Melanocortin-4 Receptor Gene Polymorphisms in Obese Patients

Obesity is a complex disease caused by both genetics and environmental factors. Melanocortin-4 receptor (MC4R) (MIM 155541) gene polymorphisms were reported to be the cause of monogenic obesity in humans. We studied three polymorphisms (Val50Met, Val103Ile, and Ser58Cys) and a mutation (Asn274Ser) of the MC4R gene in 203 obese patients and in 110 healthy subjects in the Turkish population. A high incidence of Val103Ile and Val50Met polymorphisms as well as the Asn274Ser mutation was found in the obese patients, whereas no significant correlation was found regarding the Ser58Cys polymorphism. We conclude that there is a concordance between the polymorphisms (Val103Ile, Val50Met, Ser58Cys) that were first studied in the Turkish population with obesity.     

Low 25‐Hydroxyvitamin D Does Not Affect Insulin Sensitivity in Obesity after Bariatric Surgery

Objective: A positive correlation between levels of 25‐hydroxyvitamin D [25(OH)D] and insulin sensitivity has been shown in healthy subjects. We aimed to test the hypothesis that concentration of 25(OH)D influences insulin sensitivity in obesity before and after weight loss. Research Methods and Procedures: We investigated the relation between serum 25(OH)D and insulin sensitivity (estimated by euglycemic‐hyperinsulinemic clamp) in 116 obese women (BMI ≥ 40 kg/m²) evaluated before and 5 and 10 years after biliopancreatic diversion (BPD). Body composition was estimated by the isotope dilution method. Results: Prevalence of hypovitaminosis D was 76% in the obese status and 91% and 89% at 5 and 10 years after BPD, respectively, despite ergocalciferol supplementation. 25(OH)D concentration decreased from 39.2 ± 22.3 in obesity (p = 0.0001) to 27.4 ± 16.4 and 25.1 ± 13.9 nM 5 and 10 years after BPD, respectively. Whole‐body glucose uptake increased from 24.27 ± 4.44 at the baseline to 57.29 ± 11.56 and 57.71 ± 8.41 μmol/kg_{fat free mass} per minute 5 and 10 years after BPD, respectively (p = 0.0001). Predictor of 25(OH)D was fat mass (R² = 0.26, p = 0.0001 in obesity; R² = 0.20, p = 0.02 after BPD). Parathormone correlated with fat mass (R² = 0.19; p = 0.0001) and BMI (R² = 0.053; p = 0.01) and inversely with M value (R² = 0.16; p = 0.0001), but only in obese subjects. Discussion: A high prevalence of hypovitaminosis D was observed in morbid obesity both before and after BPD. Low 25(OH)D did not necessarily imply increased insulin resistance after BPD, a condition where, probably, more powerful determinants of insulin sensitivity overcome the low circulating 25(OH)D levels. However, the present data cannot exclude some kind of influence of vitamin D status on glucose and insulin metabolism.     

Do Psychosocial Variables Predict Weight Loss or Mental Health after Obesity Surgery? A Systematic Review

Objective: The objective of this study was to present a systematic review of psychological and psychosocial predictors of weight loss and mental health after bariatric surgery. This systematic review included all controlled and noncontrolled trials of the last 2 decades with either a retrospective or prospective design and a follow‐up period of at least 1 year. Research Methods and Procedures: The relevant literature was identified by a search of computerized databases. All articles published in English and German between 1980 and 2002 were reviewed. Results: Using the above inclusion/exclusion criteria, 29 articles were identified focusing on psychosocial predictors of weight loss and mental health after obesity surgery. Discussion: Personality traits have no predictive value for the postoperative course of weight or mental state. Apart from serious psychiatric disorders including personality disorders, psychiatric comorbidity seems to be of more predictive value for mental and physical well‐being as two essential aspects of quality of life than for weight loss postsurgery. However, depressive and anxiety symptoms as correlates of psychological stress with regard to obesity seem to be positive predictors of weight loss postsurgery. The severity of the symptoms or the disorder is more relevant for the outcome of obesity surgery than the specificity of the symptoms. It is also not solely the consumption of distinct “forbidden” foods, such as sweets or soft drinks, but rather a general hypercaloric eating behavior, either as an expression of the patient's inadequate compliance or a dysregulation in energy balance, which is associated with a poor weight loss postsurgery.     

Mutations of Phosphorylation Sites in MSL1 Protein Do Not Affect Dosage Compensation in Drosophila melanogaster

Doklady Biochemistry and Biophysics - Proteins MSL1 and MSL2 form the core of the Drosophila dosage compensation complex, which specifically binds to the X chromosome of males. Phosphorylation of...     

Reduction in Incidence of Diabetes,Hypertension and Lipid Disturbances after Intentional Weight Loss Induced by Bariatric Surgery: the SOS Intervention Study

SJÖSTRÖM, c. DAVID, LAUREN LISSNER, HANS WEDEL, and LARS SJÖSTRÖM. Reduction in incidence of diabetes, hypertension and lipid disturbances after intentional weight loss induced by bariatric surgery: the SOS Intervention Study. Obes Res. Objective: To examine the effect of a large, long standing and intentional weight reduction on the incidence of diabetes, hypertension and lipid disturbances in severely obese individuals as compared to weight-stable obese controls. Research Methods and Procedures: The ongoing prospective SOS (Swedish Obese Subjects) intervention consists of a surgically treated group and a matched control group obtaining conventional obesity treatment. This report is based on 845 surgically treated patients and 845 controls (BMI41. 0±4. 6 kg/m² (mean±standard deviation [S])) followed for 2 years. Results: Surgically treated patients lost 28±15 kg and controls 0. 5±8. 9 kg (p<0. 0001). Two-year incidence of hypertension, diabetes, hyperinsulinemia, and lipid disturbances was compared in the two treatment groups. Adjusted odds ratios (95% CI) for the surgically treated group versus controls were 0. 38 (0. 22, 0. 65) for hypertension, 0. 02 (0. 00, 0. 16) for diabetes, 0. 10 (0. 03, 0. 28) for hyperinsulinemia, 0. 10 (0. 04, 0. 25) for hypertriglyceridemia, 0. 28 (0. 16, 0. 49) for low HDL-cholesterol and 1. 24 (0. 84, 1. 8) for hypercholesterolemia. Compared to controls, the 2-year recovery rates from hypertension, diabetes, hypo-HDL, and hypertriglyceridemia were significantly higher in the surgically treated group. Discussion: Intentional weight loss in the obese causes a marked reduction in the 2-year incidence of hypertension, diabetes and some lipid disturbances. The results suggest that severe obesity can and should be treated.     

Genetic Polymorphisms Affect Mouse and Human Trace Amine-Associated Receptor 1 Function

Methamphetamine (MA) and neurotransmitter precursors and metabolites such as tyramine, octopamine, and β-phenethylamine stimulate the G protein-coupled trace amine-associated receptor 1 (TAAR1). TAAR1 has been implicated in human conditions including obesity, schizophrenia, depression, fibromyalgia, migraine, and addiction. Additionally TAAR1 is expressed on lymphocytes and astrocytes involved in inflammation and response to infection. In brain, TAAR1 stimulation reduces synaptic dopamine availability and alters glutamatergic function. TAAR1 is also expressed at low levels in heart, and may regulate cardiovascular tone. Taar1 knockout mice orally self-administer more MA than wild type and are insensitive to its aversive effects. DBA/2J (D2) mice express a non-synonymous single nucleotide polymorphism (SNP) in Taar1 that does not respond to MA, and D2 mice are predisposed to high MA intake, compared to C57BL/6 (B6) mice. Here we demonstrate that endogenous agonists stimulate the recombinant B6 mouse TAAR1, but do not activate the D2 mouse receptor. Progeny of the B6XD2 (BxD) family of recombinant inbred (RI) strains have been used to characterize the genetic etiology of diseases, but contrary to expectations, BXDs derived 30–40 years ago express only the functional B6 Taar1 allele whereas some more recently derived BXD RI strains express the D2 allele. Data indicate that the D2 mutation arose subsequent to derivation of the original RIs. Finally, we demonstrate that SNPs in human TAAR1 alter its function, resulting in expressed, but functional, sub-functional and non-functional receptors. Our findings are important for identifying a predisposition to human diseases, as well as for developing personalized treatment options.     

Weight Loss after Gastric Bypass Surgery in Human Obesity Remodels Promoter Methylation

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Bariatric Surgery in the United Kingdom: A Cohort Study of Weight Loss and Clinical Outcomes in Routine Clinical Care

Background

Bariatric surgery is becoming a more widespread treatment for obesity. Comprehensive evidence of the long-term effects of contemporary surgery on a broad range of clinical outcomes in large populations treated in routine clinical practice is lacking. The objective of this study was to measure the association between bariatric surgery, weight, body mass index, and obesity-related co-morbidities.

Methods and Findings

This was an observational retrospective cohort study using data from the United Kingdom Clinical Practice Research Datalink. All 3,882 patients registered in the database and with bariatric surgery on or before 31 December 2014 were included and matched by propensity score to 3,882 obese patients without surgery. The main outcome measures were change in weight and body mass index over 4 y; incident diagnoses of type 2 diabetes mellitus (T2DM), hypertension, angina, myocardial infarction (MI), stroke, fractures, obstructive sleep apnoea, and cancer; mortality; and resolution of hypertension and T2DM. Weight measures were available for 3,847 patients between 1 and 4 mo, 2,884 patients between 5 and 12 mo, and 2,258 patients between 13 and 48 mo post-procedure. Bariatric surgery patients exhibited rapid weight loss for the first four postoperative months, at a rate of 4.98 kg/mo (95% CI 4.88–5.08). Slower weight loss was sustained to the end of 4 y. Gastric bypass (6.56 kg/mo) and sleeve gastrectomy (6.29 kg/mo) were associated with greater initial weight reduction than gastric banding (2.77 kg/mo). Protective hazard ratios (HRs) were detected for bariatric surgery for incident T2DM, 0.68 (95% CI 0.55–0.83); hypertension, 0.35 (95% CI 0.27–0.45); angina, 0.59 (95% CI 0.40–0.87);MI, 0.28 (95% CI 0.10–0.74); and obstructive sleep apnoea, 0.55 (95% CI 0.40–0.87). Strong associations were found between bariatric surgery and the resolution of T2DM, with a HR of 9.29 (95% CI 6.84–12.62), and between bariatric surgery and the resolution of hypertension, with a HR of 5.64 (95% CI 2.65–11.99). No association was detected between bariatric surgery and fractures, cancer, or stroke. Effect estimates for mortality found no protective association with bariatric surgery overall, with a HR of 0.97 (95% CI 0.66–1.43). The data used were recorded for the management of patients in primary care and may be subject to inaccuracy, which would tend to lead to underestimates of true relative effect sizes.

Conclusions

Bariatric surgery as delivered in the UK healthcare system is associated with dramatic weight loss, sustained at least 4 y after surgery. This weight loss is accompanied by substantial improvements in pre-existing T2DM and hypertension, as well as a reduced risk of incident T2DM, hypertension, angina, MI, and obstructive sleep apnoea. Widening the availability of bariatric surgery could lead to substantial health benefits for many people who are morbidly obese.     

Defect in MAPK Signaling As a Cause for Monogenic Obesity Caused By Inactivating Mutations in the Melanocortin-4 Receptor Gene

The melanocortin-4 receptor (MC4R) is a Family A G protein-coupled receptor that plays an essential role in regulating energy homeostasis, including both energy intake and expenditure. Mutations leading to a reduced MC4R function confer a major gene effect for obesity. More than 170 distinct mutations have been identified in humans. In addition to the conventional Gs-stimulated cAMP pathway, the MC4R also activates MAPKs, especially ERK1/2. We also showed there is biased signaling in the two signaling pathways, with inverse agonists in the Gs-cAMP pathway acting as agonists for the ERK1/2 pathway. In the current study, we sought to determine whether defects in basal or agonist-induced ERK1/2 activation in MC4R mutants might potentially contribute to obesity pathogenesis in patients carrying these mutations. The constitutive and ligand-stimulated ERK1/2 activation were measured in wild type and 73 naturally occurring MC4R mutations. We showed that nineteen mutants had significantly decreased basal pERK1/2 level, and five Class V variants (where no functional defects have been identified previously), C40R, V50M, T112M, A154D and S295P, had impaired ligand-stimulated ERK1/2 activation. Our studies demonstrated for the first time that decreased basal or ligand-stimulated ERK1/2 signaling might contribute to obesity pathogenesis caused by mutations in the MC4R gene. We also observed biased signaling in 25 naturally occurring mutations in the Gs-cAMP and ERK1/2 pathways.     

Separation-of-Function Mutations in Saccharomyces cerevisiae MSH2 That Confer Mismatch Repair Defects but Do Not Affect Nonhomologous-Tail Removal during Recombination

Yeast Msh2p forms complexes with Msh3p and Msh6p to repair DNA mispairs that arise during DNA replication. In addition to their role in mismatch repair (MMR), the MSH2 and MSH3 gene products are required to remove 3' nonhomologous DNA tails during genetic recombination. The mismatch repair genes MSH6, MLH1, and PMS1, whose products interact with Msh2p, are not required in this process. We have identified mutations in MSH2 that do not disrupt genetic recombination but confer a strong defect in mismatch repair. Twenty-four msh2 mutations that conferred a dominant negative phenotype for mismatch repair were isolated. A subset of these mutations mapped to residues in Msh2p that were analogous to mutations identified in human nonpolyposis colorectal cancer msh2 kindreds. Approximately half of the these MMR-defective mutations retained wild-type or nearly wild-type activity for the removal of nonhomologous DNA tails during genetic recombination. The identification of mutations in MSH2 that disrupt mismatch repair without affecting recombination provides a first step in dissecting the Msh-effector protein complexes that are thought to play different roles during DNA repair and genetic recombination.     

参考家系鸡黑素皮质素受体3基因多态性与体重关系研究

鼠遗传学研究显示黑素皮质素受体3（melanocortin-3 receptor,MC3R）和MC4R在能量平衡控制中具有互补作用。敲除MC3R基因鼠表现为独有的代谢综合征和增加脂肪重量。以8周龄高体重或低体重独立选择的高体重系（high weight,HW）和低体重系（low weight,LW）白洛克鸡3代参考家系群体作为实验材料,发现了5个新的MC3R基因单核苷酸多态性（single nucleotide polymorphisms,SNPs）;建立了基于限制性内切酶Dde I的MC3R基因型的PCR-RFLP分子检测方法。方差分析结果显示MC3R基因型显著影响公鸡和母鸡的体重,以及公鸡腹脂含量。该结果建议MC3R基因可以作为侯选基因解释杂交鸡体重显著差异的原因。     

Personality as a Predictor of Weight Loss Maintenance after Surgery for Morbid Obesity

Objective: Personality characteristics are assumed to underlie health behaviors and, thus, a variety of health outcomes. Our aim was to examine prospectively whether personality traits predict short‐ and long‐term weight loss after laparoscopic adjustable gastric banding. Research Methods and Procedures: Of patients undergoing laparoscopic adjustable gastric banding, 168 (143 women, 25 men, 18 to 58 years old, mean 37 years, preoperative BMI 45.9 ± 5.6 kg/m²) completed the Dutch Personality Questionnaire on average 1.5 years before the operation. The relationship between preoperative personality and short‐ and long‐term postoperative weight loss was determined using multilevel regression analysis. Results: The average weight loss of patients progressively increased to 10 BMI points until 18 months after surgery and stabilized thereafter. A lower baseline BMI, being a man, and a higher educational level were associated with a lower weight loss. None of the personality variables was associated with weight outcome at short‐term follow‐up. Six of seven personality variables did not predict long‐term weight outcome. Egoism was associated with less weight loss in the long‐term postoperative period. The effect sizes of the significant predictions were small. Discussion: None of the personality variables predicted short‐term weight outcome, and only one variable showed a small and unexpected association with long‐term weight outcome that needs confirmation. This suggests that personality assessment as intake psychological screening is of little use for the prediction of a poor or successful weight outcome after bariatric surgery.     

Involvement of the Melanocortin-1 Receptor in Acute Pain and Pain of Inflammatory but Not Neuropathic Origin

Background

Response to painful stimuli is susceptible to genetic variation. Numerous loci have been identified which contribute to this variation, one of which, MC1R, is better known as a gene involved in mammalian hair colour. MC1R is a G protein-coupled receptor expressed in melanocytes and elsewhere and mice lacking MC1R have yellow hair, whilst humans with variant MC1R protein have red hair. Previous work has found differences in acute pain perception, and response to analgesia in mice and humans with mutations or variants in MC1R.

Methodology and Principal Findings

We have tested responses to noxious and non-noxious stimuli in mutant mice which lack MC1R, or which overexpress an endogenous antagonist of the receptor, as well as controls. We have also examined the response of these mice to inflammatory pain, assessing the hyperalgesia and allodynia associated with persistent inflammation, and their response to neuropathic pain. Finally we tested by a paired preference paradigm their aversion to oral administration of capsaicin, which activates the noxious heat receptor TRPV1. Female mice lacking MC1R showed increased tolerance to noxious heat and no alteration in their response to non-noxious mechanical stimuli. MC1R mutant females, and females overexpressing the endogenous MC1R antagonist, agouti signalling protein, had a reduced formalin-induced inflammatory pain response, and a delayed development of inflammation-induced hyperalgesia and allodynia. In addition they had a decreased aversion to capsaicin at moderate concentrations. Male mutant mice showed no difference from their respective controls. Mice of either sex did not show any effect of mutant genotype on neuropathic pain.

Conclusions

We demonstrate a sex-specific role for MC1R in acute noxious thermal responses and pain of inflammatory origin.     

Phenylacetic and Phenylpropionic Acids Do Not Affect Xylan Degradation by Ruminococcus albus

Since the addition of either ruminal fluid or a combination of phenylacetic and phenylpropionic acids (PAA/PPA) has previously been shown to dramatically improve cellulose degradation and growth of Ruminococcus albus, it was of interest to determine the effects of these additives on xylan-grown cultures. Although cell-bound xylanase activity increased when either PAA/PPA or ruminal fluid was added to the growth medium, total xylanase did not change, and neither of these supplements affected the growth or xylan-degrading capacity of R. albus 8. Similarly, neither PAA/PPA nor ruminal fluid affected xylan degradation by multiple strains of R. albus when xylan prepared from oat spelts was used as a carbohydrate source. These results show that the xylanolytic potential of R. albus is not conditional on the availability of PAA/PPA or other components of ruminal fluid.     

Lipophosphoglycans from Leishmania amazonensis Strains Display Immunomodulatory Properties via TLR4 and Do Not Affect Sand Fly Infection

The immunomodulatory properties of lipophosphoglycans (LPG) from New World species of Leishmania have been assessed in Leishmania infantum and Leishmania braziliensis, the causative agents of visceral and cutaneous leishmaniasis, respectively. This glycoconjugate is highly polymorphic among species with variation in sugars that branch off the conserved Gal(β1,4)Man(α1)-PO₄ backbone of repeat units. Here, the immunomodulatory activity of LPGs from Leishmania amazonensis, the causative agent of diffuse cutaneous leishmaniasis, was evaluated in two strains from Brazil. One strain (PH8) was originally isolated from the sand fly and the other (Josefa) was isolated from a human case. The ability of purified LPGs from both strains was investigated during in vitro interaction with peritoneal murine macrophages and CHO cells and in vivo infection with Lutzomyia migonei. In peritoneal murine macrophages, the LPGs from both strains activated TLR4. Both LPGs equally activate MAPKs and the NF-κB inhibitor p-IκBα, but were not able to translocate NF-κB. In vivo experiments with sand flies showed that both stains were able to sustain infection in L. migonei. A preliminary biochemical analysis indicates intraspecies variation in the LPG sugar moieties. However, they did not result in different activation profiles of the innate immune system. Also those polymorphisms did not affect infectivity to the sand fly.     

Effectiveness of a Prebariatric Surgery Insurance‐required Weight Loss Regimen and Relation to Postsurgical Weight Loss

Most US insurance companies require patients to participate in a medically supervised weight loss regimen prior to bariatric surgery. However, the utility of this requirement has not been documented. Data was collected from 94 bariatric surgery patients who were required, and 59 patients who were not required, by their insurance company to participate in a presurgical weight loss regimen. Weight change in the required group, as well as group differences in weight change, was examined from 3 and 6 months presurgery to 1 week presurgery, and from 1 week presurgery to 3 months postsurgery. Weight change presurgery was then used to predict weight loss postsurgery. In the 6 months prior to surgery, required patients gained 3.7 kg ± 5.9 (s.d.) (P < 0.0005), which did not differ from nonrequired patients. From surgery to 3 months postsurgery, required patients lost 23.6 ± 8 kg (P < 0.0005), also without differing from nonrequired patients. Patients who gained more weight prior to surgery, lost more weight postsurgery (P = 0.001), while controlling for initial weight. Findings suggest that the common weight loss regimen requirements of US insurance carriers were ineffective in producing presurgical weight loss in this sample. Most patients (>70%) in this sample gained weight prior to surgery, potentially taking advantage of final opportunities to overindulge in preferred foods. Required patients fared no better in terms of weight change postsurgically and, surprisingly, presurgical weight gain predicted better postsurgical weight loss outcome. Several potential explanations for this finding are offered.     

Caloric Restriction and Diet-Induced Weight Loss Do Not Induce Browning of Human Subcutaneous White Adipose Tissue in Women and Men with Obesity

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Weight Loss Increases Soluble Leptin Receptor Levels and the Soluble Receptor Bound Fraction of Leptin

Objective: Soluble leptin receptor (sOB‐R) represents the main binding site for leptin in human blood. The aim of this study was to investigate the relationship between leptin and soluble leptin receptor and the bound/free ratio after pronounced weight reduction. Research Methods and Procedures: A total of 18 morbidly obese women participated in this prospective study. Subjects were examined for fat mass, leptin, and sOB‐R concentrations before and 1 year after Swedish adjustable gastric banding. Results: Anthropomorphic measures displayed a significant reduction of body mass index [(42.9 ± 5.6 to 32.9 ± 6.0 kg/m² (mean ± SD)]. Fat mass decreased from 56.3 ± 9.0 to 33.9 ± 12.5 kg. Plasma leptin concentration decreased from 44.6 ± 18.0 to 20.0 ± 13.1 ng/mL (p < 0.001), whereas the sOB‐R levels increased from 11.1 ± 3.6 to 16.6 ± 6.0 U/mL after weight‐reducing surgery. Thus, the sOB‐R bound fraction of leptin increased from 7% to 33%. Discussion: This work demonstrates a relationship between weight loss, leptin, and sOB‐R concentrations in vivo. During weight loss, leptin levels decreased, whereas sOB‐R levels and the receptor bound fraction of leptin increased. Thus, sOB‐R may negatively regulate free leptin.