Notch1 haploinsufficiency in mice accelerates adipogenesis

• Published in: Scientific reports Vol. 11; no. 1; p. 16761
• Main Authors: Yamaguchi, Kazutoshi, Hayashi, Motoharu, Uchida, Yasuhiro, Cheng, Xian Wu, Nakayama, Takayuki, Matsushita, Tadashi, Murohara, Toyoaki, Takeshita, Kyosuke
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 18.08.2021; Nature Publishing Group; Nature Portfolio
• Subjects: 631/80/86; 692/163/2743/393; 692/308/1426; Accumulation; Adipocytes; Adipogenesis; Adipose tissue; Blood transfusions; Body fat; Cardiology; CD34 antigen; Cell proliferation; Cyclin D1; Down-regulation; Epigenetics; Experiments; Food intake; Gene regulation; Glucose tolerance; Haploinsufficiency; High fat diet; Hospitals; Humanities and Social Sciences; Hypotheses; Insulin; Insulin receptor substrate 1; Magnetic resonance imaging; Medical laboratories; Metabolic disorders; Metabolic syndrome; Metabolism; multidisciplinary; Notch1 protein; Overexpression; Peroxisome proliferator-activated receptors; Preadipocytes; Proteins; Science; Science (multidisciplinary); Shear stress; Sox9 protein; Transcription factors
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-021-96017-z

Notch signaling has been recognized recently as a key regulator of metabolism. Here, we determined the role of Notch1 in adipogenesis in wild-type (WT) and Notch1 hetero-mutant (N1+/−) mice provided with 12-week normal or high-fat diet. Haploinsufficiency of Notch1 was associated with adipose tissue accumulation despite similar food intake. White adipose tissue (WAT) of N1+/− showed accumulation of adipogenic cells (CD34+CD68+ cells), crown-like structures, and upregulation of cell proliferation markers (cyclin D1 and Ki67). Notch1 expression in WAT reached peak levels in 8-week-old WT mice in parallel with fat accumulation, especially under HF/HS-feeding, whereas such increment was blunted in N1+/− mice. Downstream of Notch1 haploinsufficiency, over-expression of adipogenic factors PPARγ and C/EBPα was noted following down-regulation of downstream transcriptional factors of Notch signaling (Hes-1, Pref-1, and Sox9). Both pharmacological Notch signal inhibition and Notch1 knockdown enhanced adipogenesis of 3T3-L1 preadipocytes. N1+/− mice showed impaired glucose and insulin tolerance with downregulation of IRS-1 and GLUT4 in WAT after high-fat diet. Taken together, our results suggest that haploinsufficiency of Notch1 promotes fat accumulation and adipogenesis and provides a mechanistic link between Notch signaling and development of metabolic syndrome.