Potential Roles of Dec and Bmal1 Genes in Interconnecting Circadian Clock and Energy Metabolism

Abstract

The daily rhythm of mammalian energy metabolism is subject to the circadian clock system, which is made up of the molecular clock machinery residing in nearly all cells throughout the body. The clock genes have been revealed not only to form the molecular clock but also to function as a mediator that regulates both circadian and metabolic functions. While the circadian signals generated by clock genes produce metabolic rhythms, clock gene function is tightly coupled to fundamental metabolic processes such as glucose and lipid metabolism. Therefore, defects in the clock genes not only result in the dysregulation of physiological rhythms but also induce metabolic disorders including diabetes and obesity. Among the clock genes, Dec1 (Bhlhe40/Stra13/Sharp2), Dec2 (Bhlhe41/Sharp1), and Bmal1 (Mop3/Arntl) have been shown to be particularly relevant to the regulation of energy metabolism at the cellular, tissue, and organismal levels. This paper reviews our current knowledge of the roles of Dec1, Dec2, and Bmal1 in coordinating the circadian and metabolic pathways.

Keywords: Bmal1; Dec1; Dec2; clock gene; energy metabolism.

Figure 1

The core molecular mechanism of the circadian clock. The molecular clock is composed of diverse autoregulatory feedback loops. The core components of the molecular clock, CLOCK and BMAL1, activate the transcription of repressor clock genes such as Per, Cry, Rev-erbα, and Dec. CLOCK and BMAL1 also activate the transcription of inducer Rorα. The protein products of these repressor or inducer genes inhibit or promote their own transcription in distinct ways, thus forming various feedback loops that create a coordinated circadian rhythm at the gene expression level.

Figure 2

Interplay between cellular redox factors and the molecular clock. Cellular redox status directly and indirectly affects the function of the molecular clock through changes in the levels of cofactors (i.e., NADH, NADPH, and FAD) and/or the activity of NAD⁺-consuming enzymes (SIRT1 and PARP1). The molecular clock in turn regulates the transcription of the Nampt gene, which encodes the rate-limiting enzyme in the NAD⁺ salvage pathway.

Figure 3

Interplay between the regulation of bioenergy and the molecular clock. Activated AMPK directly or indirectly phosphorylates core circadian repressors (i.e., PER/CRY). DEC, another circadian repressor, suppresses the transcription of Lkb1 which codes for a serine-threonine kinase that directly phosphorylates and activates AMPK, thus forming a reciprocal relationship between regulators of bioenergy and the circadian clock.