Child body mass index, genotype and parenting in the prediction of restrictive feeding.

BACKGROUND: Restrictive feeding is implicated in pediatric obesity, and caregivers increase controlling feeding practices on the basis of higher child weight status. However, few studies have examined how child genetic and parenting characteristics together impact restrictive feeding. OBJECTIVES: We examined whether child body mass index (BMI) status predicts caregiver use of restrictive feeding and if this association is moderated by (i) caregiver strategies to manage their children's distress and (ii) child variations in the catechol-O-methyltransferase (COMT) gene (Val158 Met, rs4680). METHODS: Participants included 126 Caucasian children (50% girls) and their caregivers who were participating in a larger study in the USA. Caregivers reported on their feeding practices and responses to child distress when children were 2.5-3.5 years of age. Child anthropometric measurements were also obtained. Restrictive feeding was assessed again 1-1.5 years later. Genomic DNA was obtained from saliva samples, and COMT-rs4680 was genotyped using TaqMan® methodology. RESULTS: Child BMI percentile predicted subsequent caregiver restrictive feeding for children who were Met/Met and who had caregivers reporting higher use of negative responses to child distress. For Val carriers, BMI percentile predicted restrictive feeding when caregivers were below the mean on these responses. CONCLUSIONS: Caregivers are at risk for use of restrictive feeding practices when their children are at higher BMI percentiles, and this association increases when caregivers use more ineffective stress regulation practices and their children are homozygous for the Met allele. Prevention programmes might focus on parenting behaviours that foster emotion regulation and consider variation in child responses to parenting.

One-year follow-up changes in weight are associated with changes in blood pressure in young Mexican adults.

OBJECTIVE: Increasing overweight and obesity rates in Mexico have been associated with increases in mortality from cardiovascular disease (CVD). This study assessed changes in body mass index (BMI) and body weight over 1 year, and explored whether these were associated with changes in CVD risk factors of blood pressure and fasting glucose in a cohort of young Mexican adults. STUDY DESIGN: Longitudinal data were obtained from a cohort of young Mexican adults applying to college. METHODS: Data were collected from college applicants for the 2008 academic year who re-applied in 2009. In total, 795 college applicants aged 18-20 years, of both sexes (48% males and 52% females), were included in the study. The screen included height, weight, and systolic (SBP) and diastolic (DBP) blood pressure measurements plus a blood draw following an overnight fast for fasting glucose. RESULTS: At baseline, 31.8% of the participants were overweight or obese. The mean 1-year change in body weight and BMI were 0.80 kg and 0.35 kg/m(2), respectively. One-year changes in body weight and BMI were associated with increased SBP and DBP for both men and women (P < 0.05), independent of baseline BMI. A weight gain of 5% or more was positively associated with increases in blood pressure among women (P < 0.05), but not among men. A weight loss of 5% or more was associated with reductions in SBP among women. CONCLUSIONS: One-year changes in weight were associated with changes in blood pressure.

Adiponectin concentration and insulin indicators following overfeeding in identical twins.

UNLABELLED: Low adiponectin levels have been associated with high body mass index, low insulin sensitivity, and diabetes. OBJECTIVE: To assess the relationships between changes in serum adiponectin concentration and adiposity, glucose, and insulin in response to long-term overfeeding in identical twins and to calculate the twin resemblance in serum adiponectin concentrations. SUBJECTS AND DESIGN: Twenty-four sedentary young men [mean (+/-SD) age, 21+/-2 yr] who constituted 12 pairs of healthy identical twins were studied for metabolic and adiponectin changes in response to overfeeding. INTERVENTION: Subjects were overfed by 84,000 kcal over a 100-day period. OUTCOME MEASURES: The overfeeding study provides an opportunity to examine the relationships between adiponectin and changes in body weight, adiposity, plasma glucose and insulin. RESULTS: Serum adiponectin concentration correlated positively with body weight (r= 0.41, p=0.05) at baseline but not with indicators of adiposity or with visceral fat. No relationship existed between baseline adiponectin concentration and body weight or adiposity gains with overfeeding. However, serum adiponectin decreased significantly by -2.35+/-0.48 microg/ml (p=0.001) in response to overfeeding. Baseline adiponectin levels correlated negatively with changes in plasma fasting glucose levels (r=-0.53, p=0.01) and homeostasis model assessment index (r=-0.41, p=0.05), independently of fat mass. The intrapair coefficient for twin resemblance (r=0.75, p=0.001) strongly suggests that baseline serum adiponectin concentration is a familial trait. CONCLUSIONS: These data provide evidence that adiponectin concentration is a familial trait in normal-weight individuals, that it decreases when challenged by positive energy balance, and that its overfeeding-induced variations are correlated with glucose and insulin levels.

Variations in the four and a half LIM domains 1 gene (FHL1) are associated with fasting insulin and insulin sensitivity responses to regular exercise.

AIMS/HYPOTHESIS: The expression of the four and a half LIM domains 1 gene (FHL1) is increased in the muscle of individuals who show an improvement in insulin sensitivity index (S(I)) after 20 weeks of exercise training. The aim of the present study was to investigate associations between three FHL1 single nucleotide polymorphisms (SNPs) and variables derived from an IVGTT, both in the sedentary state and in response to exercise training, in participants in the HERITAGE Family Study. MATERIALS AND METHODS: SNPs were typed using fluorescence polarisation methodology. Analyses were performed separately by sex and in black and white individuals. RESULTS: In black participants, no associations were found with any of the SNPs. In white women (n = 207), SNP rs9018 was associated with the disposition index (D(I)), which is calculated as S(I) generated from the MINMOD program (x10(-4) min(-1)[microU/ml](-1)) multiplied by acute insulin response to glucose (AIR(g); pmol/l x 10 min), and the glucose disappearance index (K(g)) training responses (p = 0.016 and p = 0.008, respectively). In white men (n = 222), all SNPs were associated with fasting glucose levels (p < or = 0.05) and SNP rs2180062 with the insulin sensitivity index (S(I)) (p = 0.04) in the sedentary state. Two SNPs were associated with fasting insulin training response. Fasting insulin decreased to a greater extent in carriers of the rs2180062 C allele (p = 0.01) and rs9018 T allele (p = 0.04). With exercise training, S(I) (x10(-4) min(-1)[microU/ml](-1): 0.68 +/- 0.20 vs -0.77 +/- 0.44, p = 0.046), D(I) (319 +/- 123 vs -528 +/- 260, p = 0.006) and K(g) (per 100 min: 0.09 +/- 0.04 vs -0.14 +/- 0.8, p = 0.03) improved more in the C allele carriers at rs2180062 than in the T allele carriers. CONCLUSIONS/INTERPRETATION: Fasting insulin and S(I) responses to exercise training were associated with DNA sequence variation in FHL1 in white men. Whether these associations exist only in white men remains to be investigated.

Genome-wide linkage scans for prediabetes phenotypes in response to 20 weeks of endurance exercise training in non-diabetic whites and blacks: the HERITAGE Family Study.

AIMS/HYPOTHESIS: Impaired insulin secretion, insulin action, insulin-independent glucose effectiveness, glucose tolerance and the associated abnormalities in insulin and glucose metabolism phenotypes are precursors of type 2 diabetes. Genome-wide multipoint variance component linkage scans were carried out using 654 markers to identify quantitative trait loci for insulin sensitivity, acute insulin response to glucose, disposition index and glucose effectiveness training responses in whites and blacks in the HERITAGE Family Study. METHODS: These phenotypes were obtained from an IVGTT with the minimal model. The distributions of insulin sensitivity, acute insulin response to glucose and disposition index training responses (post-training minus baseline) were approximately normalised using a square-root transformation. All phenotypes were adjusted for the effects of age, BMI and their respective baseline values within sex and generation by race prior to linkage scans. RESULTS: In blacks, a promising linkage with a maximum lod score of 3.1 on 19q (54-62 Mb) for glucose effectiveness training response was found. Six interesting linkages with lod scores of at least 1.0 were found for disposition index training response in whites. They included 1p (30 Mb), 3q (152 Mb), 6p (23-42 Mb), 7q (95-96 Mb), 10p (15 Mb) and 12q (119-126 Mb). CONCLUSIONS/INTERPRETATION: Quantitative trait loci for 20 weeks of endurance exercise training responses in insulin action and glucose metabolism phenotypes were found on chromosome 19q as well as 6p and 7q, with nominal (6p, 7q) but consistent (6p) linkages across the races.

Involvement of a unique carbohydrate-responsive factor in the glucose regulation of rat liver fatty-acid synthase gene transcription.

Refeeding carbohydrate to fasted rats induces the transcription of genes encoding enzymes of fatty acid biosynthesis, e.g. fatty-acid synthase (FAS). Part of this transcriptional induction is mediated by insulin. An insulin response element has been described for the fatty-acid synthase gene region of -600 to +65, but the 2-3-fold increase in fatty-acid synthase promoter activity attributable to this region is small compared with the 20-30-fold induction in fatty-acid synthase gene transcription observed in fasted rats refed carbohydrate. We have previously reported that the fatty-acid synthase gene region between -7382 and -6970 was essential for achieving high in vivo rates of gene transcription. The studies of the current report demonstrate that the region of -7382 to -6970 of the fatty-acid synthase gene contains a carbohydrate response element (CHO-RE(FAS)) with a palindrome sequence (CATGTGn(5)GGCGTG) that is nearly identical to the CHO-RE of the l-type pyruvate kinase and S(14) genes. The glucose responsiveness imparted by CHO-RE(FAS) was independent of insulin. Moreover, CHO-RE(FAS) conferred glucose responsiveness to a heterologous promoter (i.e. l-type pyruvate kinase). Electrophoretic mobility shift assays demonstrated that CHO-RE(FAS) readily bound a unique hepatic ChoRF and that CHO-RE(FAS) competed with the CHO-RE of the l-type pyruvate kinase and S(14) genes for ChoRF binding. In vivo footprinting revealed that fasting reduced and refeeding increased ChoRF binding to CHO-RE(FAS). Thus, carbohydrate responsiveness of rat liver fatty-acid synthase appears to require both insulin and glucose signaling pathways. More importantly, a unique hepatic ChoRF has now been shown to recognize glucose responsive sequences that are common to three different genes: fatty-acid synthase, l-type pyruvate kinase, and S(14).

Polyunsaturated fatty acids suppress hepatic sterol regulatory element-binding protein-1 expression by accelerating transcript decay.

The reduction in hepatic abundance of sterol regulatory element binding protein-1 (SREBP-1) mRNA and protein associated with the ingestion of polyunsaturated fatty acids (PUFA) appears to be largely responsible for the PUFA-dependent inhibition of lipogenic gene transcription. Our initial studies indicated that the induction of SREBP-1 expression by insulin and glucose was blocked by PUFA. Nuclear run-on assays suggested PUFA reduced SREBP-1 mRNA by post-transcriptional mechanisms. In this report we demonstrate that PUFA enhance the decay of both SREBP-1a and -1c. When rat hepatocytes in monolayer culture were treated with albumin-bound 20:4(n-6) or 20:5(n-3) the half-life of total SREBP-1 mRNA was reduced by 50%. Ribonuclease protection assays revealed that the decay of SREBP-1c mRNA was more sensitive to PUFA than was SREBP-1a, i.e. the half-life of SREBP-1c and -1a was reduced from 10.0 to 4.6 h and 11.6 to 7.6 h, respectively. Interestingly, treating the hepatocytes with the translational inhibitor, cycloheximide, prevented the PUFA-dependent decay of SREBP-1. This suggests that SREBP-1 mRNA may need to undergo translation to enter the decay process, or that the decay process requires the synthesis of a rapidly turning over protein. Although the mechanism by which PUFA accelerate SREBP-1 mRNA decay remains to be determined, cloning and sequencing of the 3'-untranslated region for the rat SREBP-1 transcript revealed the presence of an A-U-rich region that is characteristic of a destablizing element.

Identification of a novel enhancer sequence in the distal promoter of the rat fatty acid synthase gene.

The proximal promoter and first intron of the fatty acid synthase (FAS) gene contains response sequences for insulin and glucose, but the 2- to 3-fold increase in FAS promoter activity attributable to these sequences falls short of the 20- to 30-fold induction in hepatic FAS gene transcription observed in fasted-refed rats. Using DNase I hypersensitivity site (HSS) mapping, two new liver specific sites were localized to the regions of: -8600 to -8500 (HSS 1) and -7300 to -7000 (HSS 2). DNase sensitivity of the -7300 to -7000 region was increased when fasted rats were refed glucose. When rat hepatocytes were transfected with a CAT construct that linked the region of -9700 and -4606 with the insulin response region located between -265 to +65, FAS promoter activity was induced 15-fold. This increase required the presence of both insulin and glucocorticoids. Deleting HSS 2 abolished the 15-fold induction in FAS promoter activity, but removing HSS 1 was without effect. Apparently the in vivo regulation of hepatic FAS gene transcription requires response elements located in the region of -7300 to -7000 and -265 to +65.

Urinary organic acids in infant malnutrition.

The metabolic derangements in severe protein-energy malnutrition (PEM) are only partially known, due to the limitations of blood collection in these patients. Urinary excretion of organic acids was studied by gas chromatography-mass spectrometry in 39 infants with four types of PEM: 1) upon hospital admission, as soon as eventual infections had been cleared, and salt and water deficits corrected, but before oral feeding was started; 2) after start of protein alimentation; 3) on the day of discharge. All of the patients showed an increased excretion of various organic acids at some point of their hospital stay, regardless of the clinical type of PEM. In nearly half of the malnourished children, results were suggestive of blocks in the pathways of propionate (15.4% with increased methylmalonate and 25.6% with 2-methylcitrate), of fatty acid beta-oxidation (30.8% with raised dicarboxylic acids with low or low normal 3-hydroxybutyrate), or of both pathways (12.8%). These abnormalities may have been caused by cofactor deficiencies (biotin, vitamin B12, riboflavin, carnitine, niacin). Dicarboxylic acids were excreted in high amounts since the initial sample, probably due to increased mobilization of fatty acids. Increased 2-methylcitrate and methylmalonate excretion was observed more frequently once patients started to be orally fed. The accumulation of potentially toxic acyl-CoA precursors of these compounds could contribute to the known clinical worsening of some malnourished infants after suddenly increased protein intake. Other less specific metabolites, such as 3-hydroxybutyrate, lactate, 4-hydroxyphenyllactate, fumarate, succinate, and 4-hydroxyphenylacetate, were also abnormally excreted in some patients. The analysis of urinary organic acids provides a new approach for the metabolic study of PEM and may have diagnostic and therapeutic implications.

Low frequency of deletion alleles in patients with steroid 21-hydroxylase deficiency in a Mexican population.

Steroid 21-hydroxylase deficiency is caused by mutations in the CYP21 gene. Approximately 95% of mutant alleles are generated by recombination events between the active gene CYP21 and its highly homologous pseudogene, CYP21P. Deletion alleles are generated by unequal crossing over, while point mutations are the result of gene conversion events. Deletions account for 20-25% of the 21-hydroxylase deficiency alleles in most populations studied. We have looked for deletions among 53 unrelated Mexican patients with steroid 21-hydroxylase deficiency and found that deletions represent less than 1% of the disease alleles. These findings suggest that nearly all mutant alleles in our patient population contain point mutations and that the low representation of deletion alleles among clinically diagnosed patients may be due to missing detection of salt wasters, mainly males, who may die during the neonatal period.