To determine the prevalence of Melanocortin-4 Receptor (MC4R) mutations in a cohort of children and adolescents with overweight or obesity and to determine whether treatment responses differed ...between carriers and noncarriers.
Using target region capture sequencing, an MC4R mutation screen was performed in 1261 Danish children and adolescents enrolled at a tertiary multidisciplinary childhood obesity treatment center. Measurements of anthropometrics, blood pressure, fasting blood biochemistry including lipid and hormone levels, and dual-energy X-ray absorptiometry were performed at baseline and throughout treatment.
Of 1209 children and adolescents that met all criteria to be included in the described analyses, 30 (2.5%) carried damaging or unresolved MC4R mutations. At baseline, mutation carriers exhibited higher concentrations of plasma thyroid-stimulating hormone (p = 0.003), and lower concentrations of plasma thyroxine (p = 0.010) compared to noncarriers. After a median of 1 year of treatment (range 0.5-4.0 years), body mass index (BMI) standard deviation score (SDS) was reduced in noncarriers but not in carriers, and this difference in treatment response was statistically significant (p = 0.005). Furthermore, HDL cholesterol was reduced in carriers, a response significantly different from that of noncarriers (p = 0.017).
Among Danish children and adolescents with overweight or obesity entering a tertiary lifestyle intervention, 2.5% carried damaging or unresolved MC4R mutations. In contrast to noncarriers, carriers of damaging or unresolved MC4R mutations failed to reduce their BMI SDS during obesity treatment, indicating a need for personalized treatment based on the MC4R genotype.
Background Weight loss after bariatric surgery varies widely between individuals, partly due to genetic differences. In addition, genetic determinants of abdominal obesity have been shown to ...attenuate weight loss after dietary intervention with special attention paid to the rs1358980-T risk allele in the VEGFA locus. Here we aimed to test if updated genetic risk scores (GRSs) for adiposity measures and the rs1358980-T risk allele are linked with weight loss following gastric bypass surgery. Methods Five hundred seventy six patients with morbid obesity underwent Roux-en-Y gastric bypass. A GRS for BMI and a GRS for waist-hip-ratio adjusted for BMI (proxy for abdominal obesity), respectively, were constructed. All patients were genotyped for the rs1358980-T risk allele. Associations between the genetic determinants and weight loss after bariatric surgery were evaluated. Results The GRS for BMI was not associated with weight loss (beta = -2.0 kg/100 risk alleles, 95% CI -7.5 to 3.3, p = 0.45). Even though the GRS for abdominal obesity was associated with an attenuated weight loss response adjusted for age, sex and center (beta = -14.6 kg/100 risk alleles, 95% CI -25.4 to -3.8, p = 0.008), it was not significantly associated with weight loss after adjustment for baseline BMI (beta = -7.9 kg/100 risk alleles, 95% CI -17.5 to 1.6, p = 0.11). Similarly, the rs1358980-T risk allele was not significantly associated with weight loss (beta = -0.8 kg/risk allele, 95% CI -2.2 to 0.6, p = 0.25). Discussion GRSs for adiposity derived from large meta-analyses and the rs1358980-T risk allele in the VEGFA locus did not predict weight loss after gastric bypass surgery. The association between a GRS for abdominal obesity and the response to bariatric surgery may be dependent on the association between the GRS and baseline BMI.
Hypothyroidism is associated with obesity, and thyroid hormones are involved in the regulation of body composition, including fat mass. Genome-wide association studies (GWAS) in adults have ...identified 19 and 6 loci associated with plasma concentrations of thyroid stimulating hormone (TSH) and free thyroxine (fT4), respectively.
This study aimed to identify and characterize genetic variants associated with circulating TSH and fT4 in Danish children and adolescents and to examine whether these variants associate with obesity.
Genome-wide association analyses of imputed genotype data with fasting plasma concentrations of TSH and fT4 from a population-based sample of Danish children, adolescents, and young adults, and a group of children, adolescents, and young adults with overweight and obesity were performed (N = 1,764, mean age = 12.0 years range 2.5-24.7). Replication was performed in additional comparable samples (N = 2,097, mean age = 11.8 years 1.2-22.8). Meta-analyses, using linear additive fixed-effect models, were performed on the results of the discovery and replication analyses.
No novel loci associated with TSH or fT4 were identified. Four loci previously associated with TSH in adults were confirmed in this study population (PDE10A (rs2983511: β = 0.112SD, p = 4.8 ∙ 10-16), FOXE1 (rs7847663: β = 0.223SD, p = 1.5 ∙ 10-20), NR3C2 (rs9968300: β = 0.194SD), p = 2.4 ∙ 10-11), VEGFA (rs2396083: β = 0.088SD, p = 2.2 ∙ 10-10)). Effect sizes of variants known to associate with TSH or fT4 in adults showed a similar direction of effect in our cohort of children and adolescents, 11 of which were associated with TSH or fT4 in our study (p<0.0002). None of the TSH or fT4 associated SNPs were associated with obesity in our cohort, indicating no pleiotropic effects of these variants on obesity.
In a group of Danish children and adolescents, four loci previously associated with plasma TSH concentrations in adults, were associated with plasma TSH concentrations in children, suggesting comparable genetic determinants of thyroid function in adults and children.
. The strongest locus which associated with type 2 diabetes (T2D) by the common variant rs7903146 is the transcription factor 7-like 2 gene (
). We aimed to quantify the interaction of diet/lifestyle ...interventions and the genetic effect of
rs7903146 on glycemic traits, body weight, or waist circumference in overweight or obese adults in several randomized controlled trials (RCTs).
. From October 2016 to May 2018, a large collaborative analysis was performed by pooling individual-participant data from 7 RCTs. These RCTs reported changes in glycemic control and adiposity of the variant rs7903146 after dietary/lifestyle-related interventions in overweight or obese adults. Gene treatment interaction models which used the genetic effect encoded by the allele dose and common covariates were applicable to individual participant data in all studies.
. In the joint analysis, a total of 7 eligible RCTs were included (
). Importantly, we observed a significant effect modification of diet/lifestyle-related interventions on the
variant rs7903146 and changes in fasting glucose. Compared with the control group, diet/lifestyle interventions were related to lower fasting glucose by -3.06 (95% CI, -5.77 to -0.36) mg/dL (test for heterogeneity and overall effect:
,
;
,
) per one copy of the
T risk allele. Furthermore, regardless of genetic risk, diet/lifestyle interventions were associated with lower waist circumference. However, there was no significant change for diet/lifestyle interventions in other glycemic control and adiposity traits per one copy of
risk allele.
. Our findings suggest that carrying the
T risk allele may have a modestly greater benefit for specific diet/lifestyle interventions to improve the control of fasting glucose in overweight or obese adults.
Metabolic health in obesity is known to differ among individuals, and the distribution of visceral (VAT) and subcutaneous adipose tissue (SAT) plays an important role in this regard. Adipose tissue ...expansion is dependent on new blood vessel formation in order to prevent hypoxia and inflammation in the tissue. Regulation of angiogenesis in SAT and VAT in response to diet is therefore crucial for the metabolic outcome in obesity.
Knowledge about the underlying genetic mechanisms determining metabolic health in obesity is very limited.
We aimed to review the literature of the inhibitor of differentiation-3 (ID3) gene in relation to adipose tissue and angiogenesis in humans in order to determine whether ID3 could be involved in the regulation of adipose tissue expansion and metabolic health in human obesity.
We find evidence that ID3 is involved in regulatory mechanisms in adipose tissue and regulates angiogenesis in many tissues including adipose tissue. We discuss how this might influence obesity and metabolic health in obesity and further discuss some potential mechanisms by which ID3 might regulate visceral and subcutaneous adipose tissue expansion.
The combined results from the reviewed literature suggest ID3 to play a potential role in the underlying regulatory mechanisms of metabolic health in human obesity. The literature is still sparse and further studies focusing on human ID3 in relation to the nature of obesity are warranted.
•Angiogenesis is closely linked to adipogenesis and adipose tissue expansion.•Angiogenesis might be involved in the metabolic outcome in obesity.•ID3 regulates transcription of many genes and is involved in angiogenesis.•We review the literature of ID3 in relation to angiogenesis and adipogenesis.•ID3 plays a potential role in the regulation of metabolic health in human obesity.
The once-weekly administered glucagon-like peptide 1 (GLP-1) receptor agonist (GLP-1RA) semaglutide, has, in clinical trials, demonstrated significant reductions in glycated haemoglobin A
(HbA
) and ...body weight in persons with type 2 diabetes. We evaluated the real-world clinical effects of semaglutide once weekly in a hospital-based diabetes out-patient clinic.
This retrospective observational cohort study included persons with type 2 diabetes (n = 119) on a broad range of antidiabetic medicine: GLP-1RA naïve persons (n = 37) and GLP-1RA-experienced persons (n = 82). Person characteristics at inclusion: age median (quartiles): 65 (57, 72) years; body weight 99 (86, 118) kg; body mass index (BMI) 33 (29, 38) kg/m²; HbA
61 (54, 69) mmol/mol/(7.7 (7.1, 8.5) %). Data were collected at baseline and after 3, 6 and 12 months of semaglutide treatment. Data were analysed using a general linear mixed model for repeated measurements.
After 12 months, the reductions in HbA
were (mean 95% confidence interval: GLP-1RA naïve: -12.8 -17.0, -8.5 mmol/mol/ -1.2 -1.6, -0.8% (p < 0.01) and GLP-1RA experienced: -6.4 -9.0, -3.8 mmol/mol/ -0.6 -0.8, -0.4% (p < 0.01), respectively. Body weight reductions in GLP-1RA naïve: -5 -6.9, -3.1 kg (p < 0.01) and GLP-1RA experienced: -3.2 -4.4, -2.0 kg (p < 0.01), respectively. Seventy-five percent received 1 mg QW semaglutide.
We observed effects of semaglutide once weekly on HbA
and body weight comparable with the effects observed in clinical studies with fewer persons in our cohort receiving maximum dose of semaglutide.
To assess the effect of the FTO genotype on weight loss after dietary, physical activity, or drug based interventions in randomised controlled trials.
Systematic review and random effects ...meta-analysis of individual participant data from randomised controlled trials.
Ovid Medline, Scopus, Embase, and Cochrane from inception to November 2015.
Randomised controlled trials in overweight or obese adults reporting reduction in body mass index, body weight, or waist circumference by FTO genotype (rs9939609 or a proxy) after dietary, physical activity, or drug based interventions. Gene by treatment interaction models were fitted to individual participant data from all studies included in this review, using allele dose coding for genetic effects and a common set of covariates. Study level interactions were combined using random effect models. Metaregression and subgroup analysis were used to assess sources of study heterogeneity.
We identified eight eligible randomised controlled trials for the systematic review and meta-analysis (n=9563). Overall, differential changes in body mass index, body weight, and waist circumference in response to weight loss intervention were not significantly different between FTO genotypes. Sensitivity analyses indicated that differential changes in body mass index, body weight, and waist circumference by FTO genotype did not differ by intervention type, intervention length, ethnicity, sample size, sex, and baseline body mass index and age category.
We have observed that carriage of the FTO minor allele was not associated with differential change in adiposity after weight loss interventions. These findings show that individuals carrying the minor allele respond equally well to dietary, physical activity, or drug based weight loss interventions and thus genetic predisposition to obesity associated with the FTO minor allele can be at least partly counteracted through such interventions.
PROSPERO CRD42015015969.
Circulating branched-chain amino acids (BCAAs) and aromatic amino acids (AAAs) have been shown to be associated with insulin resistance and diabetes risk. The common rs1440581 T allele in the protein ...phosphatase Mg2+/Mn2+ dependent 1K (PPM1K) gene has been related to elevated BCAA concentrations and risk of type 2 diabetes.
In the present study, we tested whether dietary fat and carbohydrate intakes influenced the association between the rs1440581 PPM1K genetic variant and glucose-metabolism traits during weight loss.
The rs1440581 PPM1K genetic variant was genotyped in a total of 757 nondiabetic individuals who were randomly assigned to 1 of 2 energy-restricted diets that differed in macronutrient composition (low-fat diet: 20–25% fat, 15% protein, and 60–65% carbohydrate; high-fat diet: 40–45% fat, 15% protein, and 40–45% carbohydrate). The changes in fasting glucose, fasting insulin, insulin resistance (homeostasis model assessment of insulin resistance) and homeostasis model assessment of β cell function (HOMA-B) were measured after a mean ± SD weight loss of 6.8 ± 3.4 kg over 10 wk and analyzed according to the presence of the T allele of rs1440581.
The rs1440581 T allele was associated with a smaller improvement in glucose concentrations after the 10-wk dietary intervention (β ± SE: 0.05 ± 0.02 mg/dL; P = 0.03). In addition, significant gene-diet interactions were shown for the rs1440581 PPM1K genetic variant in relation to changes in insulin and HOMA-B (P-interaction = 0.006 and 0.002, respectively). In response to the high-fat diet, the T allele was associated with a higher reduction of insulin (β ± SE: −0.77 ± 0.40 μU/mL; P = 0.04) and HOMA-B (β ± SE: −13.2 ± 3.81; P = 0.003). An opposite effect was observed in the low-fat diet group, although in this group the T allele was marginally (P = 0.10) and not significantly (P = 0.24) associated with insulin and HOMA-B, respectively.
PPM1K rs1440581 may affect changes in glucose metabolism during weight loss, and this effect is dependent on dietary fat and carbohydrate intakes. This trial was registered at controlled-trials.com as ISRCTN25867281.
Background
The weight loss after bariatric surgery shows considerable individual variation. Twin studies of response to dietary interventions and studies of bariatric surgery patients suggest that ...genetic differences may play a role. This study aimed to examine the effect of three genetic risk scores on the inter-individual variation in excess body mass index loss (EBMIL) after Roux-en-Y gastric bypass. Furthermore, we searched among known adiposity-related single nucleotide polymorphisms (SNPs) for genetic determinants of the inter-individual variation in EBMIL.
Methods
Patients with morbid obesity underwent Roux-en-Y gastric bypass and were genotyped (
n
= 577). Two genetic risk scores for weight loss after bariatric surgery and a genetic risk score for body mass index were calculated. Associations between the genetic risk scores and EBMIL were evaluated. Lasso regression was performed on 126 SNPs known to be associated with adiposity.
Results
The average EBMIL was 76.9% (range 21.7–149.2%). EBMIL was 81.1% (SD 20.6) and 73.9% (SD 21.7) in the high and low tertile groups of a genetic risk score for weight loss. Patients with a low genetic risk score for body mass index (in the lowest 5% percentile) had an EBMIL of 68.8% (SD 20.6,
p
= 0.018). Thirteen adiposity-related SNPs were identified to associate with EBMIL through lasso regression.
Discussion
A genetic risk score was associated with EBMIL after bariatric surgery, but may not yet be applicable to clinical practice. Patients genetically predisposed to low body mass index had lower weight loss after bariatric surgery.
Body fat distribution is a marker of metabolic health independent of body size. Visceral fat accumulation has been suggested to result from a decreased expandability of the subcutaneous fat depots. ...Furthermore, the visceral fat may be easier to mobilize than the peripheral fat. We examined whether differences in abdominal obesity at baseline influenced prospective body-weight changes.
In this study we examined whether body-fat distribution at baseline was associated with long-term and short-term weight changes.
We included 3 observational studies (ntotal = 7271) with mean follow-up times of 5–9 y and two 8–10-wk weight loss intervention studies (ntotal = 1091). We examined the association between baseline waist circumference and weight changes in a substitution regression model, where body weight, height, and fat-free mass were fixed so that a difference in waist circumference would reflect a difference in body fat distribution alone. The results were summarized in meta-analyses.
In the observational studies, we found no associations between baseline waist circumference and subsequent weight change in men (β: 0.03 kg; 95% CI: −0.01, 0.08 kg; P = 0.19), but a negligible inverse association in women (β: −0.05 kg; 95% CI: −0.08, −0.01 kg; P = 0.01). There was no association between baseline waist circumference and weight loss in the intervention studies (men: β: −0.05 kg; 95% CI: −0.13, 0.03 kg; P = 0.25; women: β: −0.00 kg; 95% CI: −0.03, 0.03 kg; P = 0.84). However, in all studies, the SDs of the weight change residuals were greater, the greater the waist circumference at baseline. This trend was statistically significant in women in most studies as well as in men in 1 of the studies.
With narrow CIs in 3 observational studies and 2 weight loss interventions, we did not find any clinically or epidemiologically relevant association between baseline abdominal obesity and weight change. However, the present study suggests that a greater baseline abdominal obesity is a marker for greater weight fluctuations.
The CCHS trial was registered at www.clinicaltrials.gov as NCT02993172. The Health2006 trial was registered at www.clinicaltrials.gov as NCT00316667. The ORG study was conducted before trial registration was required. The NUGENOB trial was registered at www.isrctn.com as ISRCTN25867281. The DiOGenes trial was registered atwww.clinicaltrials.gov as NCT00390637.
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