AAV-Mediated Overexpression of BMP7 in White Adipose Tissue Induces Adipogenesis and Ameliorates Insulin Resistance

Abstract

Obesity and type 2 diabetes are strongly associated and a major health problem because of their alarmingly growing prevalence worldwide. The hypertrophic expansion of white adipose tissue (WAT) promotes ectopic fat accumulation and development of insulin resistance whereas WAT hyperplasia is associated with preservation of insulin sensitivity. Several members of the Bone Morphogenetic Protein (BMP) family have been shown to play a role in white and/or brown adipogenesis and energy homeostasis. Although BMP7 has extensively been reported to induce brown adipogenesis in vitro, its role on WAT expandability and its potential contribution to insulin sensitivity remains to be elucidated. Here, we showed that local administration of adeno-associated viral vectors (AAV) encoding BMP7 in WAT resulted in hyperplasic expansion of WAT together with reduced liver steatosis and amelioration of insulin sensitivity in both HFD-fed and ob/ob obese mice. In contrast, the AAV-mediated overexpression of BMP7 specifically in the liver did not promote WAT hyperplasia although the circulating levels of BMP7 achieved were similar to those obtained after intra-WAT administration of AAV vectors. Nevertheless, when liver-derived BMP7 circulating levels were further increased, body weight and insulin sensitivity were normalised in HFD-fed as well as in ob/ob mice. Altogether, these results unravel a new role of BMP7 on white adipogenesis. In addition, this study suggests the potential of BMP7 gene therapy to ameliorate obesity and insulin resistance. Disclosure E. Casana Lorente: None. V. Jimenez: None. V. Sacristán Fraile: None. S.A. Muñoz: None. C. Jambrina Pallarés: None. J. Rodó: None. S. Darriba: None. C. Mallol: None. M. Garcia: None. X. Leon: None. I. Grass: None. S. Franckhauser: None. F. Bosch: None.