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Editorial |
1 From the Department of Pediatrics (NAS-W and CHW) and the Section of Neurobiology, Physiology, and Behavior (CHW), University of California, Davis.
See corresponding article on page 714.
2 Address reprint requests to NA Schonfeld-Warden, Department of Pediatrics, UC Davis Medical Center, 2516 Stockton Boulevard, Sacramento, CA 95817. E-mail: naschonfeldwarden{at}ucdavis.edu.
Energy expenditure (EE) and obesity vary among racial groups. For instance, the incidence of obesity is higher in African Americans than in whites (1), whereas EE seems to be lower in African Americans than in whites. Such observations lead to several specific questions. Do variations in EE influence obesity? Do specific genes have measurable influences on EE and obesity? Do specific variants of genes contribute to measurable racial differences in EE and obesity?
Obesity must result from an imbalance in the energy balance equation
 | (1) |
Thus, many investigators have searched for correlations between EE and obesity. However, longitudinal and cross-sectional studies have led to opposite correlations: longitudinal studies suggest that lower EE leads to more obesity, but cross-sectional studies show higher EE in obese persons (2). Debate continues, but in general, low EE probably leads to obesity.
EE has many components: resting metabolic rate, resting EE (REE), exercise (voluntary), nonexercise activity thermogenesis, and the thermic effect of food (eating increases body temperature) (3). Variations in any of these components might contribute to the development of obesity. Furthermore, cross-sectional studies may overlook lesser EE factors, such as EE associated with immune responses or responses to oxidants, that may have large effects over time. Finally, any reaction that uses ATP or that regulates the mitochondrial proton gradient influences EE, but current research has focused on only a few sites of EE.
Several studies (reviewed recently in the Journal; 4) compared EE in African Americans and whites. For example, African American children have a lower REE than do white children, even after normalization for puberty stage and lean mass (5). A metabolic-chamber study found that sleeping metabolic rates were lower and that respiratory quotients were higher in African American adults than in white adults, which suggests that African Americans have lower fat oxidation rates (6). Several studies showed that variance in resting metabolic rate tends to be lower within families than between them, which indicates that resting metabolic rate is at least partly genetic (2). These data support the hypothesis that genetic variation among individuals influences EE.
Only recently have candidate genes been identified that are consistently associated with obesity and EE. For example, the mitochondrial uncoupling proteins 2 and 3 (UCP2 and UCP3) influence the proton gradient across the inner mitochondrial membrane in vitro (7). They may influence EE by uncoupling the proton gradient from ATP production, thus diverting energy from fat synthesis to heat production. Most studies of UCP2 and UCP3 physiology showed that UCP2 and UCP3 do not regulate body temperature (8) even though their activity helps regulate the proton gradient in vivo. Uncoupling proteins may influence the proton gradient without influencing any of the variables measured in existing studies. For instance, no one has studied UCP-regulated EE in people or mice with active infections, despite the obvious potential relevance of uncoupling proteins to fever regulation. Uncoupling proteins may simply regulate a basal proton leak that does not vary with experimental manipulations such as cold exposure and that is such a small percentage of total EE that allele effects may be undetectable in cross-sectional studies.
Uncoupling proteins were studied in biochemical, animal-model, and human-genetics frameworks. Biochemical studies showed that UCP1, UCP2, and UCP3 all influence proton gradients. Studies in UCP knockout mice showed altered mitochondrial proton gradients but not obesity phenotypes (9–11). In contrast, genetic studies in humans found associations between alleles of UCP2 and UCP3 and obesity or EE (12). Thus, these genes are human obesity genes.
Why do the results of human and mouse studies differ? There are 2 possibilities. First, knockouts in mice often yield different, frequently opposite, phenotypes that are dependent on the background strain. Initial knockouts may not show obesity phenotypes because the background strains are unaffected by UCP2 and UCP3 knockout. Second, UCP2 and UCP3 may not be mouse obesity genes. Not all human homologues of mouse obesity genes cause obesity in humans. For example, human homologues of the mouse agouti and tubby genes have not been associated with any human obesity phenotypes, even though the agouti pathway (including melanocortin receptor 4) is clearly an obesity pathway. It is just as likely that mouse homologues of some human obesity genes may not cause obesity in mice.
In this issue of the Journal, Kimm et al (13) attempt to identify specific alleles of specific genes that contribute to racial differences in EE (and perhaps also obesity). They confirm that REE is lower in African American women than in white women, and they genotyped 2 polymorphic sites in UCP1, 2 in UCP2, and 3 in UCP3. They associate a UCP3 exon 5 polymorphism (which does not alter the amino acid sequence) with significantly lower REE in African American women with the CC genotype than in those with the TT genotype. They also observed a significant trend toward lower REE and a nonsignificant trend toward greater fat mass in African American women but not in white women. The authors suggest that this variant or another linked variant is responsible for some of the reported racial metabolic differences. The UCP3 exon 5 variant may be in linkage disequilibrium with another variant whose frequency varies between racial groups. For example, a recently reported UCP2 promoter variant accounts for 15% of all obesity in German whites (14). Because the UCP2 promoter is located between UCP2 and UCP3, the promoter variant may be in linkage disequilibrium with the UCP3 exon 5 variant and allele frequency differences between African Americans and whites may account for REE differences.
The results of the Kimm et al study are consistent with the hypothesis that variations in uncoupling proteins contribute to racial differences in EE and obesity, but many questions remain. What other UCP alleles influence observed racial differences in EE? Do other genes influence EE? Do other genes contribute to the racial differences in obesity and EE? Do variations in relatively small components of EE contribute to weight gain in the obese? Kimm et al have begun to answer the first of these questions.
REFERENCES
This article has been cited by other articles:
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  N. A Schonfeld-Warden and C. H Warden Reply to R Cooper and A Luke Am. J. Clinical Nutrition, March 1, 2003; 77(3): 752 - 753. [Full Text]
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