illness with a 14-day mortality of 17%. In the recovery phase survivors developed hypermetabolism, cachexia and myopathy with reduced muscle mass and myofiber thickness. Oxygen consumption of eWAT and rpWAT per milligram of tissue was elevated at days 3, 7 4 and 14 of sepsis recovery. However, when controlled for protein content, lipid droplet size or mitochondrial or cell number, the increase was abolished. RNA sequencing of rpWAT demonstrated up-regulation of inflammatory genes and down-regulation of genes related to oxidative phosphorylation and thermogenesis during recovery. Notably, SERCA2 mRNA and SERCA2 protein were increased. Multiphoton microscopy showed neither increased mitochondrial density nor lipid multiloculation consistent with browning. The NAD(P)H pool was, however, more oxidised in tissue from animals recovering from sepsis, indicating altered metabolism. Conclusion – Hypermetabolism, cachexia and myopathy in the recovery phase of experimental sepsis are not caused by classical browning. Calcium cycling mechanisms in adipose tissue may be implicated and merit further investigation.

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