Osteogenesis Imperfecta: The Impact of Genotype and Clinical Phenotype on Adiposity and Resting Energy Expenditure.

CONTEXT: Mutations in type I collagen or collagen-related proteins cause osteogenesis imperfecta (OI). Energy expenditure and body composition in OI could reflect reduced mobility or intrinsic defects in osteoblast differentiation increasing adipocyte development. OBJECTIVE: This study compares adiposity and resting energy expenditure (REE) in OI and healthy controls (HC), for OI genotype- and Type-associated differences. METHODS: We studied 90 participants, 30 with OI (11 COL1A1 Gly, 8 COL1A2 Gly, 4 COL1A1 non-Gly, 1 COL1A2 non-Gly, 6 non-COL; 8 Type III, 16 Type IV, 4 Type VI, 1 Type VII, 1 Type XIV) and 60 HC with sociodemographic characteristics/BMI/BMIz similar to the OI group. Participants underwent dual-energy x-ray absorptiometry to determine lean mass and fat mass percentage (FM%) and REE. FM% and REE were compared, adjusting for covariates, to examine the relationship of OI genotypes and phenotypic Types. RESULTS: FM% did not differ significantly in all patients with OI vs HC (OI: 36.6% ± 1.9%; HC: 32.7% ± 1.2%; P = 0.088). FM% was, however, greater than HC for those with non-COL variants (P = 0.016). FM% did not differ from HC among OI Types (P values > 0.05).Overall, covariate-adjusted REE did not differ significantly between OI and HC (OI: 1376.5 ± 44.7 kcal/d; HC: 1377.0 ± 96 kcal/d; P = 0.345). However, those with non-COL variants (P = 0.016) and Type VI OI (P = 0.04) had significantly lower REE than HC. CONCLUSION: Overall, patients with OI did not significantly differ in either extra-marrow adiposity or REE from BMI-similar HC. However, reduced REE among those with non-COL variants may contribute to greater adiposity.

A Genome-Wide Association Study Using a Custom Genotyping Array Identifies Variants in GPR158 Associated With Reduced Energy Expenditure in American Indians.

Pima Indians living in Arizona have a high prevalence of obesity, and we have previously shown that a relatively lower energy expenditure (EE) predicts weight and fat mass gain in this population. EE is a familial trait (heritability = 0.52); therefore, in the current study, we aimed to identify genetic variants that affect EE and thereby influence BMI and body fatness in Pima Indians. Genotypic data from 491,265 variants were analyzed for association with resting metabolic rate (RMR) and 24-h EE assessed in a whole-room calorimeter in 507 and 419 Pima Indians, respectively. Variants associated with both measures of EE were analyzed for association with maximum BMI and percent body fat (PFAT) in 5,870 and 912 Pima Indians, respectively. rs11014566 nominally associated with both measures of EE and both measures of adiposity in Pima Indians, where the G allele (frequency: Pima Indians = 0.60, Europeans <0.01) associated with lower 24-h EE (ß = -33 kcal/day per copy), lower RMR (ß = -31 kcal/day), higher BMI (ß = +0.6 kg/m2), and higher PFAT (ß = +0.9%). However, the association of rs11014566 with BMI did not directionally replicate when assessed in other ethnic groups. rs11014566 tags rs144895904, which affected promoter function in an in vitro luciferase assay. These variants map to GPR158, which is highly expressed in the brain and interacts with two other genes (RGS7 and CACNA1B) known to affect obesity in knockout mice. Our results suggest that common ethnic-specific variation in GPR158 may influence EE; however, its role in weight gain remains controversial, as it either had no association with BMI or associated with BMI but in the opposite direction in other ethnic groups.

Asymmetric energetic costs in reciprocal-cross hybrids between carnivorous mice (Onychomys).

Aerobic respiration is a fundamental physiological trait dependent on coordinated interactions between gene products of the mitochondrial and nuclear genomes. Mitonuclear mismatch in interspecific hybrids may contribute to reproductive isolation by inducing reduced viability (or even complete inviability) due to increased metabolic costs. However, few studies have tested for effects of mitonuclear mismatch on respiration at the whole-organism level. We explored how hybridization affects metabolic rate in closely related species of grasshopper mice (genus Onychomys) to better understand the role of metabolic costs in reproductive isolation. We measured metabolic rate across a range of temperatures to calculate basal metabolic rate (BMR) and cold-induced metabolic rate (MRc) in O. leucogaster, O. torridus and O. arenicola, and in reciprocal F1 hybrids between the latter two species. Within the genus, we found a negative correlation between mass-specific BMR and body mass. Although O. arenicola was smaller than O. torridus, hybrids from both directions of the cross resembled O. arenicola in body mass. In contrast, hybrid BMR was strongly influenced by the direction of the cross: reciprocal F1 hybrids were different from each other but indistinguishable from the maternal species. In addition, MRc was not significantly different between hybrids and either parental species. These patterns indicate that metabolic costs are not increased in Onychomys F1 hybrids and, while exposure of incompatibilities in F2 hybrids cannot be ruled out, suggest that mitonuclear mismatch does not act as a primary barrier to gene flow. Maternal matching of BMR is suggestive of a strong effect of mitochondrial genotype on metabolism in hybrids. Together, our findings provide insight into the metabolic consequences of hybridization, a topic that is understudied in mammals.

Effects of energy expenditure gene polymorphisms on obesity-related traits in obese children.

OBJECTIVE: To assess the frequencies of common polymorphisms of genes associated with energy expenditure among Hungarian obese children and investigate their influences on obesity-related traits and metabolic complications of common childhood obesity. RESEARCH METHODS AND PROCEDURES: In a total of 528 obese children (age 13.2±2.6 years) an oral glucose tolerance test and determination of fasting serum lipid levels were carried out, blood pressure and resting energy expenditure were measured and the children were genotyped for the following gene polymorphisms: Trp64Arg of ß3-adrenoreceptor (ADRB3), -3826 A/G of uncoupling protein (UCP)-1, exon 8 45 bp del/ins and -866 G/A of UCP-2, -55 C/T of UCP-3, and Pro12Ala of peroxisome-proliferator activated receptor gamma-2. RESULTS: Carriers of the ADRB3 Arg64 allele had a significantly higher relative body weight and relative body mass index compared with non-carriers. The UCP-2 exon 8 del/ins polymorphism was associated with higher degree of obesity, insulin resistance, dyslipideamia and lower adjusted metabolic rate. Children with UCP-3 -55 T/T genotype had a significantly lower adjusted metabolic rate than the C allele carriers. CONCLUSION: We found evidence for associations between common polymorphisms of the ADRB3, the UCP-2 and UCP-3 genes and basic metabolic rate as well as level and metabolic consequences of common obesity among Hungarian school-aged children.

Saguenay Youth Study: a multi-generational approach to studying virtual trajectories of the brain and cardio-metabolic health.

This paper provides an overview of the Saguenay Youth Study (SYS) and its parental arm. The overarching goal of this effort is to develop trans-generational models of developmental cascades contributing to the emergence of common chronic disorders, such as depression, addictions, dementia and cardio-metabolic diseases. Over the past 10 years, we have acquired detailed brain and cardio-metabolic phenotypes, and genome-wide genotypes, in 1029 adolescents recruited in a population with a known genetic founder effect. At present, we are extending this dataset to acquire comparable phenotypes and genotypes in the biological parents of these individuals. After providing conceptual background for this work (transactions across time, systems and organs), we describe briefly the tools employed in the adolescent arm of this cohort and highlight some of the initial accomplishments. We then outline in detail the phenotyping protocol used to acquire comparable data in the parents.

Association of Gln223 Arg polymorphism of the leptin receptor gene with indicators of energy expenditure in obese children.

OBJECTIVE: Gln223 Arg polymorphism of the leptin receptor (LEPR) gene is one of the most frequently examined polymorphisms of this gene and has been suggested to be associated with energy expenditure (EE). The aim of the present study was to investigate the association of this variant on indicators of EE-resting metabolic rate (RMR), postabsorptive and postprandial respiratory quotient (RQ), and food-induced thermogenesis (FIT)-in obese children. METHODS: The study included 486 genotyped children (obese, n = 355). RMR was measured by indirect calorimetry for 45 min. Subsequent to test-food consumption, FIT was measured in a subsample of obese children (n = 121, body mass index 31.9 kg/m(2) (mean ± SD 5.1). RESULTS: Obese children with the Gln223 Gln genotype showed a significantly lower post-absorptive and postprandial RQ (P = 0.0055 versus P = 0.0002, adjusted for age, sex, and lean body mass) than did groups of children with Gln223 Arg and Arg223 Arg genotypes. No significant differences were observed in FIT and RMR among the carriers and non-carriers of the 223 Arg allele. CONCLUSION: The significantly lower post-absorptive and postprandial RQ in the group of Gln223 Gln genotype children indicates that the fat oxidation of these children maybe increased before and subsequent to food consumption, which can be important in the planning of diet of these children.

Preliminary findings on the influence of FTO rs9939609 and MC4R rs17782313 polymorphisms on resting energy expenditure, leptin and thyrotropin levels in obese non-morbid premenopausal women.

Given that leptin, ghrelin and thyrotropin play a major role in the regulation of resting energy expenditure (REE) and that the FTO rs9939609 and the MC4R rs17782313 polymorphisms have been proposed to affect energy homeostasis, we hypothesized that both polymorphisms are associated with REE and that these relationships can be mediated by leptin, ghrelin and thyrotropin in obesity. Therefore, the present study aimed to examine the relationships between FTO rs9939609 and the MC4R rs17782313 with REE, leptin, ghrelin and thyrotropin levels in obese women. The study comprised 77 obese (body mass index 34.0 ± 2.8 kg/m(2)) women (age 36.7 ± 7 years). We measured body composition by dual-energy X-ray absorptiometry and REE by indirect calorimetry. We analysed fasting leptin, ghrelin and thyrotropin levels and the ratio of leptin to fat mass was calculated. Genotype distributions of the polymorphisms did not deviate from Hardy-Weinberg expectations (P values >0.2). Women carrying the A allele of the FTO rs9939609 had lower REE (1,580 ± 22 vs. 1,739 ± 35 kcal/day, P < 0.001) and higher leptin to fat mass ratio (1.33 ± 0.05 vs. 1.13 ± 0.08 ng/ml kg, P < 0.05) and thyrotropin levels (1.93 ± 0.10 vs. 1.53 ± 0.16 µU/ml, P < 0.05) regardless of age and body mass index. We found no significant influence of the MC4R rs17782313 on energy metabolism or biochemical variables. Our findings confirm that the A allele of the FTO rs9939609 is associated with lower REE and increased plasma leptin levels. We also found an association between the FTO rs9939609 and thyrotropin, suggesting the possible influence of FTO in the hypothalamic-pituitary-thyroid axis as a potential mechanism of the increased adiposity.

How does evolutionary variation in Basal metabolic rates arise? A statistical assessment and a mechanistic model.

Metabolic rates are related to the pace of life. Hence, research into their variability at global scales is of vital importance for several contemporary theories in physiology, ecology, and evolution. Here we evaluated the effect of latitude, climate, primary productivity, habitat aridity, and species trophic habits, on mass-independent basal metabolic rates (BMRs) for 195 rodent species. The aims of this article were twofold. First, we evaluated the predictive power of different statistical models (via a model selection approach), using a dimensional reduction technique on the exogenous factor matrix to achieve a clear interpretation of the selected models. Second, we evaluated three specific predictions derived from a recently proposed hypothesis, herein called the "obligatory heat" model (OHM), for the evolution of BMR. Obtained results indicate that mean/minimum environmental temperature, rainfall/primary productivity and, finally, species trophic habits are, in this order, the major determinants of mass-independent BMR. Concerning the mechanistic causes behind this variation, obtained data agree with the predictions of the OHM: (1) mean annual environmental temperature was the best single predictor of residual variation in BMR, (2) herbivorous species have greater mass-independent metabolic rates, and tend to be present at high-latitude cold environments, than species in other trophic categories.

Basal bioenergetic abnormalities in skeletal muscle from ryanodine receptor malignant hyperthermia-susceptible R163C knock-in mice.

Malignant hyperthermia (MH) and central core disease in humans have been associated with mutations in the skeletal ryanodine receptor (RyR1). Heterozygous mice expressing the human MH/central core disease RyR1 R163C mutation exhibit MH when exposed to halothane or heat stress. Considering that many MH symptoms resemble those that could ensue from a mitochondrial dysfunction (e.g. metabolic acidosis and hyperthermia) and that MH-susceptible mice or humans have a higher than normal cytoplasmic Ca(2+) concentration at rest, we evaluated the role of mitochondria in skeletal muscle from R163C compared with wild type mice under basal (untriggered) conditions. R163C skeletal muscle exhibited a significant increase in matrix Ca(2+), increased reactive oxygen species production, lower expression of mitochondrial proteins, and higher mtDNA copy number. These changes, in conjunction with lower myoglobin and glycogen contents, Myh4 and GAPDH transcript levels, GAPDH activity, and lower glucose utilization suggested a switch to a compromised bioenergetic state characterized by both low oxidative phosphorylation and glycolysis. The shift in bioenergetic state was accompanied by a dysregulation of Ca(2+)-responsive signaling pathways regulated by calcineurin and ERK1/2. Chronically elevated resting Ca(2+) in R163C skeletal muscle elicited the maintenance of a fast-twitch fiber program and the development of insulin resistance-like phenotype as part of a metabolic adaptation to the R163C RyR1 mutation.

Is UCP2 gene polymorphism associated with decreased resting energy expenditure in nondialyzed chronic kidney disease patients?

OBJECTIVE: The deletion/deletion (del/del) polymorphism of uncoupling protein 2 (UCP2) was associated with decreased energy expenditure in diabetic and obese patients. There is evidence of decreased resting energy expenditure (REE) in chronic kidney disease (CKD) patients not yet on dialysis. However, whether REE is associated with the UCP2 polymorphism was not previously investigated in this population. This study evaluated whether the del/del polymorphism of the UCP2 gene is associated with lower REE in nondialyzed CKD patients. DESIGN: This was a cross-sectional study. PATIENTS AND METHODS: Forty-four nondialyzed CKD patients (29 male; aged 52 +/- 12 years; creatinine clearance, 37 +/- 13 mL/min/1.73 m(2) [values are mean +/- SD unless otherwise noted]) were included. Their REE was assessed by indirect calorimetry, and body composition by bioelectrical impedance. High-sensitivity C-reactive protein (hs-CRP) was also evaluated. The insertion/deletion (ins/del) polymorphism of the UCP2 gene was determined in all participants. To test whether the deletion/deletion (del/del) polymorphism of the UCP2 gene was associated with lower REE, the REE of carriers of the del/del genotype (n = 24; group Del) was compared with that of carriers of the insertion and ins/del genotype (n = 20; group Ins). MAIN OUTCOME MEASURE: The main outcome measure was REE. RESULTS: The REE of group Del was similar to that of the group Ins (1379 +/- 239 kcal/day vs. 1360 +/- 289 kcal/day, respectively, P = NS). This result was maintained even after the REE was adjusted for lean body mass by analysis of covariance. In addition, in a multiple-regression analysis using REE as the dependent variable, only lean body mass and hs-CRP were significant predictors of REE. CONCLUSION: The results suggest that the del/del polymorphism of the UCP2 gene is not associated with lower REE in nondialyzed CKD patients.

Polymorphisms of the FTO gene are associated with variation in energy intake, but not energy expenditure.

The FTO gene has significant polymorphic variation associated with obesity, but its function is unknown. We screened a population of 150 whites (103F/47M) resident in NE Scotland, United Kingdom, for variants of the FTO gene and linked these to phenotypic variation in their energy expenditure (basal metabolic rate (BMR) and maximal oxygen consumption VO(2)max) and energy intake. There was no significant association between the FTO genotype and BMR or VO(2)max. The FTO genotype was significantly associated (P = 0.024) with variation in energy intake, with average daily intake being 9.0 MJ for the wild-type TT genotype and 10.2 and 9.5 MJ for the "at risk" AT and AA genotypes, respectively. Adjusting intake for BMR did not remove the significance (P = 0.043). FTO genotype probably affects obesity via effects on food intake rather than energy expenditure.

Ethnicity, energy expenditure and obesity: are the observed black/white differences meaningful?

PURPOSE OF REVIEW: Recent studies have suggested that black individuals have lower energy expenditure than whites. Many investigators hypothesized that this is why black women experience higher rates of obesity than white women. These findings initiated much research on race as a primary biological determinant of obesity and energy expenditure as a potential pathway. Race is a difficult construct to use in biomedical research. RECENT FINDINGS: Recent findings have included: an explanation for the lower resting energy expenditure observed among black adults, data showing that relative resting energy expenditure may not be a significant predictor of weight change in African-origin populations, and inconsistent data on the role of activity energy expenditure as a determinant of children's weight change. SUMMARY: The data suggest that black individuals have lower resting energy expenditure and possibly activity energy expenditure than white individuals. The lower resting energy expenditure is probably caused by a smaller mass of high metabolically active organs. It is unlikely that increased weight gain is associated with lower resting energy expenditure or activity among blacks, because no association has been found within populations. Clinically, it is important to focus on personal modifiable risk factors, e.g., energy intake and physical activity levels.

Arg64 beta3-adrenoceptor variant and the components of energy expenditure.

OBJECTIVE: To determine Trp64Arg beta(3)-adrenoceptor genotype-specific differences in the components of energy expenditure. HYPOTHESIS: We hypothesized that resting metabolic rate (RMR) and physical activity levels would be lower and that thermic effect of feeding (TEF) would be higher in those with the Arg64 allele. RESEARCH METHODS AND PROCEDURES: RMR and TEF were measured by indirect calorimetry, physical activity by questionnaire, and total energy expenditure by the doubly labeled water method. Genotype-specific measures were compared using ANOVA and analysis of covariance (ANCOVA). RESULTS: RMR in Arg64 homozygotes was significantly lower than in Trp64 homozygotes [Arg64, 1373 +/- 259 kcal/d (n = 15) vs. Trp64Arg, 1538 +/- 238 kcal/d (n = 25) vs. Trp64, 1607 +/- 290 kcal/d (n = 22); p < 0.01]. TEF was significantly higher in Arg64 homozygotes compared with Trp64 homozygotes (Arg64, 359 +/- 28 kcal/d; Trp64Arg, 322 +/- 22 kcal/d; and Trp64, 279 +/- 23 kcal/d; p < 0.05). No differences were identified between genotypes in physical activity or in total energy expenditure. DISCUSSION: Our results suggest that the Arg64 beta(3)-adrenoceptor allele contributes significantly to the genetic variability in both RMR and TEF.

Activity energy expenditure and adiposity among black adults in Nigeria and the United States.

BACKGROUND: The prevalence of obesity is higher among populations in industrialized than in developing countries. OBJECTIVE: We sought to compare the relations of activity energy expenditure (AEE) with adiposity and weight change in 2 black populations with different levels of obesity. DESIGN: Total daily energy expenditure (TDEE) and resting energy expenditure (REE) were measured and AEE was calculated in 58 Nigerian and 34 US black women and men. Weight was remeasured after > or = 1 y in a subset of participants. AEE adjusted for body size and TDEE adjusted for REE were calculated with the use of the residual regression method. The cross-sectional relations between percentage body fat and activity were modeled by using regression analysis, and longitudinal relations between weight change and adjusted energy expenditure variables were calculated. RESULTS: Women and men from the United States weighed more, had more body fat, and had higher levels of TDEE, REE, and AEE than did those from Nigeria. Cross-sectionally, AEE was negatively associated with adiposity after adjustment for body size and age (P < 0.001), regardless of site. Between 60% and 80% of the variance in adiposity was explained by AEE or TDEE. REE, AEE, and TDEE adjusted for body size and age were negatively correlated with weight change among Nigerian women but not men. CONCLUSIONS: The significant difference observed in mean adiposity between Nigerians and US blacks was not explained by differences in AEE. However, a low AEE was an important determinant of high percentages of body fat in black adults and was associated with increased weight gain in Nigerian women.

Racial differences in the relation between uncoupling protein genes and resting energy expenditure.

BACKGROUND: Lower resting energy expenditure (REE) in African American women may contribute to their obesity. The identification of uncoupling protein (UCP) genes has fueled a search for genes involved in energy metabolism in humans. OBJECTIVE: We examined variation in REE in relation to variation in UCP1, UCP2, and UCP3 in 141 women aged 18-21 y. DESIGN: Standard methods were used for REE measurements and genetic analysis. Body composition was determined with the use of dual-energy X-ray absorptiometry. Multivariate analysis was used to examine the effect of genotypes on REE and on fat mass in relation to other potentially confounding variables. RESULTS: REE was 295 kJ/d lower in African American women than in white women. No significant variation in REE was seen for UCP1, UCP2, and UCP3 (p-55; exon 3a; and exon 3b) variants after adjustment for other variables including smoking status. For the UCP3 exon 5 variant, REE was significantly (P = 0.019) lower in African American women with the CC genotype than in those with the TT genotype. In African American women, there was a significant trend (P = 0.012) toward lower REE and a weak but nonsignificant trend (P = 0.1) toward greater fat mass across the 3 genotypes (TT, CT, and CC). CONCLUSIONS: The significant and dose-dependent relation between lower REE and the C allele suggests that it may be a thrifty allele. The presence of this parsimonious energy metabolism in African American women, possibly linked to UCP3, may be implicated in their susceptibility to obesity. The absence of a UCP3 effect in white women is intriguing and needs to be explored to further understand possible interactions between UCP3 and other genes.

A longitudinal study of resting energy expenditure relative to body composition during puberty in African American and white children.

BACKGROUND: Body composition and resting energy expenditure (REE) have not been examined longitudinally during puberty. OBJECTIVE: The purpose of this longitudinal study was to examine the influence of pubertal maturation on REE relative to body composition in African American and white children. DESIGN: The study included 92 white and 64 African American children (mean age at baseline: 8.3 and 7.9 y, respectively) from Birmingham, AL. The children had 2-5 annual measurements of fat mass (FM), lean mass (LM), and REE. The Tanner stages of the children ranged from 1 to 5. Mixed-model repeated-measures analyses were used to test the change in REE relative to body composition with increasing Tanner stage among ethnic and sex groups. RESULTS: LM increased from Tanner stage 1 to subsequent stages. FM relative to LM decreased from Tanner stage 1 to stages 3, 4, and 5 but not from stage 1 to stage 2. The African American children had relatively higher limb LM and lower trunk LM than did the white children. REE declined with Tanner stage after adjustment for ethnicity, sex, FM, and LM. This decline was significant from Tanner stage 1 to stages 3, 4, and 5 but not to Tanner stage 2. After adjustment for age, Tanner stage, FM, and LM or LM distribution, REE was significantly higher in white than in African American children (by approximately 250 kJ/d). CONCLUSION: In a large sample of children at various Tanner stages, we found an ethnic difference in REE after adjustment for age, Tanner stage, FM, and LM that was not explained by the difference in LM distribution.

Differences in resting energy expenditure between black and white smokers: implications for postcessation weight gain.

OBJECTIVE: To examine differences in resting energy expenditure (REE) between black and white smokers in order to determine whether REE might contribute to postcessation weight gain. DESIGN: Cross-sectional and prospective investigation of ethnic differences in REE. Differences in REE between black and white smokers were examined at baseline while all participants were smoking, and again during 2 weeks of abstinence from smoking. SETTING: Memphis, Tennessee, USA. SUBJECTS: Sixty-six black and 112 white smokers (age 30.4 y; cigarettes per day 21.4; weight 71.7 kg; body mass index 24.5 kg/m2). RESULTS: Black smokers had a significantly lower baseline REE after adjusting for gender and body weight. Changes in REE following smoking cessation did not differ by ethnicity. CONCLUSIONS: These results suggest that black smokers may be more energy efficient, which could contribute to ethnic differences in postcessation weight gain.

Genetic influences on energy expenditure in humans.

Variations in human energy expenditure are partly because of an influence of the genotype, even after control for the well-established concomitants of energy expenditure. Using the techniques of genetic epidemiology, we have found that about 40% of the variance in resting metabolic rate, thermic effect of food, and energy cost of low-to-moderate intensity exercise (< or = 5 times the resting metabolic rate) is explained by inherited characteristics. A significant genetic effect has also been reported for the level of habitual physical activity. The existence of a genotype-environment interaction has also been investigated. Thus, in response to chronic overfeeding, as well as negative energy balance, changes in the components of energy expenditure exhibit significant identical twin pair resemblance. Nutrient partitioning is emerging as a major determinant of the individual differences in metabolic rate responses to overfeeding or negative energy balance conditions. Taken as a whole, these observations consistently support the hypothesis that heredity plays a significant role in the various components of energy expenditure in humans.