| First Author | Smith BS | Year | 2022 |
| Journal | Int J Obes (Lond) | Volume | 46 |
| Issue | 8 | Pages | 1446-1455 |
| PubMed ID | 35637262 | Mgi Jnum | J:345514 |
| Mgi Id | MGI:7579560 | Doi | 10.1038/s41366-022-01128-w |
| Citation | Smith BS, et al. (2022) Transcription factor CREB3 is a potent regulator of high-fat diet-induced obesity and energy metabolism. Int J Obes (Lond) 46(8):1446-1455 |
| abstractText | BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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. |
