Transcription factor CREB3 is a potent regulator of high-fat diet-induced obesity and energy metabolism.

Abstract

The endoplasmic reticulum senses alterations to cellular homeostasis that activates the unfolded protein response (UPR). UPR proteins are known to aid in regulating glucose and lipid metabolism. CREB3 is a UPR-associated transcription factor whose potential role in regulating energy metabolism remains unclear. Eight-week-old wild-type (WT) and Creb3+/- mice were placed on control and high-fat diets (HFD) for 8 weeks, and metabolic phenotypes characterized by weekly weighing, indirect calorimetry, body composition scans, glucose tolerance tests, plasma analysis, tissue lipid quantifications and gene/protein expression analysis. HFD weight gain in Creb3+/- males was reduced by 34% (p < 0.0001) and females by 39.5% (p = 0.014) from their WT counterparts. No differences were found in HFD food intake or total fecal lipids between genotypes. Creb3+/- mice had increased energy expenditure and respiratory exchange ratios (p = 0.002) relative to WT. Creb3+/- mice had significant reductions in absolute fat and lean tissue, while Creb3+/- females had significant reductions in body fat% and increased lean% composition (p < 0.0001) compared to WT females. Creb3+/- mice were protected from HFD-induced basal hyperglycemia (males p < 0.0001; females p = 0.0181). Creb3+/- males resisted HFD-induced hepatic lipid accumulation (p = 0.025) and glucose intolerance compared to WT (p < 0.0001) while Creb3+/- females were protected from lipid accumulation in skeletal muscle (p = 0.001). Despite the metabolic differences of Creb3+/- mice on HFD, lipid plasma profiles did not significantly differ from WT. Fasted Creb3+/- mice additionally revealed upregulation of hepatic energy expenditure and gluconeogenic genes such as Pgc-1a and Gr (glucocorticoid receptor) (p < 0.05), respectively. Reduced expression of CREB3 increased energy expenditure and the respiratory exchange ratio, and protected mice from HFD-induced weight gain, basal hyperglycemia, and sex-specific tissue lipid accumulation. We postulate that CREB3 is a novel key regulator of diet-induced obesity and energy metabolism that warrants further investigation as a potential therapeutic target in metabolic disorders.