Up-regulation of orphan nuclear estrogen-related receptor alpha expression during long-term caloric restriction in mice

Abstract

The estrogen-related receptor alpha (ERRalpha) is an orphan receptor belonging to the nuclear receptor superfamily that regulates a number of target genes encoding enzymes that participate in various metabolic pathways involved in maintaining energy balance in animals. In this study, whether long-term caloric restriction (alternate days of fasting for 3 months) in mice modulates the expression of ERRalpha in various tissues was investigated. Western blot analyses showed positive immunoreactive ERRalpha protein (53 kDa) band in various mice tissue extracts, though at varying levels. Heart, kidney, and skeletal muscles expressed significant levels of ERRalpha, with a comparatively lower level detected in the intestine, brain, and liver. Cardiac ERRalpha expression was the highest, with the least detected in the liver. Caloric restricted mice exhibited a significant increase in ERRalpha level in the heart (5.45-fold), kidney (3.70-fold), skeletal muscle (3.0-fold), small intestine (2.72-fold), and liver (2.44-fold) extracts as compared to ad libitum fed. However, caloric restriction could not evoke any detectable receptor level change in the brain. Notably, the highest ERRalpha up-regulation was detected in the heart. This up-regulation in ERRalpha level especially in highly oxidative tissues such as heart, kidney, small intestine, and skeletal muscle of caloric restricted mice may be helpful in modulating ERRalpha responsive genes that participates in maintaining energy balance. This may potentially strengthen the metabolic and biochemical adaptation in such tissues, which is necessary for animal survival under long-term caloric restriction.