Improved insulin sensitivity in obese-diabetic mice via chitosan Nanomicelles mediated silencing of pro-inflammatory Adipocytokines

Nanomedicine. 2021 Apr:33:102357. doi: 10.1016/j.nano.2020.102357. Epub 2021 Jan 15.

Abstract

Obesity induced chronic low-level inflammation is strongly associated with the development of insulin resistance and progression of type-2 diabetes. Systemic treatment with anti-inflammatory therapeutics requires high doses and is associated with serious adverse effects owing to generalized suppression of the immune system. Here we study localized knockdown of pro-inflammatory adipocytokines in adipose tissue macrophages (ATMs) and adipocytes using RNA interference for the treatment of insulin resistance. Chitosan nanomicelles conjugated to ATM and adipocyte targeting ligands were used to transfect short hairpin RNA (shRNA) against tumor necrosis factor-α (TNFα) and monocyte chemoattractant protein-1 (MCP-1). Subcutaneous administration of nanomicellar/pDNA polyplexes in obese-diabetic mice resulted in decreased concentration of pro-inflammatory cytokines TNFα, MCP-1, IL-6, and IL-1β along with increased concentration of insulin-sensitizing adipokine adiponectin. Downregulation of inflammatory cytokines resulted in improved insulin sensitivity and glucose tolerance for up to six-weeks following single dose, compared to untreated obese-diabetic mice.

Keywords: Chitosan nanomicelles; Inflammation; Insulin resistance; Obesity; RNA interference.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adipocytes / metabolism
  • Adipokines / metabolism*
  • Adiponectin / metabolism
  • Adipose Tissue / metabolism
  • Animals
  • Biocompatible Materials / chemistry
  • Chitosan / chemistry*
  • Chitosan / metabolism
  • Cytokines / metabolism
  • Diabetes Mellitus, Experimental
  • Diabetes Mellitus, Type 2 / metabolism*
  • Glucose Tolerance Test
  • Inflammation Mediators / metabolism
  • Insulin / metabolism*
  • Insulin Resistance / physiology*
  • Macrophages / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Micelles
  • Nanoparticles / chemistry*
  • Obesity / metabolism*
  • RAW 264.7 Cells
  • RNA Interference
  • Tumor Necrosis Factor-alpha / metabolism

Substances

  • Adipokines
  • Adiponectin
  • Biocompatible Materials
  • Cytokines
  • Inflammation Mediators
  • Insulin
  • Micelles
  • Tumor Necrosis Factor-alpha
  • Chitosan