Impact of endotoxin on UCP homolog mRNA abundance, thermoregulation, and mitochondrial proton leak kinetics

Linking tissue uncoupling protein (UCP) homolog abundance with functional m etabolic outcomes and with expression of putative genetic regulators promis es to better clarify UCP homolog physiological function. A murine endotoxem ia model characterized by marked alterations in thermoregulation was employ ed to examine the association between heat production, UCP homolog expressi on, and mitochondrial proton leak ("uncoupling"). After intraperitoneal lip opolysaccharide (LPS, similar to 6 mg/kg) injection, colonic temperature (T -c) in adult female C57BL6/J mice dropped to a nadir of similar to 30 degre es C by 8 h, preceded by a four- to fivefold drop in liver UCP2 and UCP5/br ain mitochondrial carrier protein 1 mRNA levels, with no change in their hi ndlimb skeletal muscle (SKM) expression. SKM UCP3 mRNA rose fivefold during development of hypothermia and was correlated with an LPS-induced increase in plasma free fatty acid concentration. UCP2 and UCP5 transcripts recover ed about three- to sixfold in both tissues starting at 6-8 h, preceding a r ecovery of T-c between 16 and 24 h. SKM UCP3 followed an opposite pattern. Such results are not consistent with an important influence of UCP3 in driv ing heat production but do not preclude a role for UCP2 or UCP5 in this pro cess. The transcription coactivator PGC-1 displayed a transient LPS-evoked rise (threefold) or drop (two- to fivefold) in SKM and liver expression, re spectively. No differences between control and LPS-treated mouse liver or S KM in vitro mitochondrial proton leak were evident at time points correspon ding to large differences in UCP homolog expression.