The discovery of UCP2 and UCP3, exhibiting significant sequence and domain structural homology to UCP1 and capacity to uncouple mitochondrial respiration (at least in the yeast expression system),20 immediately led to the notion that they might play a role in metabolic rate and fuel utilization. As described above, our initial observations that mRNA levels of UCP2 were differentially regulated in response to high-fat feeding in obesity-resistant and obesity-prone strains of mice supported this idea since this dietary upregulation occurred in at least two obesity-resistant strains. If UCP2 is an uncoupler of oxidative respiration, this would be consistent with increased expenditure of metabolic energy.2021
The mechanism responsible for this upregulation of UCP2 gene expression was postulated to be due to increased fatty acids. In support of this idea we and others reported that ligands for the PPARy and PPARa could increase UCP2 expression in adipocyte cell cultures.9192 (A follow-up study in human fat cells made similar conclusions.93) Not long after these original studies, several groups reported that fasting and/or starvation paradigms in rodents led to substantial increases in expression of both UCP2 and UCP3 in skeletal muscle and adipose tissue.9495 These observations initially led to a debate over the need to preserve body temperature vs. fuel stores. However, these studies of Dulloo and colleagues were pivotal in ultimately persuading the majority of investigators to conclude that, at least in peripheral tissues, these novel UCPs must be participating in the metabolic adaptations required during the fasted state, which requires a switch from predominantly glucose to predominantly fatty acids as a fuel source. They showed that blockading the fasting-induced rise in free fatty acids completely prevented the increase in UCP2 and UCP3 mRNA.96-98 The molecular mechanisms regulating the UCP2 and UCP3 genes are currently under investigation, and yet the larger question that remains to be answered is the true physiologic role of these UCPs.
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