MiR-409-3p targets a MAP4K3-ZEB1-PLGF signaling axis and controls brown adipose tissue angiogenesis and insulin resistance

Becker-Greene D., Li H., Perez-Cremades D., Wu W., Bestepe F., Ozdemir D., ...Daha Fazla

CELLULAR AND MOLECULAR LIFE SCIENCES, cilt.78, sa.23, ss.7663-7679, 2021 (SCI-Expanded) identifier identifier identifier

  • Yayın Türü: Makale / Tam Makale
  • Cilt numarası: 78 Sayı: 23
  • Basım Tarihi: 2021
  • Doi Numarası: 10.1007/s00018-021-03960-1
  • Dergi Adı: CELLULAR AND MOLECULAR LIFE SCIENCES
  • Derginin Tarandığı İndeksler: Science Citation Index Expanded (SCI-EXPANDED), Scopus, Academic Search Premier, Agricultural & Environmental Science Database, CAB Abstracts, Chemical Abstracts Core, Chimica, EMBASE, MEDLINE, Veterinary Science Database
  • Sayfa Sayıları: ss.7663-7679
  • Anahtar Kelimeler: Angiogenesis, Type 2 diabetes, Insulin resistance, Brown adipose tissue, MicroRNA-409-3p, GLUCOSE-HOMEOSTASIS, OBESITY, FAT, HYPOXIA, MICE, ADIPOGENESIS, INFLAMMATION, SENSITIVITY, METASTASIS, DISORDERS
  • Hacettepe Üniversitesi Adresli: Hayır

Özet

Endothelial cells (ECs) within the microvasculature of brown adipose tissue (BAT) are important in regulating the plasticity of adipocytes in response to increased metabolic demand by modulating the angiogenic response. However, the mechanism of EC-adipocyte crosstalk during this process is not completely understood. We used RNA sequencing to profile microRNAs derived from BAT ECs of obese mice and identified an anti-angiogenic microRNA, miR-409-3p. MiR-409-3p overexpression inhibited EC angiogenic properties; whereas, its inhibition had the opposite effects. Mechanistic studies revealed that miR-409-3p targets ZEB1 and MAP4K3. Knockdown of ZEB1/MAP4K3 phenocopied the angiogenic effects of miR-409-3p. Adipocytes co-cultured with conditioned media from ECs deficient in miR-409-3p showed increased expression of BAT markers, UCP1 and CIDEA. We identified a pro-angiogenic growth factor, placental growth factor (PLGF), released from ECs in response to miR-409-3p inhibition. Deficiency of ZEB1 or MAP4K3 blocked the release of PLGF from ECs and PLGF stimulation of 3T3-L1 adipocytes increased UCP1 expression in a miR-409-3p dependent manner. MiR-409-3p neutralization improved BAT angiogenesis, glucose and insulin tolerance, and energy expenditure in mice with diet-induced obesity. These findings establish miR-409-3p as a critical regulator of EC-BAT crosstalk by modulating a ZEB1-MAP4K3-PLGF signaling axis, providing new insights for therapeutic intervention in obesity.