Abstract 19339: ROCK2 Mediates the Uptake of Fatty Acids through the Transcriptional Regulation of CD36
Background: Basal metabolic rate has a profound effect on the development of obesity and protects against cold intolerance in living organisms. Rho-activated kinase 2 (ROCK2), an important mediator of the actin cytoskeleton, is also necessary for maintaining energy homeostasis. There is a particularly high expression of ROCK2 found in both the brown and white adipocytes. Adipocytes, endocrine organs for fat storage, play a major role in regulating the balance between energy storage and expenditure with the maintenance of fatty acids. Fatty acid uptake by the adipocytes is mediated through a number of fatty acid transporters. One such transporter, called fatty acid translocase (CD36), is found present in a variety of processes including inflammation, atherosclerosis, as well as lipid metabolism. Upon cold exposure, there is a continuous uptake of free fatty acids from the blood in order to maintain heat production through fatty acid oxidation in brown adipocytes. To date, the precise mechanism as to how fatty acid transporters are regulated in response to environmental cues is unknown.
Methods and Results: ROCK2 depleted mouse embryonic fibroblasts (MEF) display significantly decreased luciferase activity under the control of the CD36 promoter. Mutant mice with adipocyte-specific deletion of ROCK2 (ROCK2adipoQ-/-) exhibit a lower expression of CD36. When these mice are exposed to cold temperatures for 6 hours, electron microscopy and immunohistochemistry have demonstrated that the lipid droplets in their brown adipocytes are nearly absent as compared to control littermates. The mutant mice are unable to maintain lipid reserves in their adipose tissue, suggesting a defect in their ability to replenish or uptake fatty acids. This also led to an observation in reduced basal metabolic rate. Conversely, mutant mice with adipocyte-specific expression of the constitutively active form of ROCK (CA-ROCK) exhibit an increased expression of CD36 and enhanced adaptive capabilities.
Conclusion: Our findings indicate a critical role of ROCK2 in mediating the uptake and storage of fatty acids through the transcriptional regulation of CD36 expression and suggest that modulation of ROCK2 activity in adipocytes may have therapeutic benefits in metabolic diseases.
Author Disclosures: C.J. Park: None. E. Karrar: None. P. Chen: None. J.K. Liao: Consultant/Advisory Board; Modest; Asahi-Kasei Pharmaceuticals, Celgene, Sanofi-Aventis.
This research has received full or partial funding support from the American Heart Association.
- © 2014 by American Heart Association, Inc.