Effects of genetic background on thermoregulation and fatty acid-induced uncoupling of mitochondria in UCP1-deficient mice

An interaction between free fatty acids and UCP1 (uncoupling protein-1) lea ding to de-energization of mitochondria was assumed to be a key event for t riggering heat production in brown fat. Recently, Matthias ef al;, finding indistinguishable de-energization of isolated brown fat mitochondria by fat ty acids in UCP1-deficient mice and control mice, challenged this assumptio n (Matthias, A., Jacobsson, A., Cannon, B,, and Nedergaard, J, (1999) J, Bi ol. Chem, 274, 28150-28160). Since their results were obtained using UCP1-d eficient and control mice on an undefined genetic background, we wanted to determine unambiguously the phenotype of UCP1 deficiency with the targeted Ucp1 allele on congenic C57BL/6J and 129/SvImJ backgrounds. UCP1-deficient congenic mice have a very pronounced cold-sensitive phenotype; however, def icient mice on the F1 hybrid background were resistant to cold. We propose that heterosis provides a mechanism to compensate for UCP1 deficiency. cont rary to the results of Matthias st al,, we found a significant loss of fatt y acid-induced de-energization, as reflected by membrane potential and oxyg en consumption, in brown fat mitochondria from UCP1-deficient mice. Unlike cold sensitivity, fatty acid-induced uncoupling of mitochondria was indepen dent of the genetic background of UCP1-deficient mice. We propose that intr acellular free fatty acids directly regulate uncoupling activity of UCP1 in a manner consistent with models described in the literature.