# Role of Dach1 in Obesity-Induced Hepatic Insulin Resistance

> **NIH NIH R01** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2020 · $360,000

## Abstract

Excessive hepatic glucose production (HGP) and defective insulin signaling are critical in the
development of type 2 diabetes (T2D). Over the past few years, our work has revealed new
molecular pathways relevant to these two processes—pathways that we have shown recently in
pre-clinical studies are amenable to a new type of therapy. We showed that obesity leads to the
activation of a pathway initiated by calcium-induced activation of calcium/calmodulin-dependent
protein kinase II (CaMKII) in hepatocytes (HCs). CaMKII suppresses an ATF6-protein chaperone
module, which in turn activates a PERK-ATF4-Trb3 pathway that disrupts insulin receptor
signaling. Our new data has revealed that hepatic CaMKII phosphorylates and blocks nuclear
translocation of a class IIa histone deacetylase (HDAC4), which increases the level of a co-
repressor called Dachshund homolog 1 (Dach1). Dach1, which has never before been implicated
in metabolism, is dramatically increased in the livers of obese mice and humans and its inhibition in
obese mice protects against hyperglycemia and hyperinsulinemia, identifying Dach1 as a critical
link between obesity, insulin resistance, and metabolic dysfunction. We have proposed a series of
studies to determine the mechanisms by which hepatocyte Dach1 deficiency improves insulin
resistance in obesity (Aim 1) and to elucidate the proximal signaling events of how obesity
regulates Dach1 and the downstream molecular mechanisms of Dach1-mediated suppression of
insulin signaling (Aim 2). The involvement of hepatic Dach1 in the metabolic disturbances of
obesity is a completely new and unexplored concept. We believe upon completion of the proposed
studies, the integrated role of hepatic Dach1 in mediating insulin resistance through its effects on
insulin signaling could reveal novel insights and provide therapeutic strategies for the treatment of
T2D.

## Key facts

- **NIH application ID:** 9961570
- **Project number:** 5R01DK106045-05
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** Lale Ozcan
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $360,000
- **Award type:** 5
- **Project period:** 2016-07-15 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9961570

## Citation

> US National Institutes of Health, RePORTER application 9961570, Role of Dach1 in Obesity-Induced Hepatic Insulin Resistance (5R01DK106045-05). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/9961570. Licensed CC0.

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