Abstract 13062: Notch1 Signaling Regulates Adipogenesis in vivo
Among four homologous Notch receptors, the Notch1 signaling is known to regulate neurogenesis and angiogenesis in the developmental stages. But its role in adipogenesis is unknown. In this study, we investigated the role of the Notch1 signaling in white adipose tissue (WAT) proliferation and differentiation in vivo. We observed increased expression of Notch1 and its downstream transcriptional factor, Hes-1, in WAT from ob/ob mice compared to wild-type (WT) mice. Expression of Notch1 and Hes-1 in inguinal WAT was also increased in accordance to body weight gain in WT mice on a high-fat high-sucrose (HF/HS) diet. Therefore, we investigated inguinal WAT of Notch1 heterozygous deficient (Notch1+/-) mice. We fed normal diet or HF/HS diet to 4 week-old WT and Notch1+/- mice. Although food intake in both mice was comparable, body weight was significantly higher in Notch1+/- than WT mice after 8 weeks on both diets, and inguinal WAT weight in Notch1+/- was higher after 12 weeks on a HF/HS diet.
Followed by a HF/HS diet, population of smaller adipocytes, adipogenic cell clusters (CD34+ CD68+ cell), and expression of Ki67 and cyclin D1 in WAT were significantly increased in Notch1+/- mice compared to WT mice.
In WAT of Notch1+/- mice, expression of Notch1 and Hes-1 was decreased up to half of WT mice without expression changes of other Notch receptors. In the downstream of attenuated Notch1 signaling, preadipocyte factor 1 (Pref-1) and Sox9 were decreased. The decrease in Sox9 enhanced adipogenic potential with induction of peroxisome proliferator-activated receptor gamma (PPARγ) and CCAAT/enhancer binding protein alpha (C/EBPα).
Furthermore, Notch1+/- mice showed impaired glucose and insulin tolerance with decreased expression of insulin receptor-1 (IRS-1) and glucose transporter 4 (GLUT4) in WAT but not in skeletal muscle after 12 weeks on a HF/HS diet. Notch1+/- mice had increased total cholesterol levels compared to WT mice. Taken together, Notch1 would be involved in the regulation of adipogenesis in vivo to constrain WAT amount and attenuate diet-induced obesity. This function would be essential to maintain metabolic homeostasis.
- © 2013 by American Heart Association, Inc.