Abstract 1600: Vascular Adiponectin-Resistance in Hyperlipidemic Rats and Its Involved Mechanisms
Adiponectin (APN) is an adipocyte-derived vascular protective molecule. Recent clinical studies suggest that, like insulin resistance, patients with metabolic syndrome may also develop APN resistance. The current study attempted to determine whether hyperlipidemia may cause vascular APN resistance and, if so, elucidate the involved mechanisms. Adult male SD rats were fed a regular or high-fat diet (HF) for 2 to 16 weeks. Plasma APN levels, aortic pAMPK/AMPK ratio, and aortic APN receptor-1 (AdipoR1) expression were determined. 2-week HF diet had no significant impact on any observed parameters. Plasma APN levels were unchanged 4 weeks after HF diet, significantly increased 8 weeks after HF diet (8.79 ±0.45 vs. 6.43 ±0.45 μg/ml in control diet, P<0.05), and returned to control levels 16 weeks after HF diet. Vascular pAMPK/AMPK ratio was significantly reduced 4 weeks after HF diet (61.8±4.9% of control, P<0.01), returned to control levels 8 weeks after HF diet, and significantly reduced 16 weeks after HF diet (53±4.9% of control, P<0.01). The disassociation between plasma APN level and vascular AMPK phosphorylation after HF diet suggests development of APN resistance. Additional in vitro studies demonstrated that
AMPK phosphorylation caused by 2 μg recombinant APN was normal in aortic segments from 4- and 8-week HF fed rats, but significantly reduced 16 weeks after HF diet (76±5.6% of control, P<0.05);
Incubation of HUVEC with 8-week HF diet plasma caused significantly less APMK phosphorylation (77±4.9% of control plasma, P<0.05);
Pre-incubation of recombinant APN with 8-week HF plasma for 4h at 37oC significantly reduced its activity as determined by phosphorylation of AMPK, ACC and eNOS in HUVEC (76±3.7%, 71.8±4.9% and 67.9±5.2% of APN incubated with control plasma, respectively, P<0.01); and
Vascular AdipoR1 expression remains unchanged except 16 weeks after HF diet (79±3.9% of control, P<0.05).
Taken together, this study demonstrated that vascular APN resistance develops in hyperlipidemic rats. High lipid plasma modification/inactivation of APN is likely responsible for APN resistance with early hyperlipidemia, whereas reduced vascular AdipoR1 expression is a major cause for APN resistance with advanced hyperlipidemia.
This research has received full or partial funding support from the American Heart Association, Great Rivers Affiliate (Delaware, Kentucky, Ohio, Pennsylvania & West Virginia).