DOCK2 Deficiency Mitigates HFD-induced Obesity by Reducing Adipose Tissue Inflammation and Increasing Energy Expenditure

J Lipid Res. 2017 Sep;58(9):1777-1784. doi: 10.1194/jlr.M073049. Epub 2017 Jul 17.

Abstract

Obesity is the major risk factor for type 2 diabetes, cardiovascular disorders, and many other diseases. Adipose tissue inflammation is frequently associated with obesity and contributes to the morbidity and mortality. Dedicator of cytokinesis 2 (DOCK2) is involved in several inflammatory diseases, but its role in obesity remains unknown. To explore the function of DOCK2 in obesity and insulin resistance, WT and DOCK2-deficient (DOCK2-/-) mice were given chow or high-fat diet (HFD) for 12 weeks followed by metabolic, biochemical, and histologic analyses. DOCK2 was robustly induced in adipose tissues of WT mice given HFD. DOCK2-/- mice with HFD showed decreased body weight gain and improved metabolic homeostasis and insulin resistance compared with WT mice. DOCK2 deficiency also attenuated adipose tissue and systemic inflammation accompanied by reduced macrophage infiltration. Moreover, DOCK2-/- mice exhibited increased expression of metabolic genes in adipose tissues with greater energy expenditure. Mechanistically, DOCK2 appeared to regulate brown adipocyte differentiation because increased preadipocyte differentiation to brown adipocytes in interscapular and inguinal fat was observed in DOCK2-/- mice, as compared with WT. These data indicated that DOCK2 deficiency protects mice from HFD-induced obesity, at least in part, by stimulating brown adipocyte differentiation. Therefore, targeting DOCK2 may be a potential therapeutic strategy for treating obesity-associated diseases.

Keywords: dedicator of cytokinesis 2; high-fat diet; insulin resistance; macrophage.

Publication types

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

MeSH terms

  • Adipocytes / pathology
  • Adipose Tissue / drug effects
  • Adipose Tissue / pathology*
  • Animals
  • Cell Differentiation / genetics
  • Cell Line
  • Diet, High-Fat / adverse effects*
  • Energy Metabolism / drug effects
  • Energy Metabolism / genetics*
  • GTPase-Activating Proteins / deficiency*
  • GTPase-Activating Proteins / genetics*
  • Gene Knockout Techniques
  • Homeostasis / genetics
  • Inflammation / pathology
  • Insulin Resistance / genetics
  • Mice, Inbred C57BL
  • Obesity / chemically induced
  • Obesity / genetics*
  • Obesity / metabolism
  • Obesity / pathology*

Substances

  • DOCK2 protein, mouse
  • GTPase-Activating Proteins