Systemic Nanoparticle-Mediated Delivery of Pantetheinase Vanin-1 Regulates Lipolysis and Adiposity in Abdominal White Adipose Tissue

Abstract

Lipolysis in white adipose tissue (WAT) occurs in response to nutritional signals and helps to regulate lipid turnover/adiposity in animals. However, the causal relationships and the mechanisms controlling WAT morphology are not clear. In this report, Vanin-1, a pantetheinase, is shown to be a novel determinant for lipolysis and adiposity. The expression of Vanin-1 in the abdominal WAT is positively correlated with lipolysis both in mice and in humans. Mice with global Vanin-1 deficiency exhibit adipocyte hypertrophy and impaired lipolysis. Use of a nanosystem comprising P3-peptide, chitosan oligosaccharide lactate, and polyethylene glycol that controls Vanin-1 expression in the abdominal WAT shows that WAT-specific Vanin-1 knockdown blocks fasting-induced lipolysis and prevents WAT loss. However, WAT-specific Vanin-1 mRNA restoration rescues impaired lipolysis and improves glucose/insulin intolerance in diabetic db/db mice. Mechanistically, Vanin-1 induces PPARγ activity and subsequently facilitates its activation on the proximal promoters of lipolytic genes. Thus, an essential role of Vanin-1 in the regulation of lipolysis and adiposity is revealed, and a functional RNA delivering strategy for specific intervention of Vanin-1 expression in WAT is shown. These findings provide a promising approach to treat metabolic diseases caused by dysregulation of Vanin-1 and lipolysis.