Jens-Christian Holm

Leptin in obesity

Obesity runs in families, mainly due to genetic factors.1 Several different mendelian inherited, monogenic forms of obesity exist in rodents, but they are rare in humans.1 Analysis of the distribution of fatness in families suggests that a few major genes may act on a polygenic and environmental background, but it remains unclear which genes are involved.1 The identification and sequencing of the mouse obese (ob) gene by Friedmans group in 19942 opened important new avenues in obesity research and have already led to overwhelming research activity.3 In homozygous ob/ob mice, the mutation of the ob gene results in increased food intake, reduced energy expenditure, elevated insulin and cortisol levels, and subsequently, in massive obesity and non-insulin dependent diabetes mellitus.2 The ob gene encodes a protein, leptin, which is produced only in fat cells and secreted into the blood. There are two different strains of ob/ob mice: one with a mutation that establishes a stop codon within the ob gene, resulting in the production of a truncated, inactive protein; the other with a mutation that produces no protein at all.2 Administration of leptin corrects the multiple metabolic disturbances.4 The finding of a human homologue of …

Association studies on 11 published colorectal cancer risk loci

Background:Recently, several genome-wide association studies (GWAS) have independently found numerous loci at which common single-nucleotide polymorphisms (SNPs) modestly influence the risk of developing colorectal cancer. The aim of this study was to test 11 loci, reported to be associated with an increased or decreased risk of colorectal cancer: 8q23.3 (rs16892766), 8q24.21 (rs6983267), 9p24 (rs719725), 10p14 (rs10795668), 11q23.1 (rs3802842), 14q22.2 (rs4444235), 15q13.3 (rs4779584), 16q22.1 (rs9929218), 18q21.1 (rs4939827), 19q13.1 (rs10411210) and 20p12.3 (rs961253), in a Swedish-based cohort.Methods:The cohort was composed of 1786 cases and 1749 controls that were genotyped and analysed statistically. Genotype–phenotype analysis, for all 11 SNPs and sex, age of onset, family history of CRC and tumour location, was performed.Results:Of eleven loci, 5 showed statistically significant odds ratios similar to previously published findings: 8q23.3, 8q24.21, 10p14, 15q13.3 and 18q21.1. The remaining loci 11q23.1, 16q22.1, 19q13.1 and 20p12.3 showed weak trends but somehow similar to what was previously published. The loci 9p24 and 14q22.2 could not be confirmed. We show a higher number of risk alleles in affected individuals compared to controls. Four statistically significant genotype–phenotype associations were found; the G allele of rs6983267 was associated to older age, the G allele of rs1075668 was associated with a younger age and sporadic cases, and the T allele of rs10411210 was associated with younger age.Conclusions:Our study, using a Swedish population, supports most genetic variants published in GWAS. More studies are needed to validate the genotype–phenotype correlations.

Chronic care treatment of obese children and adolescents

OBJECTIVES Clinically-relevant protocols for the treatment of childhood obesity are lacking. This study report results for a clinic-based structured treatment program for chronic childhood obesity. METHODS Patients were measured at baseline and for up to 24 months; there were no prior eligibility criteria. At baseline, height, weight, Tanner stages, testicular size, time of menarche, and social class of the parents were registered. A structured, tailored treatment plan including best-practice-based interventions was initiated. Height, weight, and pubertal development were measured at subsequent visits. RESULTS A total of 617 children or youths were included; 325 were girls and 292 were boys. At entry, the mean age was 11.6 years and the mean body mass index (BMI) standard deviation score (SDS) was 3.0. Seventy stopped treatment, 547 were in treatment, 125 had 1 examination, and 492 had two or more examinations, with a mean visit interval of six weeks. After 12 months, the mean BMI SDS decreased by 0.23 (P < 0.0001) in girls and by 0.32 (P < 0.0001) in boys. After one year, the retention rate was 90.2%, and 68.7% had reduced BMI SDS. After two years, the retention rate was 75.0%, of which 62.5% had reduced BMI SDS. The reductions in BMI SDS were independent of baseline adiposity, age (in boys), puberty stage, and social class, but were dependent on sex, age (girls), and place of referral. CONCLUSIONS This clinical obesity treatment was safe and effective in reducing BMI SDS independent of baseline adiposity, age (boys), or social class in these young people.

Implications of Central Obesity-Related Variants in LYPLAL1, NRXN3, MSRA, and TFAP2B on Quantitative Metabolic Traits in Adult Danes

Background Two meta-analyses of genome-wide association studies (GWAS) have suggested that four variants: rs2605100 in lysophospholipase-like 1 (LYPLAL1), rs10146997 in neuroxin 3 (NRXN3), rs545854 in methionine sulfoxide reductase A (MSRA), and rs987237 in transcription factor activating enhancer-binding protein 2 beta (TFAP2B) associate with measures of central obesity. To elucidate potential underlying phenotypes we aimed to investigate whether these variants associated with: 1) quantitative metabolic traits, 2) anthropometric measures (waist circumference (WC), waist-hip ratio, and BMI), or 3) type 2 diabetes, and central and general overweight and obesity. Methodology/Principal Findings The four variants were genotyped in Danish individuals using KASPar®. Quantitative metabolic traits were examined in a population-based sample (n = 6,038) and WC and BMI were furthermore analyzed in a combined study sample (n = 13,507). Case-control studies of diabetes and adiposity included 15,326 individuals. The major G-allele of LYPLAL1 rs2605100 associated with increased fasting serum triglyceride concentrations (per allele effect (β) = 3%(1;5(95%CI)), p additive = 2.7×10−3), an association driven by the male gender (p interaction = 0.02). The same allele associated with increased fasting serum insulin concentrations (β = 3%(1;5), p additive = 2.5×10−3) and increased insulin resistance (HOMA-IR) (β = 4%(1;6), p additive = 1.5×10−3). The minor G-allele of rs10146997 in NRXN3 associated with increased WC among women (β = 0.55cm (0.20;0.89), p additive = 1.7×10−3, p interaction = 1.0×10−3), but showed no associations with obesity related metabolic traits. The MSRA rs545854 and TFAP2B rs987237 showed nominal associations with central obesity; however, no underlying metabolic phenotypes became obvious, when investigating quantitative metabolic traits. None of the variants influenced the prevalence of type 2 diabetes. Conclusion/Significance We demonstrate that several of the central obesity-associated variants in LYPLAL1, NRXN3, MSRA, and TFAP2B associate with metabolic and anthropometric traits in Danish adults. However, analyses were made without adjusting for multiple testing, and further studies are needed to confirm the putative role of LYPLAL1, NRXN3, MSRA, and TFAP2B in the pathophysiology of obesity.

Development of obesity and polycystic ovary syndrome in adolescents.

Obesity in adolescents is prevalent worldwide. Polycystic ovary syndrome (PCOS) is often associated with obesity in women, and it has serious metabolic and reproductive health implications. Although PCOS does not become clinically visible until early adolescence, its origins are likely much earlier. Therefore, we reviewed the recent literature regarding the mechanisms linking the development of PCOS and obesity in adolescent girls. We found that excess abdominal adipose tissue (AT) initiates metabolic and endocrine aberrations that are central in the progression of PCOS. As an example, abdominal AT impairs insulin action, which interacts with the progression of hyperandrogenism. In addition, excessive androgen levels lead to impaired glucose uptake, which also contributes to insulin resistance, which again increases the deposition of visceral fat. The body composition is influenced by testosterone, which decreases subcutaneous fat lipolysis and influences adipocyte distribution. These mechanisms may explain why PCOS girls have an increased visceral adipose mass independent of body mass index. Therefore, first-line treatment in adolescent PCOS is often lifestyle intervention to prevent the damaging effects of obesity. Pharmacological treatment of adolescent PCOS is not standardized because the long-term effects in adolescents have not yet been evaluated; therefore, drugs should be prescribed cautiously. Although the complex metabolic interrelationships between obesity and PCOS have yet to be fully understood, the co-occurrence of these conditions in adolescent girls tends to increase the severity of the negative health consequences of each condition.

Longitudinal changes in blood pressure during weight loss and regain of weight in obese boys and girls.

Objective: To investigate blood pressure (BP) in relation to changes in body mass index (BMI) in obese children during weight loss and subsequent weight regain. Design: A longitudinal study of obese boys and girls investigated through a 12-week weight loss intervention with follow-up investigations spanning 28 months. Results shown are from baseline; day 14, 33, and 82 during weight loss; and at months 10, 16 and 28 during follow-up. Patients: One hundred and fifteen obese children, 53 boys and 62 girls (8–15 years) with a median BMI standard deviation score (SDS) at baseline of 2.78 in boys, and 2.70 in girls. Ninety children completed the weight loss programme and 68 children entered the follow-up programme. Methods: Height, weight, systolic blood pressure (SBP), and diastolic BP (DBP) were recorded and analysed using a general linear mixed model. Results: Fifty-one percent of the obese children were pre or hypertensive at baseline. Both DBP and SBP declined significantly with weight loss, but a divergent response was found in the timing of the rebound in hypertension during the weight regain phase, that is DBP increased during weight regain, whereas SBP remained lower than baseline during 28 months of continuous weight regain. Conclusion: The effect of weight reduction upon obesity-associated hypertension is noticeable and suggests the importance of an intensified childhood obesity treatment strategy in order to reduce the burden of future cardiovascular disease.

Changes in lipidemia during chronic care treatment of childhood obesity.

BACKGROUND Childhood obesity and related co-morbidities are increasing. This intervention study assessed the associations between weight changes and lipidemia in obese children and adolescents. METHODS A total of 240 obese children and adolescents (median age, 11.3 years; range, 3.9-20.9) were enrolled in a best-practice multidisciplinary chronic care treatment program. The concentrations of total cholesterol, low-density lipoprotein (LDL), high-density lipoprotein (HDL), and triglycerides (TGs) and anthropometric data comprising height and weight were collected at baseline and after up to 39 months of continuous treatment. RESULTS The BMI standard deviation score (SDS) decreased in 51% of patients and maintained unchanged in 32% of patients during the treatment. At baseline, 65 (27.1%) of the patients exhibited dyslipidemia defined as increased concentrations of total cholesterol (>200 mg/dL), LDL (>130 mg/dL), or TGs (>150 mg/dL), or decreased HDL concentration (<35 mg/dL). Dyslipidemia improved with weight loss; the odds ratio (OR) was 0.37 per BMI SDS (p = 0.014) after adjusting for age, sex, and baseline BMI SDS. Baseline TG concentration correlated positively and HDL concentration correlated negatively with baseline BMI SDS. Weight loss was associated with a decrease in the concentrations of total cholesterol (p = 0.0005), LDL (p < 0.0001), non-HDL (p < 0.0001), and TGs (p < 0.0001), and with an increase in HDL concentration (p < 0.0001). CONCLUSION High lipid concentrations were associated with childhood obesity. The lipid profile improved during weight loss independently of the baseline BMI SDS and baseline lipid concentration.

Effect of changes in BMI and waist circumference on ambulatory blood pressure in obese children and adolescents.

Background: Weight reduction has been accompanied with a reduction in clinic blood pressure (BP) in children and adolescents; however, the effect on ambulatory BP (ABP) is uncertain. The objective was to investigate the impact of weight changes on ABP in obese children and adolescents. Methods: Sixty-one severely obese patients aged 10–18 years underwent lifestyle intervention at the Childrens Obesity Clinic. Patients were examined with ABP monitoring at baseline and after 1 year of treatment (follow-up). To account for growth, BP and BMI were standardized into z scores, whereas waist circumference was indexed by height [waist/height ratio (WHR)]. Results: Patients experienced a reduction at follow-up in the degree of obesity [&Dgr;BMI z score: −0.21, 95% confidence interval (CI) −0.32 to −0.10, P = 0.0003; and &Dgr;WHR: −0.02, 95% CI −0.03 to −0.004, P = 0.009]. &Dgr;24-h, &Dgr;daytime and &Dgr;night-time SBP and DBP in mmHg and changes in equivalent z scores were related to &Dgr;BMI z scores and &Dgr;WHR. These relationships were reproduced in multiple regression analyses adjusted for relevant confounders, for example, a reduction in one BMI z score corresponds to a reduction in 24-h SBP by 6.5 mmHg (P < 0.05). No relationship was found between changes in these anthropometric obesity measures and changes in clinic BP. Conclusion: Changes in obesity measures were closely related to changes in ABP, but not to changes in clinic BP, in severe obese children and adolescents after 1 year of lifestyle intervention. The findings emphasize the use of 24-h ABP measurements in children and adolescents.

Obese children and adolescents have elevated nighttime blood pressure independent of insulin resistance and arterial stiffness

BACKGROUND Insulin resistance has been related to elevated blood pressure (BP) in obese children and may adversely affect the vasculature by arterial stiffening. The objective was to investigate whether daytime and nighttime BP were elevated and related to insulin resistance and arterial stiffness in obese children and adolescents. METHODS Ninety-two obese patients aged 10-18 years were compared with 49 healthy control individuals. Insulin resistance was measured as the homeostatic assessment model (HOMA), and arterial stiffness was measured as carotid-femoral pulse wave velocity (cfPWV). RESULTS Mean ± SD daytime systolic BP (SBP) (obese: 125±8.3mm Hg; control: 121±10.1mm Hg; P = 0.03) and nighttime SBP (obese: 108±10.7mm Hg; control: 102±8.2mm Hg; P = 0.0001) were higher in the obese group when compared with the control group. No difference was found in daytime diastolic BP (DBP), whereas nighttime DBP (obese: 60±6.6mm Hg; control: 57±4.8mm Hg; P = 0.001) and night-to-day BP ratios were higher in the obese group. Nighttime SBP was related to BMI z score (β = 6.0; 95% confidence interval (CI) = 2.9-9.1; P = 0.0002) and waist/height ratio (β = 36.7; 95% CI = 5.6-67.9; P = 0.02) in the obese group. HOMA index (obese: median = 3.7, interquartile range (IQR) = 2.3-6.0; control: median = 2.6, IQR = 1.8-3.4; P = 0.002) was higher, whereas cfPWV (obese: 4.8±0.8 m/s; control: 5.1±0.6 m/s; P = 0.03) was lower in the obese group. CfPWV was not related to logHOMA index. In multiple regression analyses, the higher nighttime BP in the obese group was independent of logHOMA and cfPWV. CONCLUSIONS Obese children had a higher nighttime BP when compared with the control group independently of insulin resistance and arterial stiffness. No relationship was found between insulin resistance and arterial stiffness. CLINICAL TRIAL REGISTRATION Clinicaltrials.gov identifier NCT01310088.

Environmental spread of microbes impacts the development of metabolic phenotypes in mice transplanted with microbial communities from humans.

Microbiota transplantation to germ-free animals is a powerful method to study involvement of gut microbes in the aetiology of metabolic syndrome. Owing to large interpersonal variability in gut microbiota, studies with broad coverage of donors are needed to elucidate the establishment of human-derived microbiotas in mice, factors affecting this process and resulting impact on metabolic health. We thus transplanted faecal microbiotas from humans (16 obese and 16 controls) separately into 64 germ-free Swiss Webster mice caged in pairs within four isolators, with two isolators assigned to each phenotype, thereby allowing us to explore the extent of microbial spread between cages in a well-controlled environment. Despite high group-wise similarity between obese and control human microbiotas, transplanted mice in the four isolators developed distinct gut bacterial composition and activity, body mass gain, and insulin resistance. Spread of microbes between cages within isolators interacted with establishment of the transplanted microbiotas in mice, and contributed to the transmission of metabolic phenotypes. Our findings highlight the impact of donor variability and reveal that inter-individual spread of microbes contributes to the development of metabolic traits. This is of major importance for design of animal studies, and indicates that environmental transfer of microbes between individuals may affect host metabolic traits.