Chronic hyperinsulinemia promotes meta-inflammation and extracellular matrix deposition in adipose tissue: Implications of nitric oxide

Durgesh Kumar, Kripa Shankar, Saraswati Patel, Abhishek Gupta, Salil Varshney, Sanchita Gupta, Sujith Rajan, Ankita Srivastava, Achchhe Lal Vishwakarma, Anil N. Gaikwad

Research output: Contribution to journalArticlepeer-review

36 Scopus citations

Abstract

Various imperative studies support the notion that hyperinsulinemia (HI) itself serves as the common link between adipose tissue inflammation (ATI) and metabolic syndrome. However, the contribution of HI mediated ATI and its metabolic consequences are yet to be explored. We induced chronic HI per se in mice by administration of exogenous insulin for 8 weeks through mini-osmotic pumps. For the reduction of circulating insulin in response to excess calorie intake, we have partially ablated β-cells by using streptozotocin (STZ) in the diet-induced obesity (DIO) and genetic mice models (db/db). Flow cytometry analysis was performed for the quantification of immune cells in stromal vascular fraction (SVF) isolated from epididymal white adipose tissue (eWAT). Our studies demonstrated that chronic HI augmented ATI in terms of elevated pro-inflammatory cells (M1 macrophages and NK-cells) and suppressed anti-inflammatory cells (M2 macrophages, eosinophils and regulatory T-cells). These results were correlated with altered obesity-associated metabolic phenotype. Partial reduction of circulating insulin level attenuated excess calorie-induced ATI and improved insulin sensitivity. Mechanistically, an imbalance in M1 and M2 macrophage proportions in eWAT promoted iNOS (inducible nitric oxide synthase): arginase-1 imbalance that resulted into extracellular matrix (ECM) deposition and insulin resistance (IR) development. However, iNOS −/- mice were protected from HI-induced M1:M2 macrophage imbalance, ECM deposition and IR in adipose tissue. Overall, we conclude that chronic HI per se contributed in ATI and iNOS corroborated ECM deposition.

Original languageEnglish (US)
Pages (from-to)15-28
Number of pages14
JournalMolecular and Cellular Endocrinology
Volume477
DOIs
StatePublished - Dec 5 2018
Externally publishedYes

Keywords

  • Hyperinsulinemia
  • Immunometabolism
  • Insulin resistance
  • Nitric oxide
  • Obesity

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Endocrinology

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