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Background: A long-term high-fat/cholesterol (HFC) diet leads to insulin resistance (IR),which is associated with inflammation,atherosclerosis (AS),cardiac sympathovagal imbalance,and cardiac dysfunction.Peroxisome proliferator-activated receptors (PPARs) and nuclear factor κB (NF-κB)are involved in the development of IR-AS.Thus,we elucidated the pathological molecular mechanism of IR-AS by feeding an HFC diet to Tibetan minipigs to induce IR and AS.Methods: Male Tibetan minipigs were fed either a normal diet or an HFC diet for 24 weeks.Thereafter,the minipigs were tested for physiological and biochemical blood indices,blood pressure,cardiac function,glucose tolerance,heart rate variability (HRV),and PPAR-associated gene and protein expression levels.Results: HFC-fed minipigs exhibited IR through increased body weight,fasting blood glucose levels,plasma cholesterol and its composition,and insulin and free fatty acid (FFA) levels;decreased insulin sensitivity;impaired glucose tolerance;and hypertension.Increased C-reactive protein (CRP)levels,cardiac dysfunction,depressed HRV,and the up-regulation of PPAR expression in the abdominal aorta concomitant with down-regulation in the heart tissue were observed in HFC-fed minipigs.Furthermore,the levels of NF-κ Bp65,IL-1β,TNF-α,MCP-1,VCAM-1,ICAM-1,MMP-9,and CRP proteins were also significantly increased.Conclusions: These data suggest that HFC-fed Tibetan minipigs develop IR and AS and that PPARs are involved in cardiovascular remodeling and impaired function.