Effects of carnosic acid on mitochondrial biogenesis and insulin sensitivity in 3T3-L1 adipocytes are through induction of PGC-1 and ubiquitination of PARIS by parkin

The PGC-1 alpha plays a vital role in regulating mitochondrial biogenesis and insulin sensitivity. This study investigated the role of PGC-1 alpha in preventing the effects of carnosic acid (CA) against TNF-alpha-suppressed mitochondrial biogenesis and insulin signaling. Exposure of 3T3-L1 adipocytes to TNF-alpha decreased the proteins of PGC-1 alpha and nuclear respiratory factor 1 (NRF1). However, pretreatment with CA improved this change. Additionally, CA led to increases in parkin protein and decreases in PARIS protein. Using immunoprecipitation assay, the protein interaction between PARIS and ubiquitin was increased and that between PARIS and parkin was decreased after CA treatment. Parkin siRNA blocked the effects of CA on PARIS, PGC-1 alpha, and NRF1 proteins. PGC-1 alpha siRNA abolished the capacity of CA to reverse the TNF-alpha-inhibited insulin signaling and membrane GLUT4 protein translocation. Therefore, CA attenuates the TNF-alpha induced impairment of mitochondrial biogenesis and glucose uptake through activation of PGC-1 alpha via ubiquitination of PARIS by parkin.