High fat diet exacerbated glycolipid metabolism disorder in kidney Yang deficiency rats by interfering with IRS 1-PI3K (p85) -Akt-GLUT 4 pathway

Kidney Yang deficiency (KYD) is associated with disturbances in glucose and lipid metabolism. This study examined whether KYD rats on a high-fat diet (HFD) exhibit aggravated metabolic dysfunction and sought to elucidate the underlying mechanisms. Three-week-old SD rats were assigned to control (Con), KYD, HFD, and KYD + HFD groups. KYD models were induced through cold exposure and gastric perfusion of Cortex Phellodendri. The HFD groups were provided high-fat diets. After 10 weeks, metabolic parameters, organ weights, blood glucose/lipid profiles, and protein levels (PGC1α, PPARγ, IRS1, Akt, PI3K(p85), GLUT4) were assessed. KYD rats exhibited lower body temperature, weight, and weight gain (P< 0.01) compared to controls. Liver weight was reduced in the KYD group but increased in the HFD group (P< 0.01). KYD + HFD rats demonstrated increased visceral fat (P < 0.01) and decreased muscle mass. The KYD + HFD group showed a higher liver-to-body weight ratio (P < 0.05) and significantly elevated cholesterol and LDL levels (P< 0.01 vs. other groups). Muscle PPARγ was lower in the KYD group, while the AUC of glucose tolerance was elevated in the KYD + HFD group (P< 0.05). GLUT4 and PI3K(p85) levels were reduced in both KYD and HFD groups (P < 0.01,P<0.01). IRS1 expression in skeletal muscle was lower in both KYD and HFD groups (P < 0.01) but was higher in KYD compared to HFD (P < 0.01). Akt expression was marginally increased in KYD and significantly higher in HFD groups. KYD predisposes rats to visceral fat accumulation, dyslipidemia, and fatty liver despite lower weight gain. Mechanistically, the impairment of the IRS1-Akt-PI3K(p85)-GLUT4 signaling pathway in KYD compromises insulin action, exacerbating lipid metabolic disturbances under HFD. These findings highlight the dietary risks for individuals with KYD and emphasize the need for targeted interventions aimed at specific metabolic pathways.