2. Academic Validation
  3. Dual leucine zipper-bearing kinase DLK is necessary for cell autonomous regulation of insulin sensitivity

Dual leucine zipper-bearing kinase DLK is necessary for cell autonomous regulation of insulin sensitivity

  • Mol Metab. 2025 Nov:101:102244. doi: 10.1016/j.molmet.2025.102244.
Hetty N Wong 1,  Nathan Qi 2,  Edward B Arias 3,  Kae Won Cho 4,  Deepak Nihalani 1,  Gregory D Cartee 3,  Lawrence B Holzman 5
Affiliations

Affiliations

  • 1 Renal-Electrolyte and Hypertension Division, University of Pennsylvania School of Medicine, Philadelphia, PA, USA.
  • 2 Michigan Mouse Metabolic Phenotyping Center, USA.
  • 3 School of Kinesiology, University of Michigan, Ann Arbor, MI, USA.
  • 4 Soonchunhyang Institute of Medi-Bio Science (SIMS), Soonchunhyang University, Cheon-an, South Korea.
  • 5 Renal-Electrolyte and Hypertension Division, University of Pennsylvania School of Medicine, Philadelphia, PA, USA. Electronic address: [email protected].
PMID: 40902848 DOI: 10.1016/j.molmet.2025.102244
Abstract

Metabolic syndrome and Insulin resistance are driven in part by dysregulated signaling through the c-Jun N-terminal kinase (JNK) pathway. The scaffold protein JIP1 and its upstream kinase DLK (dual leucine zipper kinase) form a dynamic signaling complex that modulates JNK activity, yet the physiological role of DLK in glucose metabolism remains undefined. Here, we identify DLK as a critical regulator of Insulin sensitivity using three genetically modified mouse models: a hypomorphic DLK allele, a tamoxifen-inducible whole-body DLK knockout, and a high-fat diet-induced obese model with DLK ablation. All models exhibited enhanced Insulin sensitivity independent of adiposity, characterized by increased glucose uptake in muscle and adipose tissue, and improved suppression of hepatic glucose production during hyperinsulinemic-euglycemic clamp studies. Mechanistically, we demonstrate that DLK functions in a cell-autonomous manner, limiting Insulin signaling through modulation of Akt and IRS1 phosphorylation downstream of Insulin stimulation. In cultured myoblasts and fibroblasts, DLK was required for JNK activation and subsequent dampening of Insulin signaling. These findings establish DLK as a regulator of whole-body Insulin sensitivity, independent of obesity through a JIP-JNK signaling module. The results suggest that targeting DLK could represent a therapeutic strategy for improving Insulin sensitivity in Metabolic Disease.

Keywords

Cell-autonomous signaling; DLK; Glucose metabolism; Insulin sensitivity; JNK signaling.

Figures