Transcription factor CREB3 is a potent regulator of high-fat diet-induced obesity and energy metabolism.
Int J Obes (Lond)
; 46(8): 1446-1455, 2022 08.
Article
em En
| MEDLINE
| ID: mdl-35637262
ABSTRACT
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.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico
/
Metabolismo Energético
/
Dieta Hiperlipídica
/
Obesidade
Limite:
Animals
Idioma:
En
Ano de publicação:
2022
Tipo de documento:
Article