Body mass index stratified meta-analysis of genome-wide association studies of polycystic ovary syndrome in women of European ancestry.

BACKGROUND: Polycystic ovary syndrome (PCOS) is a complex multifactorial disorder with a substantial genetic component. However, the clinical manifestations of PCOS are heterogeneous with notable differences between lean and obese women, implying a different pathophysiology manifesting in differential body mass index (BMI). We performed a meta-analysis of genome-wide association study (GWAS) data from six well-characterised cohorts, using a case-control study design stratified by BMI, aiming to identify genetic variants associated with lean and overweight/obese PCOS subtypes. RESULTS: The study comprised 254,588 women (5,937 cases and 248,651 controls) from individual studies performed in Australia, Estonia, Finland, the Netherlands and United States of America, and separated according to three BMI stratifications (lean, overweight and obese). Genome-wide association analyses were performed for each stratification within each cohort, with the data for each BMI group meta-analysed using METAL software. Almost half of the total study population (47%, n = 119,584) were of lean BMI (≤ 25 kg/m2). Two genome-wide significant loci were identified for lean PCOS, led by rs12000707 within DENND1A (P = 1.55 × 10-12) and rs2228260 within XBP1 (P = 3.68 × 10-8). One additional locus, LINC02905, was highlighted as significantly associated with lean PCOS through gene-based analyses (P = 1.76 × 10-6). There were no significant loci observed for the overweight or obese sub-strata when analysed separately, however, when these strata were combined, an association signal led by rs569675099 within DENND1A reached genome-wide significance (P = 3.22 × 10-9) and a gene-based association was identified with ERBB4 (P = 1.59 × 10-6). Nineteen of 28 signals identified in previous GWAS, were replicated with consistent allelic effect in the lean stratum. There were less replicated signals in the overweight and obese groups, and only 4 SNPs were replicated in each of the three BMI strata. CONCLUSIONS: Genetic variation at the XBP1, LINC02905 and ERBB4 loci were associated with PCOS within unique BMI strata, while DENND1A demonstrated associations across multiple strata, providing evidence of both distinct and shared genetic features between lean and overweight/obese PCOS-affected women. This study demonstrated that PCOS-affected women with contrasting body weight are not only phenotypically distinct but also show variation in genetic architecture; lean PCOS women typically display elevated gonadotrophin ratios, lower insulin resistance, higher androgen levels, including adrenal androgens, and more favourable lipid profiles. Overall, these findings add to the growing body of evidence supporting a genetic basis for PCOS as well as differences in genetic patterns relevant to PCOS BMI-subtype.

Single-cell transcriptome analysis reveals immunosuppressive landscape in overweight and obese colorectal cancer.

BACKGROUND: Overweight and obesity are established risk factors for various types of cancers including colorectal cancer (CRC). However the underlying molecular mechanisms remain unclear. An in-depth understanding of the oncologic characteristics of overweight and obese CRC at the single-cell level can provide valuable insights for the development of more effective treatment strategies for CRC. METHODS: We conducted single-cell RNA sequencing (scRNA-seq) analysis on tumor and adjacent normal colorectal samples from 15 overweight/obese and 15 normal-weight CRC patients. Immunological and metabolic differences between overweight/obese CRC and non-obese CRC were characterized. RESULTS: We obtained single-cell transcriptomics data from a total of 192,785 cells across all samples. By evaluating marker gene expression patterns, we annotated nine main cell types in the CRC ecosystem. Specifically, we found that the cytotoxic function of effector T cells and NK cells was impaired in overweight/obese CRC compared with non-obese CRC, relating to its metabolic dysregulation. CD4+T cells in overweight/obese CRC exhibited higher expression of immune checkpoint molecules. The antigen-presenting ability of DCs and B cells is down-regulated in overweight/obese CRC, which may further aggravate the immunosuppression of overweight/obese CRC. Additionally, dysfunctional stromal cells were identified, potentially promoting invasion and metastasis in overweight/obese CRC. Furthermore, we discovered the up-regulated metabolism of glycolysis and lipids of tumor cells in overweight/obese CRC, which may impact the metabolism and function of immune cells. We also identified inhibitory interactions between tumor cells and T cells in overweight/obese CRC. CONCLUSIONS: The study demonstrated that overweight/obese CRC has a more immunosuppressive microenvironment and distinct metabolic reprogramming characterized by increased of glycolysis and lipid metabolism. These findings may have implications for the development of novel therapeutic strategies for overweight/obese CRC patients.

Analysis of differences in intestinal flora associated with different BMI status in colorectal cancer patients.

BACKGROUND: Overweight is known to be an important risk factor for colorectal cancer (CRC), and the differences in intestinal flora among CRC patients with different BMI status have not been clearly defined. The purpose of this study was to elucidate the differences in the abundance, composition and biological function of intestinal flora in CRC patients with different BMI status. METHOD: A total of 170 CRC patients were included and grouped according to the BMI data of CRC patients. BMI ≥ 24 kg/m2 was defined as overweight group, and BMI within the range of 18.5-23.9 kg/m2 was defined as normal weight group. Preoperative stool collection of patients in both groups was used for 16S rRNA sequencing. Total RNA was extracted from 17 CRC tumor tissue samples for transcriptome sequencing, and then CIBERSORT algorithm was used to convert the transcriptome data into the relative content matrix of 22 kinds of immune cells, and the correlation between different intestinal flora and immune cells and immune-related genes under different BMI states was analyzed. Finally, we identified BMI-related differential functional pathways and analyzed the correlation between these pathways and differential intestinal flora. RESULT: There was no significant difference in α diversity and ß diversity analysis between overweight group and normal weight group. Partial least square discriminant analysis (PLS-DA) could divide the flora into two different clusters according to BMI stratification. A total of 33 BMI-related differential flora were identified by linear discriminant effect size analysis (LEfSe), among which Actinomyces, Desulfovibrio and Bacteroides were significantly enriched in overweight group. ko00514: Other types of O-glycan biosynthesis are significantly enriched in overweight group. There was a significant positive correlation between Clostridium IV and Macrophages M2 and T cells regulatory (Tregs). There was a significant negative correlation with Dendritic cells activated and T cells CD4 memory activated. CONCLUSIONS: The richness and diversity of intestinal flora of CRC patients may be related to different BMI status, and the enrichment of Actinomyces, Desulphurvibrio and Bacteroides may be related to overweight status of CRC patients. The tumor microenvironment in which BMI-related differential flora resides has different immune landscapes, suggesting that some intestinal flora may affect the biological process of CRC by regulating immune cell infiltration and immune gene expression, but further experiments are needed to confirm this.

Associations of gene expression in blood with BMI and weight changes among women in the Norwegian Women and Cancer postgenome cohort.

OBJECTIVE: This study aimed to evaluate associations between blood gene expression profiles and (1) current BMI and (2) past weight changes (WCs) among women who had never been diagnosed with cancer in the Norwegian Women and Cancer (NOWAC) postgenome cohort. METHODS: This cross-sectional study (N = 1694) used gene expression profiles and information from three questionnaires: Q1 (baseline), Q2 (follow-up), and Q3 (blood collection). The authors performed gene-wise linear regression models to identify differentially expressed genes (DEGs) and functional enrichment analyses to identify their biological functions. RESULTS: When assessing BMIQ3 , the study observed 2394, 769, and 768 DEGs for the obesity-versus-normal weight, obesity-versus-overweight, and overweight-versus-normal weight comparisons, respectively. Up to 169 DEGs were observed when investigating WCQ3-Q1 (mean = 7 years, range = 5.5-14 years) and WCQ3-Q2 (mean = 1 year, range = <1 month-9 years) in interaction models with BMI categories, of which 1 to 169 genes were associated with WCs and 0 to 9 were associated with interaction effects of BMI and WCs. Biological functions of BMI-associated DEGs were linked to metabolism, erythrocytes, oxidative stress, and immune processes, whereas WC-associated DEGs were linked to signal transduction. CONCLUSIONS: Many BMI-associated but few WC-associated DEGs were identified in the blood of women in Norway. The biological functions of BMI-associated DEGs likely reflect systemic impacts of obesity, especially blood reticulocyte-erythrocyte ratio shifts.

FAAH Pro129Thr Variant Is Associated with Increased Cholesterol Levels in Normal-Weight Metabolically Unhealthy Subjects.

Introduction: The endocannabinoid system (ECS) plays an integral role in maintaining metabolic homeostasis, where an hyperactivation has been related with serum lipid alterations. The biological effects of ECS are limited by the activation of the endocannabinoid-degrading enzyme fatty acid amide hydrolase (FAAH) and by polyunsaturated fatty acid (PUFA) intake as precursors. The FAAH Pro129Thr variant has been associated with obesity in some populations. However, the association with metabolic phenotypes in the Mexican population has not been studied. This study aimed to analyze the association of the FAAH Pro129Thr variant with serum lipids and diet in Mexican adults with different metabolic phenotypes. Methods: This is a cross-sectional study with 306 subjects between 18 and 65 years of age. They were classified with normal weight (NW) or excess weight (EW) according to their body mass index (BMI). The EW group included individuals with overweight or obesity (BMI 25-39.9 kg/m2). The individuals were classified into two metabolic phenotypes, metabolically healthy and metabolically unhealthy (MUH), using the homeostatic model assessment of insulin resistance and the National Cholesterol Education Program-adenosine triphosphate III cutoff points for blood pressure, triglycerides, high-density lipoprotein cholesterol, and fasting glucose. Subjects with ≥2 of 5 altered parameters were classified as MUH. The FAAH Pro129Thr variant was determined by allelic discrimination with TaqMan® probes. Results: The total cholesterol and very low-density lipoprotein cholesterol levels were associated with the FAAH Pro129Thr variant in NW-MUH subjects. Moreover, a lower PUFA intake was found in EW-MUH subjects with the FAAH variant. Conclusions: FAAH Pro129Thr variant has an important role in lipid metabolism, especially in NW-MUH subjects. By contrast, a low dietary intake of endocannabinoid PUFA precursors may partly counteract the development of the altered lipid profile associated with overweight/obesity.

Leveraging family history data to disentangle time-varying effects on disease risk using lifecourse mendelian randomization.

Lifecourse Mendelian randomization is a causal inference technique which harnesses genetic variants with time-varying effects to develop insight into the influence of age-dependent lifestyle factors on disease risk. Here, we apply this approach to evaluate whether childhood body size has a direct consequence on 8 major disease endpoints by analysing parental history data from the UK Biobank study.Our findings suggest that, whilst childhood body size increases later risk of outcomes such as heart disease (odds ratio (OR) = 1.15, 95% CI = 1.07 to 1.23, P = 7.8 × 10- 5) and diabetes (OR = 1.43, 95% CI = 1.31 to 1.56, P = 9.4 × 10- 15) based on parental history data, these findings are likely attributed to a sustained influence of being overweight for many years over the lifecourse. Likewise, we found evidence that remaining overweight throughout the lifecourse increases risk of lung cancer, which was partially mediated by lifetime smoking index. In contrast, using parental history data provided evidence that being overweight in childhood may have a protective effect on risk of breast cancer (OR = 0.87, 95% CI = 0.78 to 0.97, P = 0.01), corroborating findings from observational studies and large-scale genetic consortia.Large-scale family disease history data can provide a complementary source of evidence for epidemiological studies to exploit, particularly given that they are likely more robust to sources of selection bias (e.g. survival bias) compared to conventional case control studies. Leveraging these data using approaches such as lifecourse Mendelian randomization can help elucidate additional layers of evidence to dissect age-dependent effects on disease risk.

Relationship Between Genetic Polymorphisms in Cell Cycle Regulatory Gene TP53 and Polycystic Ovarian Syndrome: A Case-Control Study and In Silico Analyses.

Polycystic ovarian syndrome (PCOS) is a complex endocrine and metabolic condition with several potential causes. Insulin resistance is a hallmark of PCOS that often coexists with hirsutism, hyperandrogenism, being overweight, and hormonal imbalances. The functioning of multiple replication and transcription factors is regulated by tumor suppressor genes (TSGs), which play a crucial role in maintaining genomic integrity and controlling the cell cycle of granulosa cells. In the present study, we examined how three single nucleotide polymorphisms (SNPs) in TP53, a cell cycle regulatory gene, affect the risk of developing PCOS in a sample of an Iranian population. Genomic DNA was extracted from 200 PCOS patients and 200 healthy women to analyze TP53 rs17880604, rs1625895, and rs1042522 SNPs using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. Our findings revealed that the majority of PCOS cases were overweight [25 < body mass index (BMI) < 30]. A positive association was observed between the TP53 rs1042522 SNP and the risk of PCOS under codominant heterozygous and overdominant genetic patterns (odds ratio > 1). Meanwhile, a negative association was observed between TP53 SNPs (rs1625895, rs17880604) and susceptibility to PCOS under codominant heterozygous and dominant models of inheritance (odds ratio < 1). Moreover, different genotype and haplotype combinations of rs17880604/rs1625895/rs1042522 conferred a decreased risk of PCOS in our population. We found no statistical difference in the frequency of TP53 genotypes between PCOS cases and/or controls in terms of BMI, waist circumference, prolactin level, and markers of lipid and carbohydrate profile (P > 0.05). Molecular dynamic prediction showed that the missense substitution in the 17p13.1 position (rs1042522) could change the properties and secondary structure of the p53 protein. As inherited risk factors, TP53 variations may play a  pivotal role in the pathogenesis of PCOS among Iranian women. Replicated population-based studies on other ethnicities are required to find the genetic contribution of variants of TP53, or SNPs located in other TSGs, to the etiology of this endocrine disease.

FSTL3 is highly expressed in adipose tissue of individuals with overweight or obesity and is associated with inflammation.

OBJECTIVE: This study aimed to investigate the expression of follistatin-like 3 (FSTL3) in adipose tissue in individuals with overweight or obesity and to explore the role of FSTL3 in human adipocytes, as well as the relationship between serum FSTL3 levels and fat distribution and inflammation. METHODS: This study enrolled 236 individuals (171 with overweight or obesity; aged 18-67 years). Bulk transcriptome sequencing was performed on subcutaneous and visceral adipose tissue. The function of FSTL3 was studied in human adipocytes. Serum FSTL3 levels were measured using enzyme-linked immunosorbent assay. RESULTS: Adipose FTSL3 expression was higher in individuals with overweight or obesity than in individuals with normal weight. FSTL3 was mainly expressed in mature adipocytes and stimulated by tumor necrosis factor alpha (TNFα). FSTL3 suppressed inflammatory responses in human adipocytes, whereas FSTL3 knockdown promoted inflammatory responses. Serum FSTL3 levels were correlated with adipose FTSL3 expression and obesity-related indicators (all p < 0.05). Multiple linear regression analysis showed that serum FSTL3 levels were independently associated with the visceral fat area and serum TNFα levels (both p < 0.05). CONCLUSIONS: FSTL3 was highly expressed in adipose tissue in individuals with overweight or obesity and could suppress adipocyte inflammation. Serum FSTL3 levels might be considered as a biomarker of visceral obesity and inflammation.

Folliculin-interacting protein FNIP2 impacts on overweight and obesity through a polymorphism in a conserved 3' untranslated region.

BACKGROUND: Overweight and obesity are defined by an anomalous or excessive fat accumulation that may compromise health. To find single-nucleotide polymorphisms (SNPs) influencing metabolic phenotypes associated with the obesity state, we analyze multiple anthropometric and clinical parameters in a cohort of 790 healthy volunteers and study potential associations with 48 manually curated SNPs, in metabolic genes functionally associated with the mechanistic target of rapamycin (mTOR) pathway. RESULTS: We identify and validate rs2291007 within a conserved region in the 3'UTR of folliculin-interacting protein FNIP2 that correlates with multiple leanness parameters. The T-to-C variant represents the major allele in Europeans and disrupts an ancestral target sequence of the miRNA miR-181b-5p, thus resulting in increased FNIP2 mRNA levels in cancer cell lines and in peripheral blood from carriers of the C allele. Because the miRNA binding site is conserved across vertebrates, we engineered the T-to-C substitution in the endogenous Fnip2 allele in mice. Primary cells derived from Fnip2 C/C mice show increased mRNA stability, and more importantly, Fnip2 C/C mice replicate the decreased adiposity and increased leanness observed in human volunteers. Finally, expression levels of FNIP2 in both human samples and mice negatively associate with leanness parameters, and moreover, are the most important contributor in a multifactorial model of body mass index prediction. CONCLUSIONS: We propose that rs2291007 influences human leanness through an evolutionarily conserved modulation of FNIP2 mRNA levels.

Independent association of FTO rs9939609 polymorphism with overweight and obesity in Polish adults. Results from the representative population-based WOBASZ study.

Genetic factors play an important role in the origin of obesity. We investigated the association between the FTO rs9939609 genotype and overweight and obesity, along with additional anthropometric variables in the representative sample of adult Polish population. We genotyped a random sample of 3369 adult individuals examined in a cross-sectional population survey (WOBASZ 2003-2005). More than 40% of men and women had at least one A allele. The AA genotype was found in approximately one fifth of both men and women. The frequency of the AA genotype increased with higher BMI in both sexes and was associated with higher anthropometric obesity indicators in both men and women. The FTO rs9939609 AA genotype was significantly related to abnormal BMI [OR=1.55 (1.14-2.11)] and overweight [OR=1.55 (1.11-2.16)] or obesity [OR=1.56 (1.04-235)] in men regardless of age, tobacco smoking, physical activity, diet and diabetes, while in women it was related to abnormal BMI [OR=1.45 (1.05-2.01)] and overweight [OR=1.59 (1.11-2.29)] after adjustment in addition for menopause. The frequency of the A allele in the Polish population was the same as in other European countries. About one fifth of both men and women have the FTO rs9939609 AA variant. A significant relationship was found between the FTO genotype and anthropometric obesity indicators. The AA genotype was significantly associated with abnormal BMI and overweight in both sexes, but the relation to the obesity phenotype was observed only in men.

Maternal obesity alters methylation level of cytosine in CpG island for epigenetic inheritance in fetal umbilical cord blood.

BACKGROUND: Over the past few decades, global maternal obesity prevalence has rapidly increased. This condition may induce long-lasting pathophysiological effects on either fetal or infant health that could be attributable to unknown unique changes in the umbilical blood composition. METHODS: A total of 34 overweight/obese and 32 normal-weight pregnant women were recruited. Fifteen umbilical blood samples including 8 overweight/obese subjects and 7 normal weight women were sequenced using Targeted Bisulfite Sequencing technology to detect the average methylation level of cytosine and identify the differentially methylated region (DMR). GO and KEGG analyses were then employed to perform pathway enrichment analysis of DMR-related genes and promoters. Moreover, the mRNA levels of methylation-related genes histone deacetylases (HDACs) and DNA methyltransferases (DNMTs) were characterized in the samples obtained from these two groups. RESULTS: Average methylated cytosine levels in both the CpG islands (CGI) and promoter significantly decreased in overweight/obese groups. A total of 1669 DMRs exhibited differences in their DNA methylation status between the overweight/obese and control groups. GO and KEGG analyses revealed that DMR-related genes and promoters were enriched in the metabolism, cancer and cardiomyopathy signaling pathways. Furthermore, the HDACs and DNMTs mRNA levels trended to decline in overweight/obese groups. CONCLUSIONS: Decreased methylated cytosine levels in overweight/obese women induce the gene expression activity at a higher level than in the control group. DMRs between these two groups in the fetal blood may contribute to the changes in gene transcription that underlie the increased risk of metabolic disorders, cancers and cardiomyopathy in their offspring.

Weight loss reduces circulating micro-RNA related to obesity and breast cancer in postmenopausal women.

Postmenopausal women with overweight or obesity have an increased risk of developing breast cancer but many of the mechanisms underlying this association remain to be elucidated. MicroRNAs (miRNAs), short non-coding single-stranded RNAs, regulate many physiological processes by controlling post-transcriptional regulation of mRNA. We measured circulating miRNA from 192 overweight/obese postmenopausal women (50-75 years) who were part of a randomized controlled trial, comparing independent and combined effects of a 12-month reduced-calorie weight-loss diet and exercise programme, versus control. RNA was extracted from stored plasma samples, and 23 a priori selected miRNA targets related to aetiology of breast cancer or obesity were measured using NanoString nCounter miRNA Expression assays. Changes from baseline to 12-months between controls and women in the diet/exercise weight loss arms were analysed using generalized estimating equations modification of linear regression, adjusted for confounders. We next examined changes in levels of circulating miRNA by amount of weight loss (0-10% versus ≥10%). Participants randomized to weight-loss interventions had statistically significantly greater reductions in miR-122 (-7.25%), compared to controls (+ 33.5%, P = 0.009), and miR-122 levels were statistically significantly correlated with weight loss (rho = 0.24; P = 0.001) Increasing weight loss was associated with greater reductions in miR-122 vs. controls (-11.7% (≥10% weight loss); +2.0% (0-10% weight loss) +33.5% (controls); Ptrend = 0.006), though this was not significant after correction for multiple testing (P = 0.05/23) Our study supports the effect of weight loss on regulation of miRNA.

Haptoglobin polymorphism modulates cardiometabolic impacts of four consecutive weeks, dawn to sunset Ramadan intermittent fasting among subjects with overweight/obesity.

AIMS: Haptoglobin (Hp) is a multifaceted marker of inflammation, and mediates the interplay between obesity, inflammation, and cardiometabolic dysfunction. However, the role of the Hp phenotype in modulating intermittent fasting (IF)-induced cardiometabolic changes remains to be elucidated. METHODS: Hp phenotype was determined for the study subjects. Cardiometabolic markers were assessed before and at the end of four consecutive weeks, dawn to sunset IF. RESULTS: A total of 114 subjects (75 males and 39 females, 38.7 ± 11.7 years, body mass index (BMI) of 30.41 ± 5.09 kg/m2) were recruited. Hp2-2 (n = 55, 48.2 %) and Hp2-1 (n = 53, 46.5 %) were the predominant phenotypes. Significant reductions were observed in serum Hp, IL-6, TNF-α, triglycerides (TG), total cholesterol (TC), LDL, BMI, and fat mass (FM), while a significant elevation was observed in serum CD163, HDL, and IL-10 at the end of the IF month for the whole population. Based on the Hp polymorphism, significant decreases in Hp, BMI, FM, TG, LDL, and TNF-α, with significant increases in HDL and CD163 levels were observed among subjects with Hp2-2 and Hp2-1 phenotypes. A more pronounced reduction in FM was reported in subjects with Hp2-2 in comparison with Hp2-1. CONCLUSION: Hp gene polymorphism modulates IF-induced changes in cardiometabolic markers. CLINICAL TRIAL REGISTRATION NUMBER: ISRCTN18205186; https://trialsearch.who.int/?TrialID=ISRCTN18205186.

Consensus molecular subtype differences linking colon adenocarcinoma and obesity revealed by a cohort transcriptomic analysis.

Colorectal cancer (CRC) is the third-leading cause of cancer-related deaths in the United States and worldwide. Obesity-a worldwide public health concern-is a known risk factor for cancer including CRC. However, the mechanisms underlying the link between CRC and obesity have yet to be fully elucidated in part because of the molecular heterogeneity of CRC. We hypothesized that obesity modulates CRC in a consensus molecular subtype (CMS)-dependent manner. RNA-seq data and associated tumor and patient characteristics including body weight and height data for 232 patients were obtained from The Cancer Genomic Atlas-Colon Adenocarcinoma (TCGA-COAD) database. Tumor samples were classified into the four CMSs with the CMScaller R package; body mass index (BMI) was calculated and categorized as normal, overweight, and obese. We observed a significant difference in CMS categorization between BMI categories. Differentially expressed genes (DEGs) between obese and overweight samples and normal samples differed across the CMSs, and associated prognostic analyses indicated that the DEGs had differing associations on survival. Using Gene Set Enrichment Analysis, we found differences in Hallmark gene set enrichment between obese and overweight samples and normal samples across the CMSs. We constructed Protein-Protein Interaction networks and observed differences in obesity-regulated hub genes for each CMS. Finally, we analyzed and found differences in predicted drug sensitivity between obese and overweight samples and normal samples across the CMSs. Our findings support that obesity impacts the CRC tumor transcriptome in a CMS-specific manner. The possible associations reported here are preliminary and will require validation using in vitro and animal models to examine the CMS-dependence of the genes and pathways. Once validated the obesity-linked genes and pathways may represent new therapeutic targets to treat colon cancer in a CMS-dependent manner.

Whole-Genome Shotgun Metagenomic Sequencing Reveals Distinct Gut Microbiome Signatures of Obese Cats.

Overweight and obesity are growing health problems in domestic cats, increasing the risks of insulin resistance, lipid dyscrasias, neoplasia, cardiovascular disease, and decreasing longevity. The signature of obesity in the feline gut microbiota has not been studied at the whole-genome metagenomic level. We performed whole-genome shotgun metagenomic sequencing in the fecal samples of eight overweight/obese and eight normal cats housed in the same research environment. We obtained 271 Gbp of sequences and generated a 961-Mbp de novo reference contig assembly, with 1.14 million annotated microbial genes. In the obese cat microbiome, we discovered a significant reduction in microbial diversity (P < 0.01) and Firmicutes abundance (P = 0.005), as well as decreased Firmicutes/Bacteroidetes ratios (P = 0.02), which is the inverse of obese human/mouse microbiota. Linear discriminant analysis and quantitative PCR (qPCR) validation revealed significant increases of Bifidobacterium sp., Olsenella provencensis, Dialister sp.CAG:486, and Campylobacter upsaliensis as the hallmark of obese microbiota among 400 enriched species, whereas 1,525 bacterial species have decreased abundance in the obese microbiome. Phascolarctobacterium succinatutens and an uncharacterized Erysipelotrichaceae bacterium are highly abundant (>0.05%) in the normal gut with over 400-fold depletion in the obese microbiome. Fatty acid synthesis-related pathways are significantly overrepresented in the obese compared with the normal cat microbiome. In conclusion, we discovered dramatically decreased microbial diversity in obese cat gut microbiota, suggesting potential dysbiosis. A panel of seven significantly altered, highly abundant species can serve as a microbiome indicator of obesity. Our findings in the obese cat microbiome composition, abundance, and functional capacities provide new insights into feline obesity. IMPORTANCE Obesity affects around 45% of domestic cats, and licensed drugs for treating feline obesity are lacking. Physical exercise and calorie restrictions are commonly used for weight loss but with limited efficacy. Through comprehensive analyses of normal and obese cat gut bacteria flora, we identified dramatic shifts in the obese gut microbiome, including four bacterial species significantly enriched and two species depleted in the obese cats. The key bacterial community and functional capacity alterations discovered from this study will inform new weight management strategies for obese cats, such as evaluations of specific diet formulas that alter the microbiome composition, and the development of prebiotics and probiotics that promote the increase of beneficial species and the depletion of obesity-associated species. Interestingly, these bacteria identified in our study were also reported to affect the weight loss success in human patients, suggesting translational potential in human obesity.

Association of CIDEB gene promoter methylation with overweight or obesity in adults.

OBJECTIVE: To explore the association of the methylation level of cell death-inducing DFF45-like effector B (CIDEB) gene promoter with overweight or obesity in the abdominal subcutaneous adipose tissue (SAT) and omental adipose tissue (OAT) of adults. METHODS: A total of 61 patients undergoing abdominal surgery in the hospital were selected with an average age of 51.87 years. According to the diagnostic criteria of Chinese adult obesity, the subjects were divided into normal-weight group (n = 28) and overweight/obesity group (n = 33). CIDEB promoter methylation level in abdominal SAT and OAT was detected by the MethylTarget technology, then its relationship with overweight or obesity was analyzed. RESULTS: (1) There were no statistical differences between the normal-weight group and overweight/obesity group in Methylation levels of 16 CpG sites in the CIDEB gene promoter sequence. (2) The methylation level of OAT was higher than that of SAT, and there were significant differences in 16 CpG sites. (3) There were 3 statistically significant haplotypes between the normal-weight group and overweight/obesity group (2 in SAT and 1 in OAT). CONCLUSIONS: The methylation level of CIDEB gene promoter in abdominal SAT and OAT may be related to overweight or obesity in adults, and the specific regulatory mechanism needs to be further studied.

Associations between Gene-Gene Interaction and Overweight/Obesity of 12-Month-Old Chinese Infants.

Background: Childhood overweight and obesity (OW/OB) is a worldwide public health problem, and its genetic risks remain unclear. Objectives: To investigate risks of OW/OB associated with genetic variances in SEC16B rs543874 and rs10913469, BDNF rs11030104 and rs6265, NT5C2 rs11191580, PTBP2 rs11165675, ADCY9 rs2531995, FAM120A rs7869969, KCNQ1 rs2237892, and C4orf33 rs2968990 in Chinese infants at 12-month old. Methods: We conducted a case-control study with 734 infants included at delivery and followed up to 12-month old. The classification and regression tree analysis were used to generate the structure of the gene-gene interactions, while the unconditional multivariate logistic regression models were applied to analyze the single SNP, gene-gene interactions, and cumulative effects of the genotypes on OW/OB, adjusted for potential confounders. Results: There were 219 (29.84%) OW/OB infants. Rs543874 G allele and rs11030104 AA genotype increased the risk of OW/OB in 12-month-old infants (P < 0.05). Those carrying both rs11030104 AA genotype and rs10913469 C allele had 4.3 times greater OW/OB than those carrying rs11030104 G allele, rs11191580 C allele, rs11165675 A allele, and rs543874 AA genotype. Meanwhile, the risk of OW/OB increased with the number of the risk genotypes individuals harbored. Conclusions: Rs543874, rs11030104, and rs11191580 were associated with OW/OB in 12-month-old Chinese infants, and the three SNPs together with rs10913469 and rs11165675 had a combined effect on OW/OB.

Smoking during pregnancy is associated with child overweight independent of maternal pre-pregnancy BMI and genetic predisposition to adiposity.

High maternal body mass index (BMI) and smoking during pregnancy are risk factors for child overweight. Maternal smoking tends to reduce her BMI and the association of smoking with child overweight may be confounded by or interacting with maternal genetic predisposition to adiposity. In the Danish National Birth Cohort, we investigated whether smoking during pregnancy is associated with child BMI/overweight independent of pre-pregnancy BMI and maternal genetic predisposition to adiposity estimated as total, transmitted and non-transmitted genetic risk scores (GRSs) based on 941 common genetic variants associated with BMI. Smoking during pregnancy was associated with higher child BMI and higher odds of child overweight in a dose-response relationship. The odds ratio (95% CI) for smoking 11 + cigarettes in third trimester versus no smoking was 2.42 (1.30; 4.50), irrespective of maternal BMI and maternal GRSs (total, transmitted or non-transmitted). There were no statistically significant interactions between maternal GRSs and smoking (all p-values for interactions > 0.05). In conclusion, in this study, smoking during pregnancy exhibits a dose-response association with increased child BMI/overweight, independent of maternal pre-pregnancy BMI, maternal transmitted, and non-transmitted genetic predisposition to adiposity. Avoidance of smoking during pregnancy may help prevent childhood obesity irrespective of the mother-child genetic predisposition.

Overweight/obesity-related transcriptomic signature as a correlate of clinical outcome, immune microenvironment, and treatment response in hepatocellular carcinoma.

Backgrounds: The pandemic of overweight and obesity (quantified by body mass index (BMI) ≥ 25) has rapidly raised the patient number of non-alcoholic fatty hepatocellular carcinoma (HCC), and several clinical trials have shown that BMI is associated with the prognosis of HCC. However, whether overweight/obesity is an independent prognostic factor is arguable, and the role of overweight/obesity-related metabolisms in the progression of HCC is scarcely known. Materials and methods: In the present study, clinical information, mRNA expression profile, and genomic data were downloaded from The Cancer Genome Atlas (TCGA) as a training cohort (TCGA-HCC) for the identification of overweight/obesity-related transcriptome. Machine learning and the Cox regression analysis were conducted for the construction of the overweight/obesity-associated gene (OAG) signature. The Kaplan-Meier curve, receiver operating characteristic (ROC) curve, and the Cox regression analysis were performed to assess the prognostic value of the OAG signature, which was further validated in two independent retrospective cohorts from the International Cancer Genome Consortium (ICGC) and Gene Expression Omnibus (GEO). Subsequently, functional enrichment, genomic profiling, and tumor microenvironment (TME) evaluation were utilized to characterize biological activities associated with the OAG signature. GSE109211 and GSE104580 were retrieved to evaluate the underlying response of sorafenib and transcatheter arterial chemoembolization (TACE) treatment, respectively. The Genomics of Drug Sensitivity in Cancer (GDSC) database was employed for the evaluation of chemotherapeutic response. Results: Overweight/obesity-associated transcriptome was mainly involved in metabolic processes and noticeably and markedly correlated with prognosis and TME of HCC. Afterward, a novel established OAG signature (including 17 genes, namely, GAGE2D, PDE6A, GABRR1, DCAF8L1, DPYSL4, SLC6A3, MMP3, RIBC2, KCNH2, HTRA3, PDX1, ATHL1, PRTG, SHC4, C21orf29, SMIM32, and C1orf133) divided patients into high and low OAG score groups with distinct prognosis (median overall survival (OS): 24.87 vs. 83.51 months, p < 0.0001), and the values of area under ROC curve (AUC) in predicting 1-, 2-, 3-, and 4-year OS were 0.81, 0.80, 0.83, and 0.85, respectively. Moreover, the OAG score was independent of clinical features and also exhibited a good ability for prognosis prediction in the ICGC-LIHC-JP cohort and GSE54236 dataset. Expectedly, the OAG score was also highly correlated with metabolic processes, especially oxidative-related signaling pathways. Furthermore, abundant enrichment of chemokines, receptors, MHC molecules, and other immunomodulators as well as PD-L1/PD-1 expression among patients with high OAG scores indicated that they might have better responses to immunotherapy. However, probably exclusion of T cells from infiltrating tumors resulting in lower infiltration of effective T cells would restrict immunotherapeutic effects. In addition, the OAG score was significantly associated with the response of sorafenib and TACE treatment. Conclusions: Overall, this study comprehensively disclosed the relationship between BMI-guided transcriptome and HCC. Moreover, the OAG signature had the potential clinical applications in the future to promote clinical management and precision medicine of HCC.

Body Mass Index, Weight Loss, and Mortality Risk in Advanced-Stage Non-Small Cell Lung Cancer Patients: A Focus on EGFR Mutation.

Body mass index (BMI) influences the prognosis of patients with non-small cell lung cancer (NSCLC), including both early-stage and late-stage NSCLC patients that are undergoing chemotherapies. However, earlier research on the relationship between BMI and survival in patients taking epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) yielded contradictory results. These publications either had a limited number of patients or were getting TKIs in various lines of therapy, which might explain why the outcomes were contradictory. As a result, we undertook retrospective study to examine the effect of BMI on survival outcomes in patients with advanced EGFR mutant NSCLC receiving first-line EGFR-TKIs. We also compared the findings to those with wild-type EGFR. Between November 2010 and March 2014, 513 patients with advanced NSCLC were enrolled in the study. According to the adjusted BMI cut-off point for Asia, 35 out of 513 (6.8%) patients were underweight (BMI < 18.5 kg/m2), whereas 197 (38.4%) were overweight (BMI > 24 kg/m2). Overweight patients with wild-type EGFR exhibited longer progression-free survival (4.6 vs. 2.1 months, p = 0.003) and overall survival (OS) (8.9 vs. 4.3 months, p = 0.003) than underweight patients. Overweight patients with EGFR mutations had a longer OS than normal-weight patients (23.0 vs. 20.2 months, p = 0.025). Bodyweight reduction was related to a shorter OS in both the mutant EGFR patients (17.1 vs. 30.5 months, p < 0.001) and the wild-type EGFR patients (7.8 vs. 18.7 months, p < 0.001). In conclusion, advanced stages NSCLC patients with a lower BMI and early weight loss had a worse outcome that was independent of EGFR mutation status.