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

Yerui Lai1, Anjiang Zhao2, Minghong Tan1

  • 1Department of Endocrinology, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China.

EMBO Reports
|December 31, 2019
PubMed

Insights

Dedicator of cytokinesis 5 (DOCK5) regulates hepatic insulin activity and glucose homeostasis. Its deficiency promotes obesity and insulin resistance by activating the mTOR/S6K1 pathway.

Area of Science:

  • Metabolism
  • Molecular Biology
  • Endocrinology

Background:

  • Dedicator of cytokinesis 5 (DOCK5) is linked to obesity, but its functional mechanism is unclear.
  • Hepatic DOCK5 expression declines during insulin resistance (IR).

Purpose of the Study:

  • To elucidate the role of DOCK5 in regulating hepatic metabolism and insulin sensitivity.
  • To investigate the molecular mechanisms underlying DOCK5's influence on obesity and glucose homeostasis.

Main Methods:

  • Utilized DOCK5-deficient mice and hepatocytes under high-fat diet (HFD) conditions.
  • Employed overexpression and knockdown strategies for DOCK5 in liver cells.
  • Investigated the interaction between DOCK5 and Raptor using liver-specific Raptor knockout models and viral vectors (AAV8, adenovirus).

Main Results:

  • DOCK5 deficiency in mice led to reduced energy expenditure, increased obesity, augmented IR, dysregulated glucose metabolism, and activated mTOR (Raptor)/S6K1 signaling under HFD.
  • DOCK5 overexpression in hepatocytes suppressed gluconeogenic genes, enhanced insulin receptor (InsR) and Akt phosphorylation, and inhibited mTOR/S6K1 phosphorylation.
  • DOCK5-Raptor interaction was essential for DOCK5's regulation of hepatic glucose production (HGP).

Conclusions:

  • DOCK5 plays a critical role in maintaining hepatic insulin sensitivity and glucose homeostasis.
  • DOCK5 functions by regulating the Raptor component of mTOR to control hepatic glucose metabolism.
  • Targeting DOCK5 may offer a therapeutic strategy for obesity and related metabolic disorders.
Keywords:
DOCK5glucose metabolisminsulin resistancemTOR pathway

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