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

Abstract

The dedicator of cytokinesis 5 (DOCK5) is associated with obesity. However, the mechanism by which DOCK5 contributes to obesity remains completely unknown. Here, we show that hepatic DOCK5 expression significantly decreases at a state of insulin resistance (IR). Deletion of DOCK5 in mice reduces energy expenditure, promotes obesity, augments IR, dysregulates glucose metabolism, and activates the mTOR (Raptor)/S6K1 pathway under a high-fat diet (HFD). The overexpression of DOCK5 in hepatocytes inhibits gluconeogenic gene expression and increases the level of insulin receptor (InsR) and Akt phosphorylation. DOCK5 overexpression also inhibits mTOR/S6K1 phosphorylation and decreases the level of raptor protein expression. The opposite effects were observed in DOCK5-deficient hepatocytes. Importantly, in liver-specific Raptor knockout mice and associated hepatocytes, the effects of an adeno-associated virus (AAV8)-or adenovirus-mediated DOCK5 knockdown on glucose metabolism and insulin signaling are largely eliminated. Additionally, DOCK5-Raptor interaction is indispensable for the DOCK5-mediated regulation of hepatic glucose production (HGP). Therefore, DOCK5 acts as a regulator of Raptor to control hepatic insulin activity and glucose homeostasis.

Association between circulating follistatin‐like‐1 and metabolic syndrome in middle‐aged and old population: A cross‐sectional study

“…The magnetized beads were washed, and the supernatant was discarded. The proteins were immunoblotted using an anti‐BMP4 antibody 26 …”

“…Cultured cells were maintained in a humidified incubator with 5% carbon dioxide and 95% air at 37°C. pCDNA3.1‐ FSTL‐1 and pCMV6‐ BMP4 were constructed by Gene Create Inc. (Wuhan China), as previously reported 26 …”

RHO to the DOCK for GDP disembarking: Structural insights into the DOCK GTPase nucleotide exchange factors

“…DOCK5, one of the least studied family members, preferentially activates RAC1 over other RHO or RAC GTPases ( 91 ). It is predominantly present in the brain, lung, and bone tissues such as osteoclasts, but is also present in other tissues ( 92 ). One such tissue is the liver, where DOCK5 activity increases energy expenditure and insulin signaling by impeding mammalian target of rapamycin complex (mTORC1), linking DOCK5 downregulation to obesity ( 93 ).…”

The regulation of DOCK family proteins on T and B cells

“…[14][15][16] DOCK5 is expressed in osteoclasts, myoblasts, hepatocytes, the nervous system, and lymphocytes, and is involved in the regulation of bone resorption, myoblasts fusion, insulin resistance in the liver, and B cell development. [16][17][18][19][20] DOCK6 is mainly expressed in sensory neurons and regulates the axonal extension. 21 DOCK7 is expressed in some progenitor cells and is associated with neuronal differentiation.…”

“…DOCK4 is expressed in skeletal muscle, nervous system, ovary, and prostate 14–16 . DOCK5 is expressed in osteoclasts, myoblasts, hepatocytes, the nervous system, and lymphocytes, and is involved in the regulation of bone resorption, myoblasts fusion, insulin resistance in the liver, and B cell development 16–20 . DOCK6 is mainly expressed in sensory neurons and regulates the axonal extension 21 .…”