Mitochondrial uncoupling proteins (UCPs) are transporters that are important for thermogenesis. The net result of their activity is the exothermic movement of protons through the inner mitochondrial membrane, uncoupled from ATP synthesis. We have cloned a third member of the UCP family, UCP3. UCP3 is expressed at high levels in muscle and rodent brown adipose tissue. Overexpression in yeast reduced the mitochondrial membrane potential, showing that UCP3 is a functional uncoupling protein. UCP3 RNA levels are regulated by hormonal and dietary manipulations. In contrast, levels of UCP2, a widely expressed UCP family member, showed little hormonal regulation. In particular, muscle UCP3 levels were decreased 3-fold in hypothyroid rats and increased 6-fold in hyperthyroid rats. Thus UCP3 is a strong candidate to explain the effects of thyroid hormone on thermogenesis. White adipose UCP3 levels were greatly increased by treatment with the ␤3-adrenergic agonist, CL214613, suggesting another pathway for increasing thermogenesis. UCP3 mRNA levels were also regulated by dexamethasone, leptin, and starvation, albeit differently in muscle and brown adipose tissue. Starvation caused increased muscle and decreased BAT UCP3, suggesting that muscle assumes a larger role in thermoregulation during starvation. The UCP3 gene is located close to that encoding UCP2, in a chromosomal region implicated in previous linkage studies as contributing to obesity.Changes in body weight result from the difference between energy intake and energy expenditure. It is presumed that each individual has a target weight that the body tries to maintain. Since weight remains relatively constant despite large variations in energy intake, energy expenditure must be regulated. For example, people who gain weight become metabolically less efficient, whereas those who lose weight become more efficient (1).The biochemical mechanisms responsible for the regulation of energy expenditure and the efficiency of energy usage are poorly understood. Possible ways to increase energy expenditure include increasing physical activity (2) and energy dissipation as heat by futile metabolic cycles (3-5).

Human uncoupling protein 3 ( UCP3 ) is a mitochondrial transmembrane carrier that uncouples oxidative ATP phosphorylation. With the capacity to participate in thermogenesis and energy balance, UCP3 is an important obesity candidate gene. A missense polymorphism in exon 3 (V102I) was identified in an obese and diabetic proband. A mutation introducing a stop codon in exon 4 (R143X) and a terminal polymorphism in the splice donor junction of exon 6 were also identified in a compound heterozygote that was morbidly obese and diabetic. Allele frequencies of the exon 3 and exon 6 splice junction polymorphisms were determined and found to be similar in Gullah-speaking African Americans and the Mende tribe of Sierra Leone, but absent in Caucasians. Moreover, in exon 6-splice donor heterozygotes, basal fat oxidation rates were reduced by 50%, and the respiratory quotient was markedly increased compared with wild-type individuals, implicating a role for UCP3 in metabolic fuel partitioning.

Key Points Question Can multiparametric magnetic resonance imaging (MRI) radiomic profiles be used to predict axillary lymph node metastasis (ALNM) and disease-free survival (DFS) in patients with early-stage breast cancer? Findings In this prognostic study that included 1214 patients, 2 clinical-radiomic nomograms were developed that accurately predicted ALNM and stratified patients into low-risk and high-risk groups for DFS. Meaning In this study, clinical-radiomic nomograms were useful in clinical decision-making associated with personalized selection of surgical interventions and therapeutic regimens for patients with early-stage breast cancer.