Physiological effects of variants in human uncoupling proteins: UCP2 influences body-mass index.

The purpose of this review is to summarize the evidence from more than 40 studies that naturally occurring variants of uncoupling proteins 1-3 (UCP1-3) have detectable physiological effects in humans. Although UCP1 is known to influence mitochondrial proton leak in vitro and core body temperature in mice, genetic studies in humans have produced only weak evidence for association of naturally occurring variants with body-mass index (BMI); the best-reported P value is 0.01. In contrast, current evidence is consistent with the hypothesis that UCP2 and 3 influence BMI, since the best reported P values are better: four studies report associations of 0.001 (2 studies) to 0.002 (1 study) and 0.005 (1 study) for a UCP2 insertion/deletion variant, while the best P values for association of UCP3 with BMI are 0.003 (1 study) and 0.0037 (1 study). UCP2 and 3 are adjacent to each other on chromosome 11 and variants in each are in linkage disequilibrium. Thus, variants in UCP2 or 3 may influence results from association studies of variants in the other. Since UCP2 has a greater influence on BMI in humans than UCP3, then the two most likely hypotheses are that only UCP2 affects BMI, and positive results for UCP3 result from linkage disequilibrium to UCP2, or both UCP2 and 3 affect BMI. It is unlikely that only UCP3 influences BMI. UCP2 associations have been observed in a variety of ethnic groups, including Caucasians, African Americans, South Indians and Chinese. Consistent results from diverse ethnic groups are concordant with the hypothesis that the UCP2 insertion/deletion variant itself underlies the association with BMI.

T(3) stimulates resting metabolism and UCP-2 and UCP-3 mRNA but not nonphosphorylating mitochondrial respiration in mice.

The molecular basis for variations in resting metabolic rate (RMR) within a species is unknown. One possibility is that variations in RMR occur because of variations in uncoupling protein 2 (UCP-2) and uncoupling protein 3 (UCP-3) expression, resulting in mitochondrial proton leak differences. We tested the hypothesis that UCP-2 and -3 mRNAs positively correlate with RMR and proton leak. We treated thyroidectomized and sham-operated mice with triiodothyronine (T(3)) or vehicle and measured RMR, liver, and skeletal muscle mitochondrial nonphosphorylating respiration and UCP-2 and -3 mRNAs. T(3) stimulated RMR and liver UCP-2 and gastrocnemius UCP-2 and -3 expression. Mitochondrial respiration was not affected by T(3) and did not correlate with UCP-2 and -3 mRNAs. Gastrocnemius UCP-2 and -3 expression did correlate with RMR. We conclude 1) T(3) did not influence intrinsic mitochondrial properties such as membrane structure and composition, and 2) variations in UCP-2 and -3 expression may partly explain variations in RMR. One possible explanation for these data is that T(3) stimulates the leak in vivo but not in vitro because a posttranslational regulator of UCP-2 and -3 is not retained in the mitochondrial fraction.