DOCK2 deficiency mitigates HFD-induced obesity by reducing adipose tissue inflammation and increasing energy expenditure

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.

Genetics of Obesity Traits: A Bivariate Genome-Wide Association Analysis

“…Dedicator of cytokinesis 2 (DOCK2) is involved in several inflammatory diseases. A recent experimental study indicated that DOCK2 deficiency might protect mice from high-fat-diet induced obesity by reducing adipose tissue inflammation and increasing energy expenditure (Guo et al, 2017 ). Our findings on the role of DOCK6 and DGKB in BMI-WHR were supported by two meta-analyses respectively which identified genome-wide significant signals near DOCK6 for total cholesterol in Hispanics (Below et al, 2016 ) and near DGKB for beta cell function in East Asians (Hong et al, 2014 ).…”

DOCK5 regulates energy balance and hepatic insulin sensitivity by targeting mTORC1 signaling

“…Additionally, when fed a diet with high saturated fatty acids, DOCK5 expression was found to be elevated in vivo compared with baseline levels, in conjunction with the accumulation of fat. In addition, among members of the DOCK-A subfamily, DOCK2 has been found to be associated with metabolic homeostasis, obesity, and IR [12]. In addition, among members of the DOCK-A subfamily, DOCK2 has been found to be associated with metabolic homeostasis, obesity, and IR [12].…”

Integrated bioinformatics analysis reveals novel key biomarkers and potential candidate small molecule drugs in diabetic nephropathy

“…SIT1 [93], JAML (junction adhesion molecule like) [94], TIMP1 [95], PRKCB (protein kinase C beta) [96], MMP7 [97], WNT7B [98], WNT10A [99], DUSP1 [100], WT1 [101], APOC3 [102], ERRFI1 [103], HCN2 [104], MME (membrane metalloendopeptidase) [105], STRA6 [106], SLC12A3 [107] and GC (GC vitamin D binding protein) [108] expedites epithelial to mesenchymal transition and renal brosis in DN. Previous studies have found CFD (complement factor D) [109], DOCK2 [110], LYZ (lysozyme) [111], CD5L [112], SCARA5 [113], VCAN (versican) [114], GDF5 [115], SFRP2 [116], BTG2 [117], ZFP36 [118], GPR3 [119], OLR1 [120], PM20D1 [121] and UGT2B7 [122] to be expressed in obesity, but these genes might be liable for advancement of DN. Polymorphic FCRL3 [123], FCGR2B [124], COMP (cartilage oligomeric matrix protein) [125], ERFE (erythroferrone) [126] and NPHS1 [127] expression can be altered by in ammation, which might involved in nephropathy.…”