Effects of ATF4 on PGC1α expression in brown adipose tissue and metabolic responses to cold stress.

OBJECTIVE We have shown previously that the expression of peroxisome proliferator activated receptor gamma coactivator (PGC1α) increases significantly in the white and brown adipose tissue of activating transcription factor 4 (ATF4) global knockout mice, which suggests that ATF4 is involved in the regulation of PGC1α expression. The goal of the current study is to investigate this possibility and elucidate the underlying cellular mechanisms. MATERIAL/METHODS The effects of ATF4 on PGC1α expression and on PGC1α promoter activity were analyzed in vivo and in vitro using mice, HIB-1B, and 293T cell line. The physiological functions of ATF4 in the regulation of PGC1α expression were confirmed by analysis of body temperature of Atf4(-/-) and Atf4(+/+) mice in response to cold stress as well as expression of Complex I, II, III, V in BAT. RESULTS In this study, we showed ATF4 to be a negative regulator of PGC1α expression through competitive binding with cAMP response element binding protein (CREB) at a cAMP response element (CRE) site in the PGC1α promoter. ATF4 was also found to influence the expression of mitochondria-related proteins, including Complex I, II, III, and IV through regulation of PGC1α. Finally, we showed that Atf4(-/-) mice have higher core body temperatures in reduced-temperature environments than control mice. CONCLUSION This study describes the mechanisms underlying ATF4 regulating PGC1α expression. We demonstrate a novel function of ATF4 in the regulation of thermogenesis. Taken together, these observations provide new insight into the physiological functions of ATF4, especially the regulation of thermogenesis and the response to cold stress.