DEC1 regulates the rhythmic expression of PPARγ target genes involved in lipid metabolism in white adipose tissue.

Previously, we found that the basic helix-loop-helix transcriptional repressor DEC1 interacts with the PPARγ:RXRα heterodimer, a master transcription factor for adipogenesis and lipogenesis, to suppress transcription from PPARγ target genes (Noshiro et al., Genes to Cells, 2018, 23:658-669). Because the expression of PPARγ and several of its target genes exhibits circadian rhythmicity in white adipose tissue (WAT), we examined the expression profiles of PPARγ target genes in wild-type and Dec1-/- mice. We found that the expression of PPARγ target genes responsible for lipid metabolism, including the synthesis of triacylglycerol from free fatty acids (FFAs), lipid storage and the lipolysis of triacylglycerol to FFAs, oscillates in a circadian manner in WAT. Moreover, DEC1 deficiency led to a marked increase in the expression of these genes at night (Zeitgeber times 16 and 22), resulting in disruption of circadian rhythms. Serum FFA levels in wild-type mice also showed circadian oscillations, but these were disrupted by DEC1 deficiency, leading to reduced FFA levels. These results suggest that PPARγ:RXRα and DEC1 cooperatively generate the circadian expression of PPARγ target genes through PPAR-responsive elements in WAT.

Deficiency of the basic helix-loop-helix transcription factor DEC1 prevents obesity induced by a high-fat diet in mice.

Obesity is a major public health problem in developed countries resulting from increased food intake and decreased energy consumption and usually associated with abnormal lipid metabolism. Here, we show that DEC1, a basic helix-loop-helix transcription factor, plays an important role in the regulation of lipid consumption in mouse brown adipose tissue (BAT), which is the major site of thermogenesis. Homozygous Dec1 deletion attenuated high-fat-diet-induced obesity, adipocyte hypertrophy, fat volume and hepatic steatosis. Furthermore, DEC1 deficiency increased body temperature during daytime and enhanced the expression of uncoupler protein 1, a key factor of thermogenesis, and various lipolysis-related genes in interscapular BAT. In vitro experiments suggested that DEC1 suppresses the expression of various lipolysis-related genes induced by the heterodimer of peroxisome proliferator-activated receptor γ and retinoid X receptor α (RXRα) through direct binding to RXRα. These observations suggest that enhanced lipolysis in BAT caused by DEC1 deficiency leads to an increase in lipid consumption, thereby decreasing lipid accumulation in adipose tissues and the liver. Thus, DEC1 may serve as an energy-saving factor that suppresses lipid consumption, which may be relevant to managing obesity.

Regulation of basic helix-loop-helix transcription factors Dec1 and Dec2 by RORα and their roles in adipogenesis.

DEC1 and DEC2, members of the basic helix-loop-helix superfamily, are involved in various biological phenomena including clock systems, cell differentiation and metabolism. In clock systems, Dec1 and Dec2 expression are up-regulated by the CLOCK:BMAL1 heterodimer via E-box (CACGTG), exhibiting a circadian rhythm in the suprachiasmatic nucleus (SCN), the central circadian pacemaker and other peripheral tissues. In this study, using assays of luciferase reporters, electrophoretic mobility shift and chromatin immunoprecipitation, we identified novel nuclear receptor response elements, ROR response elements (RORE), in Dec1 and Dec2 promoters. These ROREs responded to the transcriptional activator RORα, but not to the repressor REVERBα, although the Bmal1 promoter responded to both RORα and REVERBα. Therefore, RORα, but not REVERBα, is involved in the regulation of Dec1 and Dec2 expression without significantly affecting their rhythmicity. Since RORα, DEC1 and DEC2 reportedly suppressed adipogenic differentiation, we examined expression of Rorα, Dec1, Dec2 and other clock-controlled genes in differentiating 3T3-L1 adipocytes. The results suggested that RORα suppresses adipogenic differentiation at a later stage of differentiation by RORE-mediated stimulation of Dec1 and Dec2 expression.