Abstract 14096: The Immune Transcriptional Factor Irf4 is a Key Regulator of Thermogenesis
Adipocytes can be broadly classed as white or brown fat cells. While white fat cells are specialized to store energy in the form of triglyceride, brown adipocytes use their high mitochondrial content and uncoupling protein 1 (UCP1) to uncouple respiration and dissipate chemical energy as heat. Rodents and other small mammals have copious brown fat deposits, but larger mammals often lose brown fat after infancy. Recent data indicates that adult humans possess significant deposits of UCP1-positive brown fat. The transcriptional basis of thermogenesis is well-studied at the co-activator level (e.g. PGC1, RIP140, TRIP-Br2, PRDM16) but not much known about the transcription factors they bind to. We have shown that IRF4 is highly expressed in adipocytes in a fasting-dependent manner and mice lacking IRF4 specifically in fat cannot undergo lipolysis when challenged with a β-agonist, fasting, or cold exposure in epididymal WAT. Here, we demonstrate that IRF4 plays a direct role in the regulation of thermogenesis in brown adipose tissue (BAT). IRF4 expression is induced by cold exposure and forskolin in primary adipocytes, and is also increased by cAMP in human primary brown adipocytes. Furthermore, mice lacking the IRF4 specifically in Ucp1+ cells (BATI4KO) gain more weight on HFD compared to the control littermates, and display impaired insulin sensitivity and cold intolerance. Conversely, mice overexpressing IRF4 in BAT were leaner and had increased energy expenditure on HFD. Our data demonstrate that IRF4 serves as ‘master regulator’ of thermogenesis through control of lipolysis in white fat and by regulating the thermogenic gene program in BAT. These studies establish a link between IRF4 and the disposition of calories in adipose tissue, with consequences for systemic metabolic homeostasis.
- © 2013 by American Heart Association, Inc.