Disruption of Drp1 in the liver protects mice against diet-induced obesity through induction of fibroblast growth factor 21

Mitochondria and the endoplasmic reticulum (ER) physically interact by close structural juxtaposition, via the mitochondrial-associated ER membrane. Recently, great advances have been made in the understanding of inter-organelle communication between the ER and mitochondria. To clarify the role of mitochondrial dynamics in this communication, we generated mice lacking the mitochondrial fission protein dynamin-related protein 1 (Drp1) in the liver (Drp1LiKO). While intake of a high-fat diet (HFD) resulted in histological changes characterized by hepatic steatosis, inflammation, apoptosis, necrosis and fibrosis, reminiscent of nonalcoholic steatohepatitis, Drp1LiKO mice showed decreased fat mass and were protected from HFD-induced obesity. Analysis of liver gene expression profiles demonstrated marked elevation of ER stress markers. In addition, we observed increased expression of fibroblast growth factor 21 (Fgf21) through induction of activating transcription factor 4 and X-box binding protein 1, master regulators of the integrated stress response. Mice were given ad libitum access to a normal chow diet (NCD) containing 5.4% fat (CRF-1; Orient Yeast, Tokyo, Japan). For the high-fat diet (HFD) study, 4-week-old mice were fed a diet consisting of 24% fat (lard fat, 45% kcal fat, D12451; Research Diets, New Brunswick, NJ) for 24 weeks. Experiments were conducted between 10:00 a.m. and 11:00 a.m. after a 17-hour fasting period. Refeeding samples were collected between 2:00 p.m. and 3:00 p.m. after a 4-hour refeeding period following an overnight fast. Total RNA was isolated from mouse liver using TRIzol Reagent (Invitrogen Corporation, Carlsbad, CA, USA) and purified using the SV Total RNA Isolation System (Promega Corporation, Madison, WI, USA) following the manufacturer’s instructions. Gene expression profiling was performed using the Whole Mouse Genome Microarray 4x44K v2 platform containing 39,430 probes (Agilent Technologies).