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Objective: Single nucleotide polymorphisms (SNPs) in intron 1 of fat mass- and obesity-associated gene (FTO) are strongly associated with human adiposity, whereas Fto(-/-) mice are lean and Fto(+/-) mice are resistant to diet-induced obesity. We aimed to determine whether FTO mutations are disproportionately represented in lean or obese humans and to use these mutations to understand structure-function relationships within FTO.Research Design and Methods: We sequenced all coding exons of FTO in 1,433 severely obese and 1,433 lean individuals. We studied the enzymatic activity of selected nonsynonymous variants.Results: We identified 33 heterozygous nonsynonymous variants in lean (2.3%) and 35 in obese (2.4%) individuals, with 8 mutations unique to the obese and 11 unique to the lean. Two novel mutations replace absolutely conserved residues: R322Q in the catalytic domain and R96H in the predicted substrate recognition lid. R322Q was unable to catalyze the conversion of 2-oxoglutarate to succinate in the presence or absence of 3-methylthymidine. R96H retained some basal activity, which was not enhanced by 3-methylthymidine. However, both were found in lean and obese individuals.Conclusions: Heterozygous, loss-of-function mutations in FTO exist but are found in both lean and obese subjects. Although intron 1 SNPs are unequivocally associated with obesity in multiple populations and murine studies strongly suggest that FTO has a role in energy balance, it appears that loss of one functional copy of FTO in humans is compatible with being either lean or obese. Functional analyses of FTO mutations have given novel insights into structure-function relationships in this enzyme. [ABSTRACT FROM AUTHOR]

Abstract Background The Krüppel-like factor (KLF) family consists of transcription factors that can activate or repress different genes implicated in processes such as differentiation, development, and cell cycle progression. Moreover, several of these proteins have been implicated in glucose homeostasis, making them candidate genes for involvement in type 2 diabetes (T2D). Methods Variants of nine KLF genes were genotyped in T2D cases and controls and analysed in a two-stage study. The first case-control set included 365 T2D patients with a strong family history of T2D and 363 normoglycemic individuals and the second set, 750 T2D patients and 741 normoglycemic individuals, all of French origin. The SNPs of six KLF genes were genotyped by Taqman® SNP Genotyping Assays. The other three KLF genes (KLF2, -15 and -16) were screened and the identified frequent variants of these genes were analysed in the case-control studies. Results Three of the 28 SNPs showed a trend to be associated with T2D in our first case-control set (P < 0.10). These SNPs, located in the KLF2, KLF4 and KLF5 gene were then analysed in our second replication set, but analysis of this set and the combined analysis of the three variants in all 2,219 individuals did not show an association with T2D in this French population. As the KLF2, -15 and -16 variants were representative for the genetic variability in these genes, we conclude they do not contribute to genetic susceptibility for T2D. Conclusion It is unlikely that variants in different members of the KLF gene family play a major role in T2D in the French population.

Milk and dairy products are known to have a significant role in human development and tissue maintenance due to their high nutritional value. With the higher incidence of obesity and metabolic diseases, nutrition and public health authorities have recommended the intake of fat-free or low-fat dairy due to the saturated fatty acid content of whole-fat products and their effect on serum cholesterol levels. However, recent studies have questioned the association between milk fat consumption and cardiometabolic risk. This literature review aims to compile the scientific evidence of the metabolic effects of milk fatty acids in clinical and basic research studies, as well as their relationship with metabolic disorders and gut microbiota composition. Research shows that various milk fatty acids exert effects on metabolic alterations (obesity, type 2 diabetes and cardiovascular diseases) by modifying glucose homeostasis, inflammation and lipid profile-related factors. Additionally, recent studies have associated the consumption of milk fatty acids with the production of metabolites and the promotion of healthy gut microbiota. From mainly observational studies, evidence suggests that milk and dairy fatty acids are not directly linked to cardiometabolic risk, but further controlled research is necessary to clarify such findings and to assess whether dietary recommendations to choose low-fat dairy foods are necessary for the population for the prevention of obesity and cardiometabolic disease., (© 2024 British Nutrition Foundation.)

The transcription factor E-twenty-six variant 5 (ETV5) regulates acute insulin secretion. Adequate insulin secretion is dependent on pancreatic β-cell size and cell proliferation, but the effects of ETV5 on proliferation, cell number, and viability, as well as its relationship with insulin secretion, have not been established yet. Here, we partially silenced ETV5 in the INS-1 (832/13) cell line by siRNA transfection and then measured secreted insulin concentration at different time points, observing similar levels to control cells. After 72 h of ETV5 silencing, we observed decreased cell number and proliferation, without any change in viability or apoptosis. Thus, partial silencing of ETV5 modulates cell proliferation in INS-1 (832/13) independently of secreted insulin levels via upregulation of E2F1 and of inhibitors of the cyclin/CDKs complexes (p21 Cdkn1a , p27 Cdkn1b , and p57 Cdkn1c ) and downregulation of cell cycle activators (PAK3 and FOS)., (© 2023 The Authors. FEBS Open Bio published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)

Background: Obesity is defined as abnormal or excessive fat accumulation, provoking many different diseases, such as obesity and type 2 diabetes. Type 2 diabetes is a chronic-degenerative disease characterized by increased blood glucose levels. Obesity and type 2 diabetes are currently considered public health problems, and their prevalence has increased over the last few years. Because of the high cost involved in the treatment of both diseases, different alternatives have been sought. However, the general population uses medicinal plants, in the form of tea or infusions, to treat different diseases. Therefore, traditional medicine using medicinal plants has been investigated as a possible treatment for type 2 diabetes and body weight control., Aim of the Study: The purpose of this review is to find medicinal plants used in Mexico that could exert their beneficial effect by regulating insulin secretion and body weight control., Material and Method: For the development of this review, Mexican plants used in traditional medicine to treat type 2 diabetes and body weight control were searched in PubMed, Google Scholar, and Scopus. The inclusion criteria include plants that presented a significant reduction in blood glucose levels and/or an increase in insulin secretion., Results: We found 306 Mexican plants with hypoglycemic effects. However, plants that did not show evidence of an increase in insulin secretion were eliminated. Finally, only five plants were included in this review: Momordica charantia L. ( melón amargo ), Cucurbita ficifolia bouché ( chilacayote ), Coriandrum sativum L. ( cilantro ), Persea americana Mill. ( aguacate ) Bidens pilosa ( amor seco ), including 39 articles in total. Here, we summarized the plant extracts (aqueous and organic) that have previously been reported to present hypoglycemic effects, body weight control, increased secretion and sensitivity of insulin, improvement of pancreatic β cells, and glucose tolerance. Additionally, these effects may be due to different bioactive compounds present in the plants' extracts., Conclusion: Both in vivo and in vitro studies are required to understand the mechanism of action of these plant extracts regarding insulin secretion to be used as a possible treatment for type 2 diabetes and body weight control in the future.

Background: Metabolic disorders such as obesity and type 2 diabetes (T2D) coincide with an increased expression of pro-inflammatory factors. The NLRP3 inflammasome is a complex that activates the pro-inflammatory cytokine IL-1β. (NOD-like receptor protein 3). Some nutrients, such as fatty acids, influence inflammatory processes. For example, in clinical studies, higher trans-palmitoyl acid (TP) concentrations coincide with lower adiposity and lower risk of developing T2D. This study aims to evaluate the effect of TP on NLRP3 expression in a rodent model of diet-induced obesity (DIO)., Methods: C57BL/6J mice were fed ad libitum with a control or a high-fat diet (HFD), added with or without TP (3 g/kg diet), for 11 weeks. IL-1β was quantified in serum, and NLRP3-related gene expression was explored in epididymal adipose tissue., Results: Despite increased weight gain in both high-fat groups, the high-fat TP group gained less weight than the high-fat group. In addition, NLRP3 and caspase-1 expression was higher in the HFD groups, but no differences were observed between the HFD and the HFD TP groups. Serum IL-1β levels were not different among groups., Conclusions: Diet supplementation with TP prevents weight gain and has a neutral influence over NLRP3 expression and IL-1β concentration in a DIO mice model., (Copyright: © 2023 Permanyer.)

The loss of function melanocortin 4-receptor ( MC4R ) Ile269Asn mutation has been proposed as one of the most important genetic contributors to obesity in the Mexican population. However, whether patients bearing this mutation respond differently to weight loss treatments is unknown. We tested the association of this mutation with obesity in 1683 Mexican adults, and compared the response of mutation carriers and non-carriers to three different weight loss interventions: dietary restriction intervention, phentermine 30 mg/day treatment, and Roux-en-Y gastric bypass (RYGB) surgery. The Ile269Asn mutation was associated with obesity [OR = 3.8, 95% CI (1.5-9.7), p = 0.005]. Regarding interventions, in the dietary restriction group only two patients were MC4R Ile269Asn mutation carriers. After 1 month of treatment, both mutation carriers lost weight: -4.0 kg (-2.9%) in patient 1, and -1.8 kg (-1.5%) in patient 2; similar to the mean weight loss observed in six non-carrier subjects (-2.9 kg; -2.8%). Phentermine treatment produced similar weight loss in six carriers (-12.7 kg; 15.5%) and 18 non-carriers (-11.3 kg; 13.6%) after 6 months of pharmacological treatment. RYGB also caused similar weight loss in seven carriers (29.9%) and 24 non-carriers (27.8%), 6 months after surgery. Our findings suggest that while the presence of a single MC4R loss of function Ile269Asn allele significantly increases obesity risk, the presence of at least one functional MC4R allele seems sufficient to allow short-term weight loss in response to dietary restriction, phentermine and RYGB. Thus, these three different interventions may be useful for the short-term treatment of obesity in MC4R Ile269Asn mutation carriers.

The main roles of adipose tissue include triglycerides storage and adipokine secretion, which regulate energy balance and inflammation status. In obesity, adipocyte dysfunction leads to proinflammatory cytokine production and insulin resistance. Bariatric surgery is the most effective treatment for obesity, the gold-standard technique being Roux-en-Y gastric bypass (RYGB). Since metabolic improvements after RYGB are clear, a better understanding of adipose tissue molecular modifications could be derived from this study. Thus, the aim of this systematic review was to find differentially expressed genes in subcutaneous adipose tissue of lean, obese and post-RYGB (distinct timepoints). To address this objective, publications from 2015-2022 reporting gene expression (candidate genes or transcriptomic approach) of subcutaneous adipose tissue from lean and obese individuals before and after RGYB were searched in PubMed, Elsevier, and Springer Link. Excluded publications were reviews, studies analyzing serum, other types of tissues, or bariatric procedures. A risk-of-bias summary was created for each paper using Robvis, to finally include 17 studies. Differentially expressed genes in post-RYGB vs. obese and lean vs. obese were obtained and the intersection among these groups was used for analysis and gene classification by metabolic pathway. Results showed that the lean state as well as the post-RYGB is similar in terms of increased expression of insulin-sensitizing molecules, inducing lipogenesis over lipolysis and downregulating leukocyte activation, cytokine production and other factors that promote inflammation. Thus, massive weight loss and metabolic improvements after RYGB are accompanied by gene expression modifications reverting the "adipocyte dysfunction" phenomenon observed in obesity conditions.

Obesity is a worldwide epidemic associated with severe health and psychological wellbeing impairments expressed by an increased prevalence of affective disorders. Emotional dysfunction is important due to its effect on social performance. The aim of the present narrative review is to provide a general overview of human research exploring emotional information processing in overweight and obese people. Evidence suggests that obesity is associated with an attenuation of emotional experience, contradictory findings about emotion recognition, and scarce research about automatic emotional information processing. Finally, we made some concluding considerations for future research on emotional information processing in overweight and obese people., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Romero-Rebollar, García-Gómez, Báez-Yáñez, Gutiérrez-Aguilar and Pacheco-López.)

Obesity is defined as increased adiposity, which leads to metabolic disease. The growth of adipose tissue depends on its capacity to expand through hyperplasia or hypertrophy, in order to buffer energy surplus. Also, during the establishment of obesity, adipose tissue expansion reflects adipose lipid metabolism (lipogenesis and/or lipolysis). It is well known that dietary factors can modify lipid metabolism promoting or preventing the development of metabolic abnormalities that concur with obesity. Trans-palmitoleic acid (TP), a biomarker of dairy consumption, has been associated with reduced adiposity in clinical studies. Thus, we aimed to evaluate the effect of TP over adiposity and lipid metabolism-related genes in a rodent model of diet-induced obesity (DIO). To fulfil this aim, we fed C57BL/6 mice with a Control or a High-Fat diet, added with or without TP (3 g/kg diet), during 11 weeks. Body weight and food intake were monitored, fat pads were weighted, histology of visceral adipose tissue was analysed and lipid metabolism-related gene expression was explored by qPCR. Results show that TP consumption prevented weight gain induced by high-fat diet, reduced visceral adipose tissue weight and adipocyte size, while increasing the expression of lipolytic molecules. In conclusion, we show for the first time that TP influences adipose tissue metabolism, specifically lipolysis, resulting in decreased adiposity and reduced adipocyte size in a DIO mice model.

The genus Fusarium can be utilized to produce a great variety of secondary metabolites under specific culture conditions, including pigments of increasing biotechnological interest, such as bikaverin. Such pigments are important due to the biological properties they possess, including antitumor and antibiotic activities, among others. In Fusarium fujikuroi, bik1-bik6 have been identified as the genes that are responsible for the synthesis of bikaverin. Therefore, in this study, we screened for the presence of bik genes and examined changes in mRNA levels of the bik genes under the influence of NH 4 NO 3 (0.024, 0.048, 0.50, 1.0, and 4.60 g L -1 ) and NH 4 Cl (0.50 and 1.0 g L -1 ) as nitrogen sources for the phytopathogen Fusarium oxysporum f. sp. lycopersici. Our results indicated the presence of at least six bik (bik1-bik6) genes and showed increased mRNA levels for bik4, bik5, and bik6 in conditions where NH 4 NO 3 was used at pH 3.0. The characteristic coloration of bikaverin was obtained in 10 out of 16 culture conditions, except when the fungus was grown with higher concentrations of NH 4 NO 3 (1.0 and 4.60 g L -1 ). The pigment was chloroform-extracted from the culture conditions of NH 4 NO 3 (0.024, 0.048, and 0.50 g L -1 ) and NH 4 Cl (0.50 and 1.0 g L -1 ) with 3 and 9 days of incubation. Analysis via visible spectroscopy and matrix-assisted laser desorption ionization-time of flight mass spectrometry were used for the identification of bikaverin., (© 2021. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Background: Gut microbiota is a complex organized collection of microorganisms that confers multiple metabolic advantages to the host. The reduced diversity and proportion of specific gut microbial species have been associated with obesity and metabolic disorders. Multidimensional interventions, including modifications in dietary and physical activity habits, are associated with favorable changes in microbiota composition. This pilot study aimed to evaluate changes in the gut microbiota composition of Mexican children with obesity before and after a 6-week multidimensional intervention., Methods: Blood and stool samples were collected, and anthropometric measurements were obtained from six children with obesity before and after the intervention. The intervention consisted of modeling a hypo energetic diet and giving nutritional and physical activation recommendations. DNA from stool samples was used to characterize gut microbial composition by sequencing the 16S rRNA gene., Results: The decrease in waist circumference was associated with increased Odoribacter relative abundance. However, gut microbiota composition and diversity remained unchanged., Conclusions: Although no modifications in the body mass index, body fat, composition, or diversity of the gut microbiota were observed with the intervention, it was possible to associate the reduction in waist circumference with the presence of Odoribacter after a multidimensional intervention in Mexican children with obesity., (Copyright: © 2022 Permanyer.)

Obesity is a multifactorial disease in which environmental conditions and several genes play an important role in the development of this disease. Obesity is associated with neurodegenerative diseases (Alzheimer, Parkinson, and Huntington diseases) and with neurodevelopmental diseases (autism disorder, schizophrenia, and fragile X syndrome). Some of the environmental conditions that lead to obesity are physical activity, alcohol consumption, socioeconomic status, parent feeding behavior, and diet. Interestingly, some of these environmental conditions are shared with neurodegenerative and neurodevelopmental diseases. Obesity impairs neurodevelopment abilities as memory and fine-motor skills. Moreover, maternal obesity affects the cognitive function and mental health of the offspring. The common biological mechanisms involved in obesity and neurodegenerative/neurodevelopmental diseases are insulin resistance, pro-inflammatory cytokines, and oxidative damage, among others, leading to impaired brain development or cell death. Obesogenic environmental conditions are not the only factors that influence neurodegenerative and neurodevelopmental diseases. In fact, several genes implicated in the leptin-melanocortin pathway ( LEP , LEPR , POMC , BDNF , MC4R , PCSK1 , SIM1 , BDNF , TrkB , etc.) are associated with obesity and neurodegenerative and neurodevelopmental diseases. Moreover, in the last decades, the discovery of new genes associated with obesity ( FTO, NRXN3, NPC1, NEGR1, MTCH2, GNPDA2 , among others) and with neurodegenerative or neurodevelopmental diseases ( APOE, CD38, SIRT1, TNF α, PAI-1, TREM2, SYT4, FMR1, TET3 , among others) had opened new pathways to comprehend the common mechanisms involved in these diseases. In conclusion, the obesogenic environmental conditions, the genes, and the interaction gene-environment would lead to a better understanding of the etiology of these diseases., (Copyright © 2020 Flores-Dorantes, Díaz-López and Gutiérrez-Aguilar.)

Background: new alternatives for entry site closure (ESC) in per-oral endoscopy myotomy (POEM) and gastric peroral endoscopy myotomy (G-POEM) have appeared., Objective: to compare the over-the-scope-clip (OTSC®) and conventional clips (CC) for ESC in POEM and G-POEM., Material and Methods: a retrospective review of a prospective POEM and G-POEM database was performed between January 2015 and August 2019. A description was made of outcomes, using either OTSC® or CC for submucosal tunnel closure., Results: forty-six POEM and 26 G-POEM were included in the study (23/13 per group [CC/OTSC®]). There were no clinical or procedure differences. ESC was performed with 1 OTSC® vs 5 CC and 1 vs 6 (p = 0.01) for POEM and G-POEM, respectively. Adverse events associated with clips were 21.7% vs 13% (p = 0.01) and 7.7% vs 0% (p = 0.02) for CC and OTSC® in POEM and G-POEM, respectively., Conclusion: OTSC® represents a safe and effective alternative for entry site closure in POEM and G-POEM cases. Further studies are needed to recommend OTSC® as the first option for submucosal tunnel closure in these procedures.

Using a mathematical model, we explore the problem of availability versus overdemand of critical hospital processes (e.g., critical beds) in the face of a steady epidemic expansion such as is occurring from the COVID-19 pandemic. In connection with the statistics of new cases per day, and the assumption of maximum quota, the dynamics associated with the variables number of hospitalized persons (critical occupants) and mortality in the system are explored. A parametric threshold condition is obtained, which involves a parameter associated with the minimum daily effort for not collapsing the system. To exemplify, we include some simulations for the case of Chile, based on a parameter of effort to be sustained with the purpose of lowering the daily infection rate.

We present a straightforward projection with data up to 21/03/2020 of the evolution of the number of COVID-19 cases per day in Chile using data from the Ministry of Health. Assuming an arithmetical growth in the second variation of the data, we present a cubic adjustment model in which we estimate over 100 000 cases at 120 days consistent with the data recorded to date. Furthermore, we use an exponential total case model to represent (using a parameter) the daily effort to reduce a high initial daily growth rate. We simulate this model with different numerical scenarios of feasibility and desired future prevalence.

Obesity prevalence has increased in the last decades worldwide leading to metabolic complications, such as type 2 diabetes, steatosis, cardiovascular disease, among others; its development is influenced by genetic factors and environmental factors, such as intestinal microbiome. In Mexico, 33.3% of the adults present this disease. Obesity is defined as an excessive adipose tissue accumulation, provoking its dysfunction. Adipose tissue remodeling, which involves angiogenesis, hypoxia and inflammation, is implicated in the developing of obesity and metabolic modifications. Bariatric surgery is the most used and successful intervention to control morbid obesity, leading a maintained loss of weight and remission of some of its comorbidities as type 2 diabetes. Here, we review some of the molecular aspects of the metabolic changes provoked by bariatric surgery and its impact in weight loss and comorbidities remission. In summary, this article reviews the genetic aspects, microbiome and molecular facts (adipose tissue remodeling) that are involved in obesity development. In addition, some of the molecular aspects about bariatric surgery are described and the mechanisms that are regulated to control obesity and its comorbidities., (Copyright: © 2019 Permanyer.)

Adipose tissue is an endocrine organ with high metabolic activity. Countless adipose tissue-secreted adipokines and lipokines, as well as peptides and lipids with biological activity have thus far been discovered. Both white and brown and beige adipose tissue are known to contribute to energy homeostasis and metabolic regulation. The purpose of this review is to report on the most recent findings related to adipose tissue according to its color and its relationship with metabolic alterations associated with obesity. After a review of the specialized literature, white, brown and beige adipocyte populations were identified to be able to coexist within the same structure, and to modify global metabolic state in physiological or pathological situations., (Copyright: © 2020 Permanyer.)

The monounsaturated fatty acid palmitoleate (palmitoleic acid) is one of the most abundant fatty acids in serum and tissues, particularly adipose tissue and liver. Its endogenous production by stearoyl-CoA desaturase 1 gives rise to its cis isoform, cis-palmitoleate. Although trans-palmitoleate is also synthesized in humans, it is mainly found as an exogenous source in ruminant fat and dairy products. Recently, palmitoleate was considered to be a lipokine based on evidence demonstrating its release from adipose tissue and its metabolic effects on distant organs. After this finding, research has been performed to determine whether palmitoleate has beneficial effects on metabolism and to elucidate the underlying mechanisms. Thus, the aim of this work was to review the current status of knowledge about palmitoleate, its metabolism, and its influence on metabolic abnormalities. Results have shown mixed cardiovascular effects, direct or inverse correlations with obesity, and hepatosteatosis, but a significant amelioration or prevention of insulin resistance and diabetes. Finally, the induction of palmitoleate release from adipose tissue, dietary intake, and its supplementation are all interventions with a potential impact on certain metabolic diseases., Competing Interests: 3Author disclosures: ME Frigolet is a member of the Scientific Committee of the Mexican Danone Institute. R Gutiérrez-Aguilar, no conflicts of interest., (© 2017 American Society for Nutrition.)

Pdx-1 (pancreatic-duodenal homeobox-1), a MODY4 homeodomain transcription factor, serves as a master regulator in the pancreas because of its importance during organogenesis and in adult islet insulin-producing beta cell activity. Here, we show that KLF11, an SP/Krüppel-like (SP/KLF) transcription factor, mutated in French maturity onset diabetes of the young patients (MODY7), regulates Pdx-1 transcription in beta cells through two evolutionarily conserved GC-rich motifs in conserved Area II, a control region essential to islet beta cell-enriched expression. These regulatory elements, termed GC1 (human base pair -2061/-2055) and GC2 (-2036/-2027), are also nearly identical to the consensus KLF11 binding sequence defined here by random oligonucleotide binding analysis. KLF11 specifically associates with Area II in chromatin immunoprecipitation assays, while preventing binding to GC1- and/or GC2-compromised Pdx1-driven reporter activity in beta cell lines. Mechanistically, we find that KLF11 interacts with the coactivator p300 via its zinc finger domain in vivo to mediate Pdx-1 activation. Together, our data identified a hierarchical regulatory cascade for these two MODY genes, suggesting that gene regulation in MODY is more complex than anticipated previously. Furthermore, because KLF11 like most MODY-associated transcription factors uses p300, these data further support a role for this coactivator as a critical chromatin link in forms of type 2 diabetes.

Common polymorphisms in the fat mass and obesity-associated gene (FTO) have shown strong association with obesity in several populations. In the present study, we explored the association of FTO gene polymorphisms with obesity and other biochemical parameters in the Mexican population. We also assessed FTO gene expression levels in adipose tissue of obese and nonobese individuals. The study comprised 788 unrelated Mexican-Mestizo individuals and 31 subcutaneous fat tissue biopsies from lean and obese women. FTO single-nucleotide polymorphisms (SNPs) rs9939609, rs1421085, and rs17817449 were associated with obesity, particularly with class III obesity, under both additive and dominant models (P = 0.0000004 and 0.000008, respectively). These associations remained significant after adjusting for admixture (P = 0.000003 and 0.00009, respectively). Moreover, risk alleles showed a nominal association with lower insulin levels and homeostasis model assessment of B-cell function (HOMA-B), and with higher homeostasis model assessment of insulin sensitivity (HOMA-S) only in nonobese individuals (P (dom) = 0.031, 0.023, and 0.049, respectively). FTO mRNA levels were significantly higher in subcutaneous fat tissue of class III obese individuals than in lean individuals (P = 0.043). Risk alleles were significantly associated with higher FTO expression in the class III obesity group (P = 0.047). In conclusion, FTO is a major risk factor for obesity (particularly class III) in the Mexican-Mestizo population, and is upregulated in subcutaneous fat tissue of obese individuals.

Context: The transcription factor Krüppel-like zinc finger 11 (KLF11) has been suggested to contribute to genetic risk of type 2 diabetes (T2D). Our previous results showed that four KLF11 variants, in strong linkage disequilibrium (LD block including +185 A>G/Gln62Arg and -1659 G>C) were associated with T2D in a north European case-control study. Here we further analyzed these variants for T2D association in a general Danish population and assess their possible effect on gene function., Methods: We genotyped Gln62Arg variant, representative for the LD block, in 5864 subjects of the INTER99 study to assess association to T2D and glucose metabolism-related quantitative traits. We studied effects of LD-block variants on KLF11 function and in particular, the effect of -1659G>C on transcriptional regulation of KLF11 using EMSA, chromatin immunoprecipitation, gene reporter assays, and small interfering RNA transfection., Results: We could not confirm T2D association of the KLF11 LD block, however, in glucose-tolerant subjects; it was significantly associated with higher fasting serum insulin and C-peptide levels and increased homeostasis model assessment insulin resistance indexes (P = 0.00004, P = 0.006, and P = 0.00002, respectively). In addition, binding of signal transducer and activator of transcription (STAT)-3 to the wild-type (-1659G>C) allele stimulated gene transcription, whereas STAT3 did not bind onto the mutant allele., Conclusions: We showed that KLF11 may interfere with glucose homeostasis in a Danish general population and that STAT3-mediated up-regulation of KLF11 transcription was impaired by the -1659G>C variant. Overall, KLF11 variants may have a deleterious effect on insulin sensitivity, although that may not be sufficient to lead to T2D.

The transcription factor 7-like 2 (TCF7L2) rs7903146 T allele was previously associated with type 2 diabetes (T2D) and decreased BMI whereas haplotypes carrying the rs7903146 C and rs10885406 A alleles (HapA) were associated with increased BMI. The functional relevance of TCF7L2 polymorphisms and their effects on T2D and obesity remained to be further investigated. In white European populations, we found that the rs7903146 T allele was more associated with T2D in 3,547 non-obese individuals (odds ratio (OR) = 1.88 (1.69-2.10)) than in 1,110 class III obese subjects (OR = 1.24 (1.03-1.50)). No direct effect of the rs7903146 C allele and HapA was found on any form of obesity in 3,507 normal glucose tolerant (NGT) individuals, 1,106 pedigrees with familial obesity and 5,512 individuals from the French general population. However, in T2D subjects, the rs7903146 C allele was less prevalent in the 1,111 non-obese individuals (55.2%) compared to 659 class III obese subjects (67.5% OR = 1.69 (1.46-1.95)). Functional studies showed that the rs7903146 T allele is less prone to be bound by protein factors than the C allele in 3T3-L1, HepG2 and beta-TC3 cell lines and that TCF7L2 expression decreases in subcutaneous adipose tissue from NGT obese T/T carriers under calorie restriction. In conclusion, TCF7L2 is not a risk factor for obesity in European populations, but its effect on T2D risk is modulated by obesity. Furthermore, our data suggest that the rs7903146 T allele may be possibly functional and associated with a nominal decrease in TCF7L2 expression in adipose tissue of individuals under calorie restriction.

Background: The Krüppel-like factor (KLF) family consists of transcription factors that can activate or repress different genes implicated in processes such as differentiation, development, and cell cycle progression. Moreover, several of these proteins have been implicated in glucose homeostasis, making them candidate genes for involvement in type 2 diabetes (T2D)., Methods: Variants of nine KLF genes were genotyped in T2D cases and controls and analysed in a two-stage study. The first case-control set included 365 T2D patients with a strong family history of T2D and 363 normoglycemic individuals and the second set, 750 T2D patients and 741 normoglycemic individuals, all of French origin. The SNPs of six KLF genes were genotyped by Taqman SNP Genotyping Assays. The other three KLF genes (KLF2, -15 and -16) were screened and the identified frequent variants of these genes were analysed in the case-control studies., Results: Three of the 28 SNPs showed a trend to be associated with T2D in our first case-control set (P < 0.10). These SNPs, located in the KLF2, KLF4 and KLF5 gene were then analysed in our second replication set, but analysis of this set and the combined analysis of the three variants in all 2,219 individuals did not show an association with T2D in this French population. As the KLF2, -15 and -16 variants were representative for the genetic variability in these genes, we conclude they do not contribute to genetic susceptibility for T2D., Conclusion: It is unlikely that variants in different members of the KLF gene family play a major role in T2D in the French population.

Background: Familial hypercholesterolemia (FH) and familial defective apolipoprotein B-100 (FDB) are relatively common lipid disorders caused by mutations of the low-density lipoprotein receptor (LDLR) and apolipoprotein B (apoB) genes, respectively. A third locus on chromosome 1p34.1-p32 was recently linked to FH and the responsible gene has been identified [protein convertase subtilisin/kexin type 9 (PCSK9)]., Methods: We assessed the contribution of the LDLR, apoB, and PCSK9 genes as cause of FH in Mexico. Forty six unrelated probands, as well as 68 affected and 60 healthy relatives, were included., Results: All index cases were diagnosed as having heterozygous autosomal dominant FH. Seventeen of the 46 index cases had LDLR gene mutations, four of which were novel (Fs92ter108, C268R, Q718X, and Fs736ter743); and only one patient had an apoB mutation (R3500Q). We sequenced the PCSK9 gene in the remainder of the 28 probands with no identified LDLR or APOB gene defects; however, no PCSK9 mutations were found, including one large kindred with positive linkage to the 1p34.1-32 locus (multipoint LOD score of 3.3) and two small pedigrees. Linkage was excluded from these three loci in at least four kindreds suggesting that other yet uncharacterized genes are involved., Conclusions: Our results underline substantial genetic heterogeneity for FH in the Mexican population.