Causal relationship between obesity, leptin, and brain structure and functional connectivity: evidence based on bidirectional and mediation mendelian randomisation analyses

This study used Mendelian randomisation (MR) to explore the putative causal relationship between obesity, leptin, brain alternations represented by magnetic resonance imaging (MRI) phenotypes, and Mediation MR to confirm the mediating role of leptin in obesity and brain changes. The fusiform surface area (SA) (pFDR = 0.005), the bankssts SA (pFDR = 0.022), and the second principal components for fractional anisotropy (FA PC) in posterior thalamic radiation (pFDR = 0.042) had negative causal effects on obesity. Obesity risk had negative causal effects on the first FA PC in superior frontal-occipital fasciculus (pFDR = 0.020) and mean fractional anisotropy (FA) of superior frontal-occipital fasciculus (pFDR = 0.020). Leptin content was positively associated with the risk of obesity (pFDR = 0.020). The inferior parietal SA was negatively correlated with leptin content (p = 0.022). Leptin may serve as a potential mediator of obesity-induced shrinkage of the inferior parietal SA (95% CI = -0.012 to 1.111; p = 0.049). This study supports the potential bidirectional causal relationship between obesity and several aspects of brain macro- and microstructure and functional connectivity (FC), and leptin may be involved in the causal pathway from obesity to brain alterations.