Bilobalide safeguards 3T3-L1 adipocytes from hypoxia through protecting mitochondrial bioenergetics, biogenesis and dynamics

Abstract

Natural products are the cornerstone of modern therapeutics. Bilobalide was found to be effective against hypoxia induced alterations in innate antioxidant status in our earlier study. Adipose tissue hypoxia in obesity contributes to insulin resistance via mitochondrial dysfunctions. Mitochondria are a central control point of many metabolic pathways and various pathophysiological conditions. In the present investigation, we evaluated the effect of hypoxia on crucial mitochondrial functions in 3T3-L1 adipocytes and possible protection with bilobalide. Hypoxia for 24 hours substantially increased (P ≤ 0.05) HIF-1α expression (5.3 fold) as well as PDK-1 expression (2.3 fold) at the protein level in 3T3-L1 adipocytes. The aconitase enzyme activity was significantly (P ≤ 0.05) reduced (4.5 fold) in the hypoxic group indicating an elevated level of mitochondria-generated ROS production. It also affected mitochondrial bioenergetics like oxygen consumption (2.23 fold), ATP synthesis (4.32 fold), and the activities of respiratory chain complexes such as complexes I, III and IV (2.05, 2.35 & 2.9 fold) in hypoxic adipocytes. Hypoxia also impaired (P ≤ 0.05) mitochondrial dynamics such as mitochondrial biogenesis and fusion/fission balance in 3T3-L1 adipocytes. Bilobalide protected the 3T3-L1 adipocytes from adverse effects of hypoxia by safeguarding mitochondrial bioenergetics and dynamics, via downregulating HIF-1α expression. These findings suggest that bilobalide could be used as a therapeutic agent for adipocyte hypoxia-mediated mitochondrial dysfunctions in obesity.