Targeted SHP-1 Silencing Modulates the Macrophage Phenotype, Leading to Metabolic Improvement in Dietary Obese Mice

• Main Authors: Yadhu Sharma, Altaf Ahmad, Prabhu Srinivas Yavvari, Sandeep Kumar Muwal, Avinash Bajaj, Farah Khan
• Format: Article
• Language: English
• Published: Elsevier 2019-06-01
• Series: Molecular Therapy: Nucleic Acids
• Online Access: http://www.sciencedirect.com/science/article/pii/S2162253119300939

Chronic over-nutrition promotes adipocyte hypertrophy that creates inflammatory milieu leading to macrophage infiltration and their phenotypic switching during obesity. The SH2 domain-containing protein tyrosine phosphatase 1 (SHP-1) has been identified as an important player in inflammatory diseases involving macrophages. However, the role of SHP-1 in modulating the macrophage phenotype has not been elucidated yet. In the present work, we show that adipose tissue macrophage (ATM)-specific deletion of SHP-1 using glucan particle-loaded siRNA improves the metabolic phenotype in dietary obese insulin-resistant mice. The molecular mechanism involves AT remodeling via reducing crown-like structure formation and balancing the pro-inflammatory (M1) and anti-inflammatory macrophage (M2) population. Therefore, targeting ATM-specific SHP-1 using glucan-particle-loaded SHP-1 antagonists could be of immense therapeutic use for the treatment of obesity-associated insulin resistance. Keywords: glucan particles, targeted delivery, adipose tissue macrophage, obesity, SHP-1, siRNA