Effect of General Adiposity and Central Body Fat Distribution on the Circulating Metabolome: A Multicohort Nontargeted Metabolomics Observational and Mendelian Randomization Study

Abstract

Obesity is associated with adverse health outcomes, but the metabolic effects have not yet been fully elucidated. We aimed to investigate the association between adiposity with circulating metabolites and to address causality with Mendelian randomization (MR). Metabolomics data was generated by non-targeted ultra-performance liquid-chromatography coupled to time-of-flight mass-spectrometry in plasma and serum from three population-based Swedish cohorts: ULSAM (N=1,135), PIVUS (N=970), and TwinGene (N=2,059). We assessed associations between general adiposity measured as body mass index (BMI) and central body fat distribution measured as waist-to-hip ratio adjusted for BMI (WHRadjBMI) with 210 annotated metabolites. We employed MR analysis to assess causal effects. Lastly, we attempted to replicate the MR findings in the KORA and TwinsUK cohorts (N=7,373), the CHARGE consortium (N=8,631), the Framingham Heart Study (N=2,076) and the DIRECT consortium (N=3,029). BMI was associated with 77 metabolites, while WHRadjBMI was associated with 11 and 3 metabolites in women and men, respectively. The MR analyses in the Swedish cohorts suggested a causal association (p-value <0.05) of increased general adiposity and reduced levels of arachidonic acid, dodecanedioic acid and lysophosphatidylcholine (P-16:0) as well as with increased creatine levels. The replication effort provided support for a causal association of adiposity on reduced levels of arachidonic acid (p-value 0.03). Adiposity is associated with variation of large parts of the circulating metabolome, however causality needs further investigation in well-powered cohorts.

The metabolic profile of waist to hip ratio–A multi-cohort study

“…In the other study based on three other Swedish samples using around 200 named metabolites [ 15 ], with almost exclusively European descent, one sphingomyelin (32:2) were amongst the metabolites found to be related to WHRadjBMI. In that study fat mass was not evaluated directly.…”

“…A great number of studies have investigated the metabolic profile of obesity, as reviewed in [ 7 ]. Some studies have also evaluated the metabolomics of fat distribution [ 8 – 15 ], but to the best of our knowledge, no other study have tried to link metabolites to WHR when taking fat mass into account. This approach aimed to identify metabolites linked to an altered fat distribution, independently of general obesity.…”

“…A great number of studies have investigated the metabolic profile of obesity, as reviewed in [7]. Some studies have also evaluated the metabolomics of fat distribution [8][9][10][11][12][13][14][15], but to the best of Twenty-four validated metabolites were associated with WHR in men only (Table 3). Of those, five showed an interaction with sex with p<0.05 (one GPE and four amino acid derivatives).…”

“…There are also studies on the metabolomic profile of an altered fat distribution [8][9][10][11][12][13]. However, only a few studies have tried to disentangle if the metabolic profile of a disadvantageous fat distribution was different from that found in general obesity [14,15].…”

Alternation of the gut microbiota in metabolically healthy obesity: An integrated multiomics analysis

“…Among the 35 significantly-changed metabolites, we found changed activities of lipids molecules correlated with MHO phenotype. Dodecanedioic acid (DA), arachidic acid (AA), and mevalonic acid (MVA) are fatty acyls that may be involved in antiobesity activities, such as the inhibition of inflammation, prevention of weight gain, postponing muscle fatigue, and acceleration of fatty acid utilization ( Salinari et al., 2006 ; Shao et al., 2021 ; Ahmad et al., 2022 ). These fatty acyls were decreased in MHO mice, indicating a potential risk of weight gain and may also be involved in metabolic syndromes.…”