# Regulation of hepatic gene expression and metabolism by FoxO proteins

> **NIH VA I01** · JESSE BROWN VA MEDICAL CENTER · 2020 · —

## Abstract

Project Summary/Abstract
 Excessive production of glucose by the liver plays a central role in the development of
diabetes, where the ability of insulin to regulate hepatic glucose production (HGP) is impaired.
FoxO transcription factors are major targets of insulin and play an important role in mediating
effects of insulin on multiple aspects of glucose and lipid metabolism in the liver, including
gluconeogenesis, glycolysis and lipogenesis. However, the mechanisms by which FoxO
proteins exert these diverse effects in an integrated fashion remain poorly understood.
 During our previous funding period, we found that a) FoxO proteins also exert important
effects on intrahepatic lipolysis and fatty acid oxidation via the regulation of adipose
triacylglycerol lipase (ATGL), which mediates the first step in lipolysis, and its inhibitor, the
G0/S1 switch 2 gene (G0S2), and b) ATGL-dependent lipolysis plays a critical role in mediating
diverse effects of FoxO proteins in the liver, including effects on gluconeogenic, glycolytic and
lipogenic gene expression and metabolism. These studies also indicate that ATGL-dependent
lipolysis is required to mediate effects of FoxO1 on glycolytic and gluconeogenic gene
expression, and additional studies are planned in mouse models and isolated hepatocytes to
better understand specific mechanisms mediating this novel link between lipid metabolism and
glucoregulation by the insulin/FoxO pathway.
 In addition, using liver-specific insulin receptor (IR) knockout (LIRKO) and IR/FoxO1
double knockout (LIRFKO) mice, we also found that disrupting FoxO1 in the liver was sufficient
to restore the ability of insulin to maintain glucose homeostasis and suppress HGP (based on
euglycemic hyperinsulinemic clamp studies) in mice lacking the hepatic insulin receptor. These
results indicate that (a) inhibition of FoxO1 is critical for both direct (hepatic) and indirect effects
of insulin on HGP and glucose utilization, and (b) extrahepatic effects of insulin are sufficient to
maintain normal whole-body and hepatic glucose metabolism when liver FoxO1 activity is
disrupted. Based on these findings, additional studies utilizing transgenic and knockout mouse
models, cell culture and insulin clamp techniques are planned to determine whether ATGL-
dependent lipolysis also plays a critical role in mediating effects of FoxO1 on hepatic glucose
metabolism in the setting of hepatic insulin resistance, and whether targeting ATGL and its
downstream effectors may provide an effective strategy for treatment of diabetes mellitus in
patients with hepatic insulin resistance.

## Key facts

- **NIH application ID:** 9898262
- **Project number:** 5I01BX001968-08
- **Recipient organization:** JESSE BROWN VA MEDICAL CENTER
- **Principal Investigator:** Terry G. Unterman
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2020
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2012-10-01 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9898262

## Citation

> US National Institutes of Health, RePORTER application 9898262, Regulation of hepatic gene expression and metabolism by FoxO proteins (5I01BX001968-08). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9898262. Licensed CC0.

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