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 (T3) or vehicle and measured RMR, liver, and skeletal muscle mitochondrial nonphosphorylating respiration and UCP-2 and -3 mRNAs. T3 stimulated RMR and liver UCP-2 and gastrocnemius UCP-2 and -3 expression. Mitochondrial respiration was not affected by T3 and did not correlate with UCP-2 and -3 mRNAs. Gastrocnemius UCP-2 and -3 expression did correlate with RMR. We conclude 1) T3 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 T3 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.
The hypothalamic-pituitary-adrenal (HPA) axis is responsible for stress response after injury, yet its function after severe burn injury in children is unclear. The purpose of this study was to define the effects of burn injury on the HPA axis and to evaluate the utility of total serum cortisol in measuring adrenal function in children with major burns in the 2 months after injury. Children ages 0 to 17 years who were admitted within 72 hours to our pediatric burn center with 20% TBSA or greater full-thickness burns were eligible for the study. Serum total cortisol, adrenocorticotropic hormone (ACTH), dehydroepiandrosterone, vasopressin, Pediatric Risk of Mortality (PRISM) score, serum albumin level, and electrolytes were obtained on admission and weekly for 8 weeks. An ACTH stimulation test (250 microg for children >2 years, 125 microg for children < or =2 years) was administered weekly at 8:00 am. Total serum cortisol was measured before and 60 minutes after the administration of ACTH. Twenty-five children with mean age 7.6 +/- 1.1 years and TBSA burn 41.8 +/- 3.8% were enrolled in the study. Baseline total serum cortisol was 12.4 +/- 0.7 microg/dl in the 8 weeks after injury and increased to 24.4 +/- 0.8 microg/dl after the administration of ACTH. Cortisol level did not correlate with PRISM score, albumin, vasopressin, ACTH, or mortality. Although the adrenal response to acute and chronic stress is intact after severe burn injury, the ACTH/adrenal feedback loop is disrupted. Random total serum cortisol measurements overestimate adrenal dysfunction; thus, ACTH stimulation testing should be used to assess adrenal function before the administration of exogenous steroids.
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.
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.
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