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.     

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.     

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.     

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。     

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.     

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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Behavioral and Psychological Care in Weight Loss Surgery: Best Practice Update

The objective of this study is to update evidence‐based best practice guidelines for psychological evaluation and treatment of weight loss surgery (WLS) patients. We performed a systematic search of English‐language literature on WLS and mental health, quality of life, and behavior modification published between April 2004 and May 2007 in MEDLINE and the Cochrane Library. Key words were used to narrow the search for a selective review of abstracts, retrieval of full articles, and grading of evidence according to systems used in established evidence‐based models. Our literature search identified 17 articles of interest; 13 of the most relevant were reviewed in detail. From these, we developed evidence‐based best practice recommendations on the psychological assessment and treatment of WLS patients. Regular updates of evidence‐based recommendations for best practices in psychological care are required to address the impact of mental health on short‐ and long‐term outcomes after WLS. Key factors in patient safety include comprehensive preoperative evaluation, use of appropriate and reliable evaluation instruments, and the development of short‐ and long‐term treatment plans.     

Moderate-Intensity Rotating Magnetic Fields Do Not Affect Bone Quality and Bone Remodeling in Hindlimb Suspended Rats

Abundant evidence has substantiated the positive effects of pulsed electromagnetic fields (PEMF) and static magnetic fields (SMF) on inhibiting osteopenia and promoting fracture healing. However, the osteogenic potential of rotating magnetic fields (RMF), another common electromagnetic application modality, remains poorly characterized thus far, although numerous commercial RMF treatment devices have been available on the market. Herein the impacts of RMF on osteoporotic bone microarchitecture, bone strength and bone metabolism were systematically investigated in hindlimb-unloaded (HU) rats. Thirty two 3-month-old male Sprague-Dawley rats were randomly assigned to the Control (n = 10), HU (n = 10) and HU with RMF exposure (HU+RMF, n = 12) groups. Rats in the HU+RMF group were subjected to daily 2-hour exposure to moderate-intensity RMF (ranging from 0.60 T to 0.38 T) at 7 Hz for 4 weeks. HU caused significant decreases in body mass and soleus muscle mass of rats, which were not obviously altered by RMF. Three-point bending test showed that the mechanical properties of femurs in HU rats, including maximum load, stiffness, energy absorption and elastic modulus were not markedly affected by RMF. µCT analysis demonstrated that 4-week RMF did not significantly prevent HU-induced deterioration of femoral trabecular and cortical bone microarchitecture. Serum biochemical analysis showed that RMF did not significantly change HU-induced decrease in serum bone formation markers and increase in bone resorption markers. Bone histomorphometric analysis further confirmed that RMF showed no impacts on bone remodeling in HU rats, as evidenced by unchanged mineral apposition rate, bone formation rate, osteoblast numbers and osteoclast numbers in cancellous bone. Together, our findings reveal that RMF do not significantly affect bone microstructure, bone mechanical strength and bone remodeling in HU-induced disuse osteoporotic rats. Our study indicates potentially obvious waveform-dependent effects of electromagnetic fields-stimulated osteogenesis, suggesting that RMF, at least in the present form, might not be an optimal modality for inhibiting disuse osteopenia/osteoporosis.     

Selected ABCB1, ABCB4 and ABCC2 Polymorphisms Do Not Enhance the Risk of Drug-Induced Hepatotoxicity in a Spanish Cohort

Background and Aims

Flawed ABC transporter functions may contribute to increased risk of drug-induced liver injury (DILI). We aimed to analyse the influence of genetic variations in ABC transporters on the risk of DILI development and clinical presentations in a large Spanish DILI cohort.

Methods

A total of ten polymorphisms in ABCB1 (1236T>C, 2677G>T,A, 3435T>C), ABCB4 (1954A>G) and ABCC2 (−1774G>del, −1549A>G, −24C>T, 1249G>A, 3972C>T and 4544G>A) were genotyped using Taqman 5′ allelic discrimination assays or sequencing in 141 Spanish DILI patients and 161 controls. The influence of specific genotypes, alleles and haplotypes on the risk of DILI development and clinical presentations was analysed.

Results

None of the individual polymorphisms or haplotypes was found to be associated with DILI development. Carriers homozygous for the ABCC2 −1774del allele were however only found in DILI patients. Hence, this genotype could potentially be associated with increased risk, though its low frequency in our Spanish cohort prevented a final conclusion. Furthermore, carriers homozygous for the ABCC2 −1774G/−1549A/−24T/1249G/3972T/4544G haplotype were found to have a higher propensity for total bilirubin elevations when developing DILI.

Conclusions

Our findings do not support a role for the analysed polymorphisms in the ABCB1, ABCB4 and ABCC2 transporter genes in DILI development in Spanish patients. The ABCC2 −1774deldel genotype was however restricted to DILI cases and could potentially contribute to enhanced DILI susceptibility.