A missense variant in CREBRF, rs373863828, is associated with fat-free mass, not fat mass in Samoan infants.

BACKGROUND/OBJECTIVES: In Samoa, where 80% of the adult population is living with obesity, understanding the determinants of adiposity and growth during infancy may inform prevention efforts. We examined the association of a missense variant, rs373863828, in the CREBRF gene with body composition in Samoan infants. Adults with one or more copies of the rs373863828 minor allele (A) have higher odds of obesity, based on body-mass index (BMI), but paradoxically decreased odds of diabetes compared to those without the allele. Our study may offer novel insight into the natural history and pathogenesis of this unexpected relationship. SUBJECTS/METHODS: In a prospective study, we measured body composition in early infancy, and at 2- and 4-months of age using anthropometry and dual-energy x-ray absorptiometry (DXA). We genotyped subjects at the CREBRF rs373863828 locus and compared infants with (AA/AG) and without (GG) the variant. In longitudinal analyses, we calculated the absolute change in each outcome from the early infant to the 4-month assessment, adjusting for baseline and other covariates. RESULTS: In cross-sectional analyses, there was no significant difference in infant BMI or fat mass by genotype. After adjusting for covariates, infants with the variant had 4.0 ± 1.8 g more bone mass (p = 0.026) and 210.9 ± 79.6 g more lean mass (p = 0.009) at 4-months and accumulated 176.9 ± 73.0 g more lean mass between the early infant and 4-month assessment (p = 0.017). CONCLUSIONS: The CREBRF rs373863828 minor allele (A) was not associated with increased BMI or adiposity in Samoan infants, but instead with increased lean and bone mass. Our findings suggest that lean (i.e., muscle) and bone mass accretion should be explored as pathways to explain the "protective" effect of the CREBRF variant against diabetes.

Effects of supervised and unsupervised physical activity programmes for weight loss.

OBJECTIVES: Physical activity is important for weight management. However, it remains unclear what type of physical activity prescription/programme is optimal for increasing physical activity during a standard behavioural weight loss intervention. This study examined changes in physical activity after a 12-week supervised programme prescribed in minutes per week (SUP-PA), an unsupervised programme prescribed in minutes per week (UNSUP-PA) and an unsupervised programme prescribed in steps per day (STEP). METHODS: Fifty-two adults who were overweight or obese (age: 43.5 ± 10.1 years, BMI: 31.5 ± 3.5 kg·m-2) were randomized to STEP (n = 18), UNSUP-PA (n = 17) and SUP-PA (n = 17). Subjects attended weekly in-person group intervention sessions and were prescribed a calorie-restricted diet (1,200-1,800 kcals·day-1) combined with increased physical activity (150 min·week-1 or 10,000 steps·day-1 with 2,500 brisk steps·day-1). RESULTS: All three groups significantly increased moderate-to-vigorous physical activity (STEP: 80.6 ± 218.5 min·week-1, UNSUP-PA: 112.9 ± 180.4 min·week-1 and SUP-PA: 151.1 ± 174.0 min·week-1, p < 0.001) with no differences between groups (p = 0.94) or group by time interaction (p = 0.81). In addition, there were no significant differences in weight loss between the groups (p = 0.81). CONCLUSIONS: In this short-term study, all three physical activity programmes increased physical activity and elicited modest weight loss when combined with a standard behavioural weight loss intervention.

The rat corpulent (cp) mutation maps to the same interval on (Pgm1-Glut1) rat chromosome 5 as the fatty (fa) mutation.

The autosomal recessive obesity mutations fatty (fa) and corpulent (cp) arose in separate rat strains, 13M and Koletsky, respectively. By complementation analysis, the two mutations appear to be in the same gene. The somewhat different phenotypes of fa/fa and cp/cp animals probably reflect the fact that the mutations are segregating on different rat strains. The fa mutation has been mapped to the interval between Pgm1 and Glut1 on rat Chr 5, but cp has not been mapped genetically. We mapped cp in 30 obese progeny of a LA/N-BN cp/+ intercross using microsatellite markers for these flanking genes. Cp maps to the same genetic interval as rat fa and mouse db. Cp is flanked by Glut1 and Pgm1: Pgm1-------- cp -------- Glut1 map distance (cM) 1.67 6.67 Thus, cp and fa map to the same approximately 8 cm interval of the rat genome. In conjunction with the complementation studies alluded to above, these findings indicate that cp and fa are mutations in the same gene (Lepr).

Phenotype of fatty due to Gln269Pro mutation in the leptin receptor (Lepr).

The rat fatty (fa) mutation produces profound obesity of early onset caused by hyperphagia, defective nonshivering thermogenesis, and preferential deposition of energy into adipose tissue. Genetic mapping studies indicate that fa and diabetes (db) are homologous loci in the rat and mouse genomes, respectively. It has been shown that db alleles carry mutations in the Lepr (leptin receptor) gene. This paper describes a point mutation in the fatty allele of Lepr. A nucleotide substitution at position 880 (A-->C) causes an amino acid substitution at position 269 (Gln-->Pro). The mutation generates a novel Msp I site that cosegregates with fa in 1,028 meioses examined in obese F2 progeny from two crosses (Bnx13M and WKYx13M) and is still segregating in three rat colonies. PCR-based mutagenesis was used to introduce the fa mutation into the mouse Lepr cDNA. Transient transfection studies indicate that the mutant Lepr cDNA has greatly reduced binding of leptin (Lep) at the cell surface. These data are strong evidence that the single nucleotide substitution in the fa allele of Lepr (Leprfa) is responsible for the obese phenotype.

Perinatal energy stores and excessive fat deposition in genetically obese (fa/fa) rats.

To find out whether perinatal differences in energy stores are essential for the phenotypic manifestation of the fa/fa genotype in 16-day-old rats, we investigated Zucker rats (13M) x Brown Norway (BN) hybrids. +/fa and fa/fa hybrids were identified by molecular polymorphisms approximately 1 cM from the fa locus. The fat content of all pups increased rapidly after birth, and differences between +/fa and fa/fa hybrid pups were significant in 7- and 16-day-old rats but not at 0, 1, and 4 days of age. For 16-day-old 13MBN hybrids as well as 13M Zucker rats, plots of carcass fat vs. body mass were closely fitted by parallel regression lines, with carcass fat similarily higher in fa/fa than +/fa pups of both strains. Fetal and neonatal plasma insulin concentration and hepatic glycogen in the 13MBN hybrid pups did not differ between +/fa and fa/fa litter-mates, nor did the hepatic and adipose tissue triglycerides in 24-h-old 13MBN hybrid pups. The manifest differences between fatty and lean 16-day-old pups thus do not depend on differences in perinatal energy stores.

Molecular mapping of SSRs for Pgm1 and C8b in the vicinity of the rat fatty locus.

Recessive mutations at the rat fatty locus (fa, facp), which produce obesity, insulin resistance, and diabetes, provide useful experimental models for similar phenotypes in humans. The molecular pathogenesis of the metabolic phenotype in animals segregating for fa is unknown and difficult to study once the confounding metabolic effects of obesity are present. Although various experimental methods distinguish preobese from lean rats (phenotypic markers and molecular markers genetically linked to fatty), technical difficulties limit their utility. We report the identification of two (GT)n simple sequence repeats (SSRs) near the rat phosphoglucomutase gene (Pgm1) gene and two SSRs, (GA)n and (GT)n, near the rat complement component 8 beta gene (C8b). These SSRs map to an approximately 4-cM interval flanking the fatty locus on rat chromosome 5. Use of these molecular markers in combination offers an improved method for early assessment of gene dosage for fa and hence for studying the fundamental molecular physiology underlying the derangements of metabolism and behavior resulting from mutations in this gene.