# Anatomical Regulation of Glucose and Lipid Metabolism by Insulin Signaling in Hepatocytes

> **NIH NIH R01** · BOSTON CHILDREN'S HOSPITAL · 2024 · $450,289

## Abstract

Abstract
 This application is entitled ‘Anatomical regulation of glucose and lipid metabolism by insulin
signaling in hepatocytes’. The liver is a multitasking organ, performing diverse functions that are critical for
maintaining glucose and lipid homeostasis. Previous studies of hepatic insulin signaling have been done with
the assumption that all hepatocytes are equivalent. Recently single-cell transcriptomics has revealed that
around half of hepatocyte genes are expressed in a zoned manner, in which periportal hepatocytes might
coordinate fasting metabolism, whereas pericentral hepatocytes might manage postprandial metabolism. A
clear understanding of how insulin signaling coordinates energy homeostasis at spatial levels is necessary.
 This proposal brings our focus to the important problem of how anatomical segregation of insulin signaling
in the liver regulates glucose and lipid metabolism in physiological and pathological conditions. By using
promoter knock-in mouse models, we will perform the functional study in vivo by using Gls2CreER mouse line to
target periportal hepatocytes and Cyp1a2CreER mouse line to target pericentral hepatocytes. This real-time
molecular strategy is innovative as previous work that has relied upon static approaches. By intercrossing with
floxed mice targeting insulin signaling components, this project has the potential to reveal important insight into
the anatomical segregation of insulin signaling in the liver to control energy homeostasis. First, impaired insulin
signal transduction in periportal hepatocytes is expected to promote hepatic glucose production but might
retain insulin sensitivity in pericentral hepatocytes for lipid metabolism, producing the pathological combination
of hyperglycemia and hyperlipidemia. This strategy might provide an innovative model to investigate the
metabolic features of insulin resistance in humans. Second, our preliminary data shows that total hepatic
insulin signaling deficiency impairs hepatic de novo lipogenesis and prevents diet-induced fatty liver in mice,
which contradicts the excess lipogenesis in insulin-resistant humans. Direct investigation of insulin signaling in
pericentral hepatocytes can reveal the relationship between insulin resistance and NAFLD. Third, selective
insulin resistance has implications for therapy; however, how to precisely target this paradox is still unresolved.
It would be desirable to employ drug targets that could alleviate both T2D and NAFLD. Thus, we propose to
identify novel candidate genes that contribute to HFD-induced hyperglycemia and hepatic steatosis.
 Together, the proposed experiments can discern the function of insulin signaling in the regulation of
glucose and lipid metabolism in the periportal and pericentral hepatocytes, which would reveal foundational
mechanisms coordinated by hepatic insulin action that moderate glucose and lipid metabolism under
physiological and pathological conditions.

## Key facts

- **NIH application ID:** 10865048
- **Project number:** 5R01DK133388-02
- **Recipient organization:** BOSTON CHILDREN'S HOSPITAL
- **Principal Investigator:** Rongya Tao
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $450,289
- **Award type:** 5
- **Project period:** 2023-07-01 → 2028-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10865048

## Citation

> US National Institutes of Health, RePORTER application 10865048, Anatomical Regulation of Glucose and Lipid Metabolism by Insulin Signaling in Hepatocytes (5R01DK133388-02). Retrieved via AI Analytics 2026-06-01 from https://api.ai-analytics.org/grant/nih/10865048. Licensed CC0.

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