Editors' ChoiceCircadian Rhythms

Setting the Metabolic Beat

Science's STKE  29 May 2007:
Vol. 2007, Issue 388, pp. tw183
DOI: 10.1126/stke.3882007tw183

Many metabolic processes, like other physiological and behavioral phenomena, ebb and flow in a circadian pattern; the mechanisms linking circadian cycling to energy metabolism, however, have been unclear. Liu et al. found that expression of exogenous PGC-1α [for peroxisome proliferator-activated receptor (PPAR) γ coactivator 1 α, an inducible transcriptional coactivator implicated in regulating energy metabolism] in primary hepatocytes and C2C12 myotubes stimulated the expression of the clock genes Bmal1 and Clock. Microarray analysis of transduced hepatocytes revealed that expression of a subset of rhythmically expressed hepatic genes was enhanced by PGC-1α; moreover, expression of mouse liver PGC-1α mRNA and protein themselves oscillated, with peak protein abundance coinciding with transcriptional activation of Bmal. PGC-1α enhanced transcriptional activation of a Bmal gene reporter by the orphan nuclear receptors ROR (retinoic acid-related orphan receptor) α and γ and increased Bmal mRNA abundance synergistically with RORα. Further, chromatin immunoprecipitation (ChIP) analysis in HepG2 cells indicated that PGC-1α associated with the Bmal promoter, to which it recruited histone acetyltransferases, near the ROR response element. Diurnal patterns of locomotor activity, body temperature, and oxygen consumption were aberrant in mice lacking PGC-1α, as were the patterns of Clock and Per expression and those of rhythmically expressed genes encoding various metabolic enzymes. Selective knockdown of liver PGC-1α with RNAi indicated that its peripheral effects were not mediated through the central circadian clock, as did experiments involving cultured fibroblasts lacking PGC-1α. Thus, the authors propose that PGC-1α plays a central role in coordinating the circadian clock with energy metabolism. Grimaldi and Sassone-Corsi provide commentary and discuss implications of this research.

C. Liu, S. Li, T. Liu, J. Borjigin, J. D. Lin, Transcriptional coactivator PGC-1α integrates the mammalian clock and energy metabolism. Nature 447, 477-481 (2007). [PubMed]

B. Grimaldi, P. Sassone-Corsi, Metabolic clockwork. Nature 447, 386-387 (2007). [PubMed]