The porcine fat mass and obesity associated (FTO) gene is associated with fat deposition in Italian Duroc pigs

In humans, common variants in the fat mass and obesity associated ( FTO ) gene are associated with body mass index and obesity. Here we sequenced exon 4, parts of introns 3 and 4 and two portions of the 3'-untranslated region of the porcine FTO gene in a panel of nine pigs of different breeds and identified three SNPs. Allele frequencies of the g.276T>G ( AM931150 ) mutation were studied in seven pig breeds. This mutation was used to linkage-map FTO to SSC6. Association analyses between the g.276T>G polymorphism and several traits [pH of semimembranosus muscle and estimated breeding values (EBV) for average daily gain, back fat thickness, lean cuts, ham weight and feed:gain ratio] were carried out in 257 sib-tested Italian Large White pigs. Only feed:gain ratio showed P  <   0.05. A selective genotyping approach was applied, analysing two extreme and divergent groups of Italian Large White pigs selected on the basis of back fat thickness EBV (50 with most positive and 50 with most negative values). Fisher's exact test (two-tailed) was not significant when comparing the allele frequencies of these two groups. The same approach was used in the Italian Duroc breed for which two extreme and divergent groups of animals were selected according to visible intermuscular fat EBV. Differences of allele frequencies between these two groups were highly significant ( P  <   0.00001, P  <   0.001 and P  <   0.0001, considering all animals or only two- or three-generation unrelated animals respectively), indicating association between the analysed FTO marker and intermuscular fat deposition.     

The rs9939609 polymorphism in the fat mass and obesity associated (FTO) gene is associated with obesity in Tunisian population

Abstract

Context: Variations in the fat mass and obesity-associated gene (FTO) has been associated with obesity in many populations, but the results are conflicting.

Objective: The aim of this study was to evaluate the effect of the rs9939609 polymorphism in the FTO gene on obesity risk and plasma leptin, adiponectin, insulin and lipid concentrations in Tunisians.

Materials and methods: Four hundred and ninety-four subjects with obesity and 334 non-obese participated in this study. The rs9939609 (T/A) genotype was determined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method.

Results: Significant differences in genotype frequencies were observed between cases and controls. In the separate analysis by gender, the association between the AA genotype and obesity was statistically significant in women but not in men. After stratification by obesity class this association remains only with obesity class III.

Discussion: Our study is in agreement with studies on Caucasian, Portuguese and Cebu Filipino populations where a gender-specific association was found between rs9939609 polymorphism and obesity. It is also in agreement with studies on Mexican, Spanish and European populations, where an association was found with obesity class III.

Conclusion: The rs9939609 polymorphism of FTO gene is associated with obesity, especially obesity class III in women.     

The FTO gene is associated with adulthood obesity in the Mexican population

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.     

The fat mass and obesity associated gene FTO functions in the brain to regulate postnatal growth in mice

FTO (fat mass and obesity associated) was identified as an obesity-susceptibility gene by several independent large-scale genome association studies. A cluster of SNPs (single nucleotide polymorphism) located in the first intron of FTO was found to be significantly associated with obesity-related traits, such as body mass index, hip circumference, and body weight. FTO encodes a protein with a novel C-terminal α-helical domain and an N-terminal double-strand β-helix domain which is conserved in Fe(II) and 2-oxoglutarate-dependent oxygenase family. In vitro, FTO protein can demethylate single-stranded DNA or RNA with a preference for 3-methylthymine or 3-methyluracil. Its physiological substrates and function, however, remain to be defined. Here we report the generation and analysis of mice carrying a conditional deletion allele of Fto. Our results demonstrate that Fto plays an essential role in postnatal growth. The mice lacking Fto completely display immediate postnatal growth retardation with shorter body length, lower body weight, and lower bone mineral density than control mice, but their body compositions are relatively normal. Consistent with the growth retardation, the Fto mutant mice have reduced serum levels of IGF-1. Moreover, despite the ubiquitous expression of Fto, its specific deletion in the nervous system results in similar phenotypes as the whole body deletion, indicating that Fto functions in the central nerve system to regulate postnatal growth.     

The MTHFR gene polymorphism is associated with lean body mass but not fat body mass

Along with aging, human body composition undergoes notable changes and may incur sarcopenia, obesity or osteoporosis. Sarcopenia is related to a wide series of human health problems and can be largely characterized by loss of lean body mass (LBM). Studies have showed relevance of methylenetetrahydrofolate reductase (MTHFR) with variation in LBM and fat body mass (FBM). To test if polymorphism of the MTHFR gene is underlying the pathology of sarcopenia and obesity, we concurrently tested five single nucleotide polymorphisms (SNPs) of the MTHFR gene for association with LBM, FBM and body mass index (BMI) in 405 Caucasian nuclear families comprising 1,873 individuals. After correction for multiple testing, we detected significant associations for LBM with rs2066470 (P = 0.0006), rs4846048 (P = 0.0007) and with rs3737964 (P = 0.004), as well as for BMI with rs4846048 (P = 0.009). Polymorphism of rs2066470 explains 3.67% of LBM variation in this sample. The association between BMI and rs4846048 diminished after adjusting for LBM, suggesting that the association between BMI and rs4846048 is largely due to LBM instead of the fat component. In concert, no significant associations were identified for FBM with any of the studied SNPs. The results of single-locus association analyses were corroborated by haplotype-based analyses. In summary, the MTHFR gene polymorphism is associated with LBM, suggesting that MTHFR may play an important role in LBM variation. In addition, the MTHFR gene polymorphism is not associated with FBM or obesity in this sample.     

Polycystic ovary syndrome is linked with the fat mass obesity (FTO) gene variants rs17817449 and rs1421085 in western Saudi Arabia

Polycystic ovary syndrome (PCOS) is characterised by infertility, obesity, insulin resistance and clinical and/or biochemical signs of hyperandrogenism. Obesity is known to be correlated with PCOS causing ovulatory dysfunction and hormone imbalances. Moreover, fat mass and the obesity gene (FTO) were linked with obesity and PCOS. Therefore, it is of interest to determine the genotype and allele frequency for three FTO variants - rs17817449 (G/T), rs1421085 (C/T) and rs8050136 (A/C) -in western Saudi population. 95 PCOS patients and 94 controls were recruited for this study. The genetic variants were assayed using real-time polymerase chain reaction using TaqMan genotyping assays. The chi-squared test was applied to investigate the difference between single nucleotide polymorphisms on PCOS and control subjects, and binary logistic regression was used to determine the association of FTO variants with PCOS symptoms. Variants rs17817449 and rs1421085 were significantly linked with PCOS susceptibility in the study population. Rs17817449 and rs8050136 were significantly associated with hair loss in the PCOS group. Furthermore, rs1421085 and rs8050136 were associated with a high body mass index (BMI>30 kg/m2). Risk alleles in our population associated with hair loss and elevated BMI in women with PCOS were homozygous C for rs8050136. This data will help in defining the genetic predisposition of PCOS among women in western Saudi Arabia.     

Genome wide association (GWA) study for early onset extreme obesity supports the role of fat mass and obesity associated gene (FTO) variants

Background

Obesity is a major health problem. Although heritability is substantial, genetic mechanisms predisposing to obesity are not very well understood. We have performed a genome wide association study (GWA) for early onset (extreme) obesity.

Methodology/Principal Findings

a) GWA (Genome-Wide Human SNP Array 5.0 comprising 440,794 single nucleotide polymorphisms) for early onset extreme obesity based on 487 extremely obese young German individuals and 442 healthy lean German controls; b) confirmatory analyses on 644 independent families with at least one obese offspring and both parents. We aimed to identify and subsequently confirm the 15 SNPs (minor allele frequency ≥10%) with the lowest p-values of the GWA by four genetic models: additive, recessive, dominant and allelic. Six single nucleotide polymorphisms (SNPs) in FTO (fat mass and obesity associated gene) within one linkage disequilibrium (LD) block including the GWA SNP rendering the lowest p-value (rs1121980; log-additive model: nominal p = 1.13×10⁻⁷, corrected p = 0.0494; odds ratio (OR)_CT 1.67, 95% confidence interval (CI) 1.22–2.27; OR_TT 2.76, 95% CI 1.88–4.03) belonged to the 15 SNPs showing the strongest evidence for association with obesity. For confirmation we genotyped 11 of these in the 644 independent families (of the six FTO SNPs we chose only two representing the LD bock). For both FTO SNPs the initial association was confirmed (both Bonferroni corrected p<0.01). However, none of the nine non-FTO SNPs revealed significant transmission disequilibrium.

Conclusions/Significance

Our GWA for extreme early onset obesity substantiates that variation in FTO strongly contributes to early onset obesity. This is a further proof of concept for GWA to detect genes relevant for highly complex phenotypes. We concurrently show that nine additional SNPs with initially low p-values in the GWA were not confirmed in our family study, thus suggesting that of the best 15 SNPs in the GWA only the FTO SNPs represent true positive findings.     

No genetic footprints of the fat mass and obesity associated (FTO) gene in human plasma 1H CPMG NMR metabolic profiles

In this paper it was investigated if any genotypic footprints from the fat mass and obesity associated (FTO) SNP could be found in 600 MHz ¹H CPMG NMR profiles of around 1,000 human plasma samples from healthy Danish twins. The problem was addressed with a combination of univariate and multivariate methods. The NMR data was substantially compressed using principal component analysis or multivariate curve resolution-alternating least squares with focus on chemically meaningful feature selection reflecting the nature of chemical signals in an NMR spectrum. The possible existence of an FTO signature in the plasma samples was investigated at the subject level using supervised multivariate classification in the form of extended canonical variate analysis, classification tree modeling and Lasso (L1) regularized linear logistic regression model (GLMNET). Univariate hypothesis testing of peak intensities was used to explore the genotypic effect on the plasma at the population level. The multivariate classification approaches indicated poor discriminative power of the metabolic profiles whereas univariate hypothesis testing provided seven spectral regions with p < 0.05. Applying false discovery rate control, no reliable markers could be identified, which was confirmed by test set validation. We conclude that it is very unlikely that an FTO-correlated signal can be identified in these ¹H CPMG NMR plasma metabolic profiles and speculate that high-throughput un-targeted genotype-metabolic correlations will in many cases be a difficult path to follow.     

Major gender difference in association of FTO gene variant among severely obese children with obesity and obesity related phenotypes

Recent studies have shown that SNPs in the FTO gene predispose to childhood and adult obesity. In this study, we examined the association between variants in FTO and KIAA1005, a gene that maps closely to FTO, and obesity, as well as obesity related traits among 450 well characterised severely obese children and 512 normal weight controls. FTO showed significant association with several obesity related traits while SNPs in KIAA1005 did not. When stratified by gender, the FTO variant rs9939609 showed association with obesity and BMI among girls (P = 0.006 and 0.004, respectively) but not among boys. Gender differences were also found in the associations of the FTO rs9939609 with obesity related traits such as insulin sensitivity and plasma glucose. This study suggests that FTO may have an important role for gender specific development of severe obesity and insulin resistance in children.     

The common rs9939609 gene variant of the fat mass- and obesity-associated gene FTO is related to fat cell lipolysis

We investigated the rs9939609 single nucleotide polymorphism of the FTO gene in relation to fat cell function and adipose tissue gene expression in 306 healthy women with a wide range in body mass index (18-53 kg/m(2)). Subcutaneous adipose tissue biopsies were taken for fat cell metabolism studies and in a subgroup (n = 90) for gene expression analyses. In homozygous carriers of the T-allele, the in vitro basal (spontaneous) adipocyte glycerol release was increased by 22% (P = 0.007) and the in vivo plasma glycerol level was increased by approximately 30% (P = 0.037) compared with carriers of the A allele. In contrast, there were no genotype effects on catecholamine-stimulated lipolysis or basal or insulin-induced lipogenesis. We found no difference between genotypes for adipose tissue mRNA levels of FTO, hormone-sensitive lipase, adipose triglyceride lipase, perilipin, or CGI-58. Finally, the adipose tissue level of FTO mRNA was increased in obesity (P = 0.002), was similar in subcutaneous and omental adipose tissue, was higher in fat cells than in fat tissue (P = 0.0007), and was induced at an early stage in the differentiation process (P = 0.004). These data suggest a role of the FTO gene in fat cell lipolysis, which may be important in explaining why the gene is implicated in body weight regulation.     

Nucleotide variability and haplotype heterogeneity at the porcine fat mass and obesity‐associated (FTO) gene

A large number of studies have confirmed that variants within the fat mass and obesity‐associated (FTO) gene are associated with higher obesity risk in humans. We and others have shown that FTO polymorphisms are associated with fat deposition and related traits in several pig populations, thus confirming the role of this gene in fatness across species. However, some differences observed in different pig populations may be derived, at least in part, from genetic heterogeneity at this locus. Here, we characterise the nucleotide variability and haplotype diversity of the porcine FTO gene in breeds having different predispositions to fat deposition traits. We resequenced 4749 bp of coding and non‐coding regions of the porcine FTO gene in 44 pigs of eight different breeds and identified 27 single nucleotide polymorphisms (SNPs) and four insertions/deletions. A positive Tajima's D‐value (P < 0.10) obtained in Italian Duroc pigs may be compatible with putative balancing selection. From the sequenced pig panel, 20 haplotypes were inferred, some of which clustered according to the breed of origin (Meishan and Italian Duroc). Genetic heterogeneity at this locus could complicate the dissection of the effects of this gene on fat deposition and production traits in pigs. This situation resembles, to some extent, what has been reported in humans, thus making the study of the porcine FTO gene variability especially interesting, as it could be used as a model to understand the complex and elusive role of this gene in human obesity.     

FTO and MC4R gene variants are associated with obesity in polycystic ovary syndrome

Polycystic ovary syndrome (PCOS) is the leading cause of anovulatory infertility in women. It is also associated with metabolic disturbances that place women at increased risk for obesity and type 2 diabetes. There is strong evidence for familial clustering of PCOS and a genetic predisposition. However, the gene(s) responsible for the PCOS phenotypes have not been elucidated. This two-phase family-based and case-control genetic study was designed to address the question of whether SNPs identified as susceptibility loci for obesity in genome-wide association studies (GWAS) are also associated with PCOS and elevated BMI. Members of 439 families having at least one offspring with PCOS were genotyped for 15 SNPs previously shown to be associated with obesity. Linkage and association with PCOS was assessed using the transmission/disequilibrium test (TDT). These SNPs were also analyzed in an independent case-control study involving 395 women with PCOS and 176 healthy women with regular menstrual cycles. Only one of these 15 SNPs (rs2815752 in NEGR1) was found to have a nominally significant association with PCOS (χ² = 6.11, P = 0.013), but this association failed to replicate in the case-control study. While not associated with PCOS itself, five SNPs in FTO and two in MC4R were associated with BMI as assessed with a quantitative-TDT analysis, several of which replicated association with BMI in the case-control cohort. These findings demonstrate that certain SNPs associated with obesity contribute to elevated BMI in PCOS, but do not appear to play a major role in PCOS per se. These findings support the notion that PCOS phenotypes are a consequence of an oligogenic/polygenic mechanism.     

Acquired obesity is associated with increased liver fat, intra-abdominal fat, and insulin resistance in young adult monozygotic twins

We determined whether acquired obesity is associated with increases in liver or intra-abdominal fat or impaired insulin sensitivity by studying monozygotic (MZ) twin pairs discordant and concordant for obesity. We studied nineteen 24- to 27-yr-old MZ twin pairs, with intrapair differences in body weight ranging from 0.1 to 24.7 kg [body mass index (BMI) range 20.0-33.9 kg/m2], identified from a population-based FinnTwin16 sample. Fat distribution was determined by magnetic resonance imaging, percent body fat by dual-energy X-ray absorptiometry, liver fat by proton spectroscopy, insulin sensitivity by measuring the fasting insulin concentration, and whole body insulin sensitivity by the euglycemic insulin clamp technique. Intrapair differences in BMI were significantly correlated with those in intra-abdominal fat (r = 0.82, P < 0.001) and liver fat (r = 0.57, P = 0.010). Intrapair differences in fasting insulin correlated with those in subcutaneous abdominal (r = 0.60, P = 0.008), intra-abdominal (r = 0.75, P = 0.0001) and liver (r = 0.49, P = 0.048) fat. Intrapair differences in whole body insulin sensitivity correlated with those in subcutaneous abdominal (r = -0.72, P = 0.001) and intra-abdominal (r = -0.55, P = 0.015) but not liver (r = -0.20, P = 0.20) fat. We conclude that acquired obesity is associated with increases in intra-abdominal and liver fat and insulin resistance, independent of genetic factors.     

Adipocyte size is associated with NAFLD independent of obesity,fat distribution,and PNPLA3 genotype

Objective: Adipocyte hypertrophy has been suggested to be causally linked with inflammation and systemic insulin resistance. The aim of the study was to determine whether increased adipocyte size is associated with increased liver fat content due to nonalcoholic fatty liver disease (NAFLD) in humans independent of obesity, fat distribution and genetic variation in the patatin‐like phospholipase domain‐containing 3 gene (PNPLA3; adiponutrin) at rs738409. Design and Methods: One hundred nineteen non‐diabetic subjects in a cross‐sectional study with a median age of 39 ( 26 ) years, mean ± SD BMI of 30.0 ± 5.7 kg m^?2 were studied. Abdominal subcutaneous (SC) adipocyte size, liver fat [proton magnetic resonance spectroscopy (¹H‐MRS)], intra‐abdominal (IA), and abdominal SC adipose tissue volumes [magnetic resonance imaging (MRI)] and the PNPLA3 genotype at rs738409 were determined. Univariate and multiple linear regression analysis were used to identify independent predictors of liver fat content. Results: In multiple linear regression analysis, age, gender, BMI, the IA/SC ratio, and PNPLA3 genotype explained 42% of variation in liver fat content. Addition of adipocyte size (P < 0.0001) to the model increased the percent of explanation to 53%. Thus, 21% of known variation in liver fat could be explained by adipocyte size alone. Conclusions: Increased adipocyte size highly significantly contributes to liver fat accumulation independent of other causes.     

Risk of obesity and metabolic syndrome associated with FTO gene variants discloses clinically relevant gender difference among Turks

Gene variations in the fat mass- and obesity-associated gene (FTO) have shown controversial associations with obesity and metabolic syndrome (MetS) in several populations. We explored the association of FTO gene with obesity, MetS, and insulin-related parameters separately in men and women. Two SNPs in the FTO, gene rs9939609 and rs1421085, were genotyped by the Taqman System in 1967 adults (mean age of the whole group 50.1 ± 12.0; 48.4 % male). A random sample of the Turkish Adult Risk Factor cohort was cross-sectionally analyzed. Both SNPs exhibited strong linkage disequilibrium (r² = 0.85) and minor alleles were associated with risk of obesity in women and of MetS in men. Carriers of the rs1421085 C-allele exhibited higher body mass index (BMI) in each gender. Adjusted fasting insulin and HOMA index were significantly higher in C-allele carriers in men alone. Logistic regression analysis demonstrated significantly increased likelihood for obesity in female C-risk allele carriers (OR 1.61; 95 % CI 1.19–2.18), after adjustment for age, smoking status, alcohol usage, physical activity grade and presence of diabetes mellitus. Male C-allele carriers were at increased risk for MetS (OR 1.44; 95 % CI 1.07–1.95), adjusted for age, smoking status, alcohol consumption, and physical activity. Further adjustment for BMI attenuated the MetS risk, indicating interaction between C-allele, gender and BMI. The FTO gene in Turkish adults contributes independently to obesity in women and—by interacting with BMI—to MetS and insulin resistance in men.     

Common variants in the CD36 gene are associated with oral fat perception, fat preferences, and obesity in African Americans

Animal studies show that CD36, a fatty acid translocase, is involved in fat detection and preference, but these findings have not been reported in humans. The objective of this study was to determine whether human genetic variation in 5 common CD36 polymorphisms is associated with oral fat perception of Italian salad dressings, self-reported acceptance of high-fat foods and obesity in African-American adults (n = 317). Ratings of perceived oiliness, fat content, and creaminess were assessed on a 170-mm visual analogue scale (VAS) in response to salad dressings that were 5%, 35%, and 55% fat-by-weight content. Acceptance of added fats and oils and high-fat foods was self-reported and anthropometric measures were taken in the laboratory. DNA was isolated from saliva and genotyped at 5 CD36 polymorphisms. Three polymorphisms, rs1761667, rs3840546, and rs1527483 were associated with the outcomes. Participants with the A/A genotype at rs1761667 reported greater perceived creaminess, regardless of the fat concentration of the salad dressings (P < 0.01) and higher mean acceptance of added fats and oils (P = 0.02) compared to those with other genotypes at this site. Individuals who had C/T or T/T genotypes at rs1527483 also perceived greater fat content in the salad dressings, independent of fat concentration (P = 0.03). BMI and waist circumference were higher in participants who were homozygous for a deletion (D/D) at rs3840546, compared to I/D or D/D individuals (P < 0.001), but only 2 D/D individuals were tested, so this finding needs replication. This is the first study to demonstrate an association between common variants in CD36 and fat ingestive behaviors in humans.     

The CAPN10 gene is associated with insulin resistance phenotypes in the Spanish population

Cardiovascular disease is the leading cause of morbidity and mortality in the industrialized world. Familial aggregation of cardiovascular risk factors is a frequent finding, but genetic factors affecting its presentation are still poorly understood. The calpain 10 gene (CAPN10) has been associated with type 2 diabetes (T2DM), a complex metabolic disorder with increased risk of cardiovascular disease. Moreover, the CAPN10 gene has been associated with the presence of metabolic syndrome (MS) in T2DM and in polycystic ovary syndrome (PCOS). In this work, we have analysed whether the polymorphisms UCSNP44, -43, -19 and -63 are related to several cardiovascular risk factors in the context of MS. Molecular analysis of CAPN10 gene was performed in 899 individuals randomly chosen from a cross-sectional population-based epidemiological survey. We have found that CAPN10 gene in our population is mainly associated with two indicators of the presence of insulin resistance: glucose levels two hours after a 75-g oral glucose tolerance test (OGTT) and HOMA values, although cholesterol levels and blood pressure values are also influenced by CAPN10 variants. In addition, the 1221/1121 haplogenotype is under-represented in individuals that fulfil the International Diabetes Federation (IDF) diagnostic criteria for MS. Our results suggest that CAPN10 gene is associated with insulin resistance phenotypes in the Spanish population.     

The polymorphisms of UCP1 genes associated with fat metabolism,obesity and diabetes

Uncoupling protein 1 (UCP1), a 32-kDa protein located in the inner mitochondrial membrane, is abundant in brown adipose tissue, as a proton transporter in mitochondria inner membrane which uncouples oxidative metabolism from ATP synthesis and dissipates energy through the heat. UCP1 has been reported to play important roles for energy homeostasis in rodents and neonate of larger mammals including human. Recently, numerous candidate genes were searched to determine the genetic factors implicated in the pathogenesis of obesity, related metabolic disorders and diabetes. UCP-1, which plays a major role in thermogenesis, was suggested to be one of the candidates. This review summarizes data supporting the existence of brown adipocytes and the role of UCP1 in energy dissipation in adult humans, and the genetic variety association with the fat metabolism, obesity and diabetes.     

The different correlations between obesity and osteoporosis after adjustment of static mechanical loading from weight and fat free mass

Objectives:To explore complex correlations between obesity (OB) and osteoporosis (OP) after adjustment of static mechanical loading from weight and fat free mass (FFM).Methods:A total of 3749 Chinese aged ≥65 years were selected from our ongoing cohort study. OB indices and bone mineral density (BMD) were measured for each subject. Linear regression analyses were performed to explore the correlations between OB indices and OP under three adjustment models (unadjusted, adjusted with weight and adjusted with FFM).Results:Under no adjustment, three general obesity indices (body mass index: BMI, fat mass: FM, and percentage FM: PFM) were positively associated with BMD at three skeletal sites (P<0.001) in the regression analyses. However, after the adjustment with weight, these associations were mostly significant but reverse i.e., negatively in direction. After adjustment with FFM, the three indices were still positively and significantly (P<0.001) associated with BMD but regression coefficients were smaller compared to the unadjusted associations. Similar associations were observed for central adiposity and lower limb adiposity indices.Conclusions:The combined relation of OB to OP due to the physiological factors secreted from adipose tissues and the static mechanical loading from FM is positive in direction.