Metabolic Syndrome (MetS) is a cluster of metabolic disorders that substantially increase the risk of developing other chronic diseases such as cardiovascular disease and type II diabetes. Diet is known to play a crucial role in the development of MetS and dietary intervention studies are a useful tool to investigate the effect of diet on MetS. However, the slow onset of MetS and difficulties associated with adhering to new diets, especially for long-term, makes it challenging to perform extensive dietary intervention studies on humans. To overcome this limitation, we sought to investigate the impact of diet on the risk of MetS by taking an in silico systems biology approach. We employed a whole-body model (WBM) of metabolism that accounts for 26 organs, including six sex organs, to computationally evaluate, at genome-scale, the effect of ten different diets on the serum levels of five key metabolites implicated in MetS namely glucose, triacylglycerides (TAG), LDL-C, HDL-C, and palmitoyl-CoA. We performed separate simulations for males and females using the sex specific WBMs. Our analyses elucidated molecular mechanisms that support the current hypothesis that an unhealthy diet can significantly elevate the risk of developing MetS while a healthy diet helps promote metabolic homeostasis. Furthermore, our investigation uncovered novel insights into the contribution of specific organs and tissues to the risk of MetS under these diets in males and females. For example, we found that glucose and TAG secretion by adipocytes into the blood are substantially lower and higher, respectively, under the unhealthy diet compared to other diets. Striking differences were also observed between the unhealthy diet and other diets for LDL-C, HDL-C, and palmitoyl-CoA in males. In females, we observed patterns that resembled those in males although other organs, such as the breast or uterus, also contributed to the serum levels of these key metabolites. Our study offers a promising strategy for investigating the effect of various dietary regimens on human metabolism and MetS at organ-level resolution. This paves the way for the in silico design of new dietary interventions to treat MetS. / 2026-02-12T00:00:00Z

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