Soy Protein Outperforms Whey Protein in Ameliorating Insulin Resistance but Not Obesity in High-Fat Diet-Induced Obese Mice

<b>Background/Objectives:</b> To date, few studies have investigated the therapeutic effects of soy versus whey protein supplementation on obesity and insulin resistance (IR), yielding inconsistent findings. The aim of the present study was to compare the therapeutic efficacy of soy versus whey protein on obesity and IR and to elucidate their potential molecular mechanisms. <b>Methods:</b> Forty male C57BL/6J mice were randomly divided into two groups and fed either a normal diet (<i>n</i> = 8) or a high-fat diet (HFD, <i>n</i> = 32) for 16 weeks to induce obesity. After 16 weeks, HFD-induced obese mice were further randomized into three groups: HFD control, HFD + 20% whey protein isolate (WPI), and HFD + 20% soy protein isolate (SPI) for 6 weeks (<i>n</i> = 8). <b>Results:</b> Body weight, weight gain, body mass index, and Lee index showed no significant differences between the WPI and SPI groups. Compared with the WPI group, serum concentrations of insulin and leptin and the homeostasis model assessment of IR (HOMA-IR) were significantly lower, and thymus wet weight, fetal total cholesterol level, and serum glucose-dependent insulinotropic polypeptide concentration were significantly higher in the SPI group. Compared with the WPI group, the protein levels of GLUT4 and p-PI3K/PI3K were significantly higher in the SPI group. Metabolomics analysis showed that hepatic phosphocholine levels were significantly higher in the SPI group than in the WPI group. Moreover, hepatic differentially abundant metabolites of SPI- and WPI-fed mice were primarily enriched in the glycerophospholipid metabolism pathway. <b>Conclusions:</b> Soy protein was more effective than whey protein in ameliorating IR in HFD-induced obese mice, probably by modulating the PI3K-GLUT4 pathway and glycerophospholipid metabolism. Moreover, soy protein and whey protein showed comparable anti-obesity efficacy.