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 β€˜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.