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Adiposity is an established risk factor for multiple diseases, but the causal relationships of different adiposity types with circulating protein biomarkers have not been systematically investigated. We examine the causal associations of general and central adiposity with 2923 plasma proteins among 3977 Chinese adults (mean BMI = 23.9 kg/m²). Genetically-predicted body mass index (BMI), body fat percentage (BF%), waist circumference (WC), and waist-to-hip ratio (WHR) are significantly (FDR < 0.05) associated with 399, 239, 436, and 283 proteins, respectively, with 80 proteins associated with all four and 275 with only one adiposity trait. WHR is associated with the most proteins (n = 90) after adjusting for other adiposity traits. These associations are largely replicated in Europeans (mean BMI = 27.4 kg/m²). Two-sample Mendelian randomisation (MR) analyses in East Asians using cis-protein quantitative trait locus (cis-pQTLs) identified in GWAS find 30/2 proteins significantly affect levels of BMI/WC, respectively, with 10 showing evidence of colocalisation, and seven (inter-alpha-trypsin inhibitor heavy chain H3, complement factor B, EGF-containing fibulin-like extracellular matrix protein 1, thioredoxin domain-containing protein 15, alpha-2-antiplasmin, fibronectin, mimecan) are replicated in separate MR using different cis-pQTLs identified in Europeans. These findings identified potential novel mechanisms and targets, to our knowledge, for improved treatment and prevention of obesity and associated diseases., (© 2024. The Author(s).)

Adiposity is associated with multiple diseases and traits, but little is known about the causal relevance and mechanisms underlying these associations. Large-scale proteomic profiling, especially when integrated with genetic data, can clarify mechanisms linking adiposity with disease outcomes. We examined the associations of adiposity with plasma levels of 1463 proteins in 3977 Chinese adults, using measured and genetically-instrumented BMI. We further used two-sample bi-directional MR analyses to assess if certain proteins influenced adiposity, along with other (e.g. enrichment) analyses to clarify possible mechanisms underlying the observed associations. Overall, the mean (SD) baseline BMI was 23.9 (3.3) kg/m 2 , with only 6% being obese (i.e. BMI ≥ 30 kg/m 2 ). Measured and genetically-instrumented BMI was significantly associated at FDR < 0.05 with levels of 1096 (positive/inverse: 826/270) and 307 (positive/inverse: 270/37) proteins, respectively, with FABP4, LEP, IL1RN, LSP1, GOLM2, TNFRSF6B, and ADAMTS15 showing the strongest positive and PON3, NCAN, LEPR, IGFBP2 and MOG showing the strongest inverse genetic associations. These associations were largely linear, in adiposity-to-protein direction, and replicated (> 90%) in Europeans of UKB (mean BMI 27.4 kg/m 2 ). Enrichment analyses of the top > 50 BMI-associated proteins demonstrated their involvement in atherosclerosis, lipid metabolism, tumour progression and inflammation. Two-sample bi-directional MR analyses using cis-pQTLs identified in CKB GWAS found eight proteins (ITIH3, LRP11, SCAMP3, NUDT5, OGN, EFEMP1, TXNDC15, PRDX6) significantly affect levels of BMI, with NUDT5 also showing bi-directional association. The findings among relatively lean Chinese adults identified novel pathways by which adiposity may increase disease risks and novel potential targets for treatment of obesity and obesity-related diseases., (© 2023. The Author(s).)

We used an established mediation analysis to investigate the role of adiposity in the relation between serum 25(OH)D with markers of inflammation and glucose and insulin metabolism. We used data from National Health and Nutrition Examination Survey (2005-2010), to evaluate the associations between serum 25(OH)D and markers of insulin resistance (IR) or inflammation, and whether these associations are mediated by adiposity factors. Analysis of co-variance and conceptual causal mediation analysis were conducted taking into consideration the survey design and sample weights. BMI was found to have significant mediation effects (to varied extent) on the associations between serum 25(OH)D and CRP, apo-B, fasting glucose, insulin, HOMA-IR, HOMA-B and HbA1c (all P < 0·05). Both WC and apVAT were also found to partly mediate the associations between serum 25 25(OH)D with CRP, FBG, HbA1c, TAG and HDL-cholesterol (all P < 0·05). These findings support the importance of optimising 25(OH)D status in conditions with abnormal adiposity (i.e. obesity) and treatments for the prevention of cardiometabolic diseases affecting adipose tissue metabolism (i.e. weight loss).

Background and Aims: While low-density lipoprotein cholesterol (LDL-C) is a good predictor of atherosclerotic cardiovascular disease, apolipoprotein B (ApoB) is superior when the two markers are discordant. We aimed to determine the impact of adiposity, diet and inflammation upon ApoB and LDL-C discordance., Methods and Results: Machine learning (ML) and structural equation models (SEMs) were applied to the National Health and Nutrition Examination Survey to investigate cardiometabolic and dietary factors when LDL-C and ApoB are concordant/discordant. Mendelian randomisation (MR) determined whether adiposity and inflammation exposures were causal of elevated/decreased LDL-C and/or ApoB. ML showed body mass index (BMI), dietary saturated fatty acids (SFA), dietary fibre, serum C-reactive protein (CRP) and uric acid were the most strongly associated variables (R 2  = 0.70) in those with low LDL-C and high ApoB. SEMs revealed that fibre (b = -0.42, p = 0.001) and SFA (b = 0.28, p = 0.014) had a significant association with our outcome (joined effect of ApoB and LDL-C). BMI (b = 0.65, p = 0.001), fibre (b = -0.24, p = 0.014) and SFA (b = 0.26, p = 0.032) had significant associations with CRP. MR analysis showed genetically higher body fat percentage had a significant causal effect on ApoB (Inverse variance weighted (IVW) = Beta: 0.172, p = 0.0001) but not LDL-C (IVW = Beta: 0.006, p = 0.845)., Conclusion: Our data show increased discordance between ApoB and LDL-C is associated with cardiometabolic, clinical and dietary abnormalities and that body fat percentage is causal of elevated ApoB., Competing Interests: Declaration of competing interest None declared., (Copyright © 2021 The Italian Diabetes Society, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition and the Department of Clinical Medicine and Surgery, Federico II University. All rights reserved.)

We explored the role of lipid accumulation products and visceral adiposity on the association between red meat consumption (RMC) and markers of insulin resistance (IR) and inflammation in USA adults. Data on RMC and health outcome measurements were extracted from the 2005-2010 US National Health and Nutrition Examination Surveys. Overall 16 621 participants were included in the analysis (mean age = 47·1 years, 48·3 % men). ANCOVA and 'conceptus causal mediation' models were applied while accounting for survey design. In adjusted models, a lower RMC was significantly associated with a cardio-protective profile of IR and inflammation. BMI had significant mediation effects on the association between RMC and C-reactive protein (CRP), apo B, fasting blood glucose (FBG), insulin, homoeostatic model assessment of IR and β-cell function, glycated Hb (HbA1c), TAG:HDL ratio and TAG glucose (TyG) index (all Ps < 0·05). Both waist circumference and anthropometrically predicted visceral adipose tissue mediated the association between RMC and CRP, FBG, HbA1c, TAG:HDL ratio and TyG index (all Ps < 0·05). Our findings suggest that adiposity, particularly the accumulation of abdominal fat, accounts for a significant proportion of the associations between red meat consumption, IR and inflammation.

Background: In animal models, histological and biochemical changes are observed in response to choline deficiency. It is unclear whether dietary choline is linked to non-alcoholic fatty liver disease (NAFLD). Objective: We examined the link among liver tests, fatty liver index (FLI), and choline consumption. Furthermore, we evaluated the impact of adiposity on this association. Method: The National Health and Nutrition Examination Survey (NHANES) was used to obtain data on choline intake and liver function biomarkers. Masked variance and weighting methodology were performed to account for the complex NHANES data. Results: Of the 20,643 participants, 46.8% were men and 45.6% had NAFLD (defined as United States FLI ≥30). In a fully adjusted model (for demographic, dietary, and clinical factors), a significant negative association was found between FLI and choline consumption ( β  = -0.206, p  < 0.001). Participants in the highest quartile (Q4) of choline intake had a 14% lower risk of NAFLD compared with those in the first quartile (Q1). This link was stronger for postmenopausal women; women in Q4 had a 26% lower risk of NAFLD compared with those in Q1. Body mass index (BMI) strongly moderated the link between FLI and choline intake. For example, when choline consumption increased from low (272 mg/d) to high (356 mg/d), FLI decreased from 79.3 to 74.1 in the low BMI category (mean BMI = 22.1 kg/m 2 ) and from 32.1 to 20.6 in the high BMI category (mean BMI =35.9 kg/m 2 ). Conclusions: Our results suggest the presence of a reverse significant association between choline intake and risk of NAFLD. Furthermore, BMI was shown to mediate this relationship since changes in FLI, in relation to choline consumption, were more pronounced in participants with a higher BMI.

Background: The prevalence of non-alcoholic fatty liver disease (NAFLD) is rising. This increase may be associated with obesity. It has been suggested that trans-fatty acids (TFAs) play an important role in non-communicable diseases., Aim: We examined the link between liver tests, fatty liver index (FLI) and plasma TFAs. Furthermore, we evaluated the impact of adiposity on this link., Methods: The National Health and Nutrition Examination Survey (NHANES) was used to obtain the data on TFAs and liver function biomarkers. We took account of complex NHANES data, masked variance and weighting methodology., Results: Of the 4252 participants, 46.4% were men. The mean age was 50.6 years overall; 51.3 years for men and 49.8 years for women (p = 0.206). In a fully adjusted model (demographic and clinical factors), FLI increased as trans-9-hexadecenoic acid and trans-11-octadecenoic acid levels increased; FLI was 38.1 and 42.3 for the first quarter (Q1) of trans-9-hexadecenoic acid and trans-11-octadecenoic acid, respectively, reaching 65.1 and 69.3 for the highest quarters (Q4) (p < 0.001 for all comparisons). Multivariable logistic regression showed for all four studied TFAs, the likelihood of NAFLD (determined by FLI) increased with increasing TFAs levels (quartiles) in a stepwise manner (p < 0.001 for all comparisons). Based on moderation analysis, a strong impact of body mass index (BMI) on the link between FLI and TFAs was observed., Conclusions: Our results suggest a direct significant association between plasma TFAs, liver tests and NAFLD (assessed by FLI). Furthermore, BMI was shown to mediate this relationship. These findings highlight the importance of avoiding TFAs consumption in order to minimize cardiometabolic risk., (Copyright © 2018. Published by Elsevier B.V.)

We examined the association between plasma antioxidant levels and markers of inflammation, including C-reactive protein (CRP) and fibrinogen (FG) in US adults. National Health and Nutrition Examination Survey participants examined between 2001 and 2002 were included, if data on CRP or FG levels. Serum vitamins A and E, two retinyl esters, and six carotenoids were measured using HPLC with photodiode array detection. Multivariable-adjusted linear regression analyses accounted for the survey design and sample weights. A total of 784 eligible participants were included; 47·5 % (n 372) were men. In multivariable linear regression models, serum α-carotene, trans-β-carotene, cis-β-carotene, β-cryptoxanthin, combined lutein/zeaxanthin, trans-lycopene, retinyl palmitate, α-tocopherol, retinol and 25-hydroxy vitamin D were negatively associated with serum CRP (P3 mg/l, decreased with increasing levels of antioxidants (α-carotene, trans-β-carotene, cis-β-carotene, vitamins A and E). Furthermore, we found a moderate impact of adiposity on the link between antioxidants and CRP. Our results suggest that the lower the antioxidants levels, the higher the inflammatory burden, based on CRP and FG levels. Adiposity moderately affects this association. Furthermore, an inverse relationship between CVD risk and antioxidant levels was observed. This finding suggests that reduced levels of vitamins with antioxidant properties may predispose to increased CVD risk.

Background: Growing evidence suggests an inverse association between whole grain (WG) consumption and insulin resistance (IR) or inflammation. However, it is still unclear whether adiposity plays a role in this relationship. We investigated whether the associations between WG intake with IR, glucose homeostasis and inflammation are mediated by adiposity in US adults., Methods: The 2005-2010 National Health and Nutrition Examination Surveys participants were included. WG intake was assessed and markers of IR and glucose homeostasis, inflammation, general and central adiposity. Analysis of co-variance and mediation analysis were applied, while accounting for survey design., Results: Overall 16,621 participants were included in this analysis (mean age = 47.1 years, 48.3% men). After adjustment for age, gender, and race, mean C-reactive protein (CRP), apolipoprotein B (apo-B), fasting blood glucose (FBG), insulin, homeostatic model assessment of IR (HOMA-IR) and β cell function (HOMA-β), hemoglobin A 1c (HbA 1c ), and 2 h glucose after an oral glucose tolerance test decreased with increasing quarters of WG (all p < 0.001). Body mass index (BMI) had significant mediation effects on the associations between WG intake and CRP, apo-B, fasting glucose, insulin, HOMA-IR, HOMA-B, HbA 1c , triglyceride to high density lipoprotein-cholesterol (TG:HDL-C) ratio and triglyceride-glucose (TyG) index (all p < 0.05) after adjustment for age, gender, race/ethnicity, educational status, smoking and level of physical activity. Both waist circumference (WC) and anthropometrically predicted visceral adipose tissue (apVAT) mediated the association between WG intakes with CRP, FBG, HbA 1c , TG:HDL-C ratio and TyG index, i.e. WC and apVAT had indirect effect (all p < 0.05)., Conclusion: Our findings provide insights into the favourable impact of WG consumption on IR and inflammation, which may be affected by both central and visceral adiposity, i.e. the link between WG with IR and inflammation is more mediated in overweight/obese compared with lean individuals.

The impacts of different macronutrients on body weight regulation remain unresolved, with different studies suggesting increased dietary fat, increased carbohydrates (particularly sugars), or reduced protein may all stimulate overconsumption and drive obesity. We exposed C57BL/6 mice to 29 different diets varying from 8.3% to 80% fat, 10% to 80% carbohydrate, 5% to 30% protein, and 5% to 30% sucrose. Only increased dietary fat content was associated with elevated energy intake and adiposity. This response was associated with increased gene expression in the 5-HT receptors, and the dopamine and opioid signaling pathways in the hypothalamus. We replicated the core findings in four other mouse strains (DBA/2, BALB/c, FVB, and C3H). Mice regulate their food consumption primarily to meet an energy rather than a protein target, but this system can be over-ridden by hedonic factors linked to fat, but not sucrose, consumption., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background and Aims: Conflicting results suggest a link between serum uric acid (SUA), inflammation and glucose/insulin homeostasis; however, the role of adiposity in this relationship is not clear. Therefore, we evaluated the role of different adiposity factors, including central body mass index (BMI), peripheral waist circumference (WC), and visceral adiposity [visceral adipose tissue (apVAT)], on the association between SUA, inflammation and glucose/insulin homeostasis among US adults., Methods: Data were extracted from the 2005-2010 US National Health and Nutrition Examination Surveys. Overall, 16,502 participants were included in the analysis (mean age = 47.1 years, 48.2% men). Analysis of co-variance and "conceptus causal mediation" models were applied, while accounting for survey design., Results: Corrected models showed that subjects with higher SUA levels have a less favorable profile of inflammation and glucose/insulin homeostasis parameters (all p < 0.001). We found that all our potential mediators (BMI, WC and apVAT) had an impact (to various extents) on the link between variables, including serum C-reactive protein (CRP), apolipoprotein-B (apoB), insulin resistance markers, 2-h blood glucose (2hG) and triglyceride, and fasting blood glucose (FBG) (TyG) index (all p < .001), while none of the potential mediators (BMI, apVAT, WC) had an impact on the link between FBG and glycated hemoglobin with SUA (all p > 0.05). We have found that all of our mediators partially mediated the link between inflammation and glucose/insulin homeostasis parameters and SUA. Of note, apVAT fully mediated the association between SUA and 2hG., Conclusions: By applying advanced statistical techniques, we shed light on the complex link of SUA with inflammation and glucose/insulin homeostasis and quantify the role of adiposity factors in that link., (Copyright © 2017. Published by Elsevier B.V.)

Aim: We aimed to investigate the changes in adiposity and other cardiometabolic risk factors in the year following Roux-en-Y gastric bypass (RYGB) in patients of Chinese ethnicity., Methods: The study recruited 209 patients who met the indications for bariatric surgery. Adiposity and cardiometabolic risk factors were assessed at baseline and over the 12 months following surgery in all participants. SPSS® software was used for statistical analysis., Results: The mean body mass index (BMI) was 29.98 kg/m 2 at baseline and steadily decreased to 25.32 kg/m 2 at 12 months, giving a relative change of -15.5% (p < 0.001). All of the lipid profile fractions except high-density lipoprotein (HDL) declined during the first 12 months of follow up; serum HDL increased during this time (all ANOVA p < 0.001). The mean fasting plasma glucose was 9.49 mmol/L at baseline and gradually decreased to 5.69 mmol/L at 12 months, giving a relative change of -40.0% (p < 0.001)., Conclusion: Following the RYGB procedure, changes in measures of adiposity were paralleled by a significant improvement in cardiometabolic factors for 12 months after surgery.