# Regulation of Insulin sensitivity by Glucocorticoid-Angiopoietin-like 4-Ceramide Axis

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA BERKELEY · 2020 · $365,448

## Abstract

Abstract
Glucocorticoids (GC) play a key role in metabolic adaptation during stress. However, chronic exposure to
GC, is harmful and results in disorders such as insulin resistance. We previously identified angiopoietin-like 4
(Angptl4) as a GC-regulated gene encoding a secreted protein that promotes adipocyte lipolysis and inhibits
extracellular lipoprotein lipase (LPL). We showed that Angptl4 is required for GC-promoted lipolysis in white
adipose tissue (WAT) and in Angptl4 null mice (Angptl4-/-), excess GC-induced fatty liver and
hypertriglyceridemia are diminished. Our recent preliminary studies further demonstrated that GC-induced
insulin resistance was compromised in Angptl4-/- mice. Intriguingly, GC treatment increased hepatic ceramide
levels, but such GC effect was attenuated in the absence of Angptl4. Indeed, myriocin, which inhibits
ceramide synthesis, decreased GC-induced insulin resistance in wild type (WT) but not Angptl4-/- mice. We
additionally found that GC exposure elevated the activity of PP2A and PKCζ (two downstream effectors of
ceramides) as well as the expression of a list of ceramide synthetic genes in liver. In Angptl4-/- mice, the
activity of PP2A and PKCζ was mitigated and the expression of ceramide synthase 3-6 (Cers3-6) was
specifically impaired. Based on these preliminary data, we hypothesize that GC augment the expression of
Angptl4, which promotes WAT lipolysis mobilizing fatty acids (FA) to liver to serve as substrates and signals
required for GC to increase Cers3-6 expression. This elevates the production of specific ceramide species to
activate PP2A and PKCζ to suppress insulin action. In this proposal, we will examine this model. In Aim 1,
our preliminary study found that the fibrinogen-like domain (FLD) of Angptl4 promotes adipocyte lipolysis
without inhibiting LPL. We will test whether FLD restores GC-induced insulin resistance in Angptl4-/- mice.
We will also examine the role of FA mobilization to the liver in GC-induced insulin resistance using mice with
reduced expression of two major hepatic FA transporters, Fatp5 and Cd36. Moreover, hyperinsulinemic-
euglycemic clamps will be used to determine the role of Angptl4 in GC-augmented hepatic glucose
production, a hallmark of hepatic insulin resistance. In Aim 2, we will determine which ceramide synthase(s),
Cers3-6, are involved in GC-induced insulin resistance. PPARα can be activated by FA and has been shown
to increase ceramide synthesis in certain tissues. Thus, its role in GC-induced hepatic Cers3-6 expression
and ceramide production will be examined. In Aim 3, we will analyze the role of PP2A and PKCζ in GC-
induced insulin resistance and will identify ceramide synthase(s) that activate PP2A and PKCζ to cause
insulin resistance. Overall, this study will be the first to establish the FLD of Angptl4 as a lipid mobilization
factor participating in GC-induced insulin resistance and for the first time, specific ceramide synthases that
activate PKCζ and PP2A wi...

## Key facts

- **NIH application ID:** 9844467
- **Project number:** 5R01DK113019-03
- **Recipient organization:** UNIVERSITY OF CALIFORNIA BERKELEY
- **Principal Investigator:** Jen-Chywan Wang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $365,448
- **Award type:** 5
- **Project period:** 2017-12-07 → 2021-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9844467

## Citation

> US National Institutes of Health, RePORTER application 9844467, Regulation of Insulin sensitivity by Glucocorticoid-Angiopoietin-like 4-Ceramide Axis (5R01DK113019-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9844467. Licensed CC0.

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