# Role of NgBR in regulating hepatic gluconeogenesis and insulin resistance

> **NIH NIH R01** · NEW YORK UNIVERSITY D/B/A NYU LONG ISLAND SCHOOL OF MEDICINE · 2024 · $574,937

## Abstract

PROJECT SUMMARY
Obesity-related type 2 diabetes (T2D) is the most common emerging metabolic disease in the US population.
Insulin resistance is a key etiological factor of T2D. Adiponectin is an adipocyte-secreted hormone and
prevents the development of insulin resistance. Recent studies show that adiponectin decreases the
expression of hepatic gluconeogenic enzymes, attenuates glucose production, and enhances the hepatic
effects of insulin through the AMP-activated protein kinase (AMPK) pathway. However, the resilience factors
that are required to maintain adiponectin-mediated AMPK activation in the liver remain unclear. This proposal
is designed to fill gaps in our knowledge concerning the role of NgBR in regulating adiponectin-
mediated AMPK activation and hepatic gluconeogenesis, and to determine if preserving hepatic NgBR
expression is sufficient to prevent the onset of obesity-related T2D. Recent studies from our laboratory
suggest that NgBR plays a previously unrecognized role in maintaining AMPK activation because NgBR binds
the farnesylated form of liver kinase B1 (LKB1-farn), a key regulator of AMPK. Preliminary results show that
NgBR expression decreases in the liver of diabetic animal models and the liver of T2D obese patients
compared to non-T2D obese subjects. NgBR hepatocyte-specific knockout (hepKO) mice showed an increase
in fasting glucose levels and further increases plasma glucose to T2D levels after high-fat diet (HFD) feeding.
NgBR deficiency in hepatocytes impairs AMPK activation induced by AdipoRon (an agonist of adiponectin
receptors). These findings lead us to propose a central hypothesis that NgBR is a resilience factor required
for preserving adiponectin-mediated insulin sensitivity and preventing the onset of obesity-caused T2D, and
disruption of the NgBR-dependent regulation system in the liver leads to impairing gluconeogenesis regulation
and insulin sensitivity. Our overall objectives are to elucidate the molecular mechanisms by which NgBR
enhances adiponectin-mediated insulin sensitivity and the roles that NgBR plays in the pathogenesis of insulin
resistance and T2D. Delineating the mechanisms by which NgBR regulates LKB1 translocation will allow us to
develop new therapeutic strategies for preventing the onset of T2D in obese subjects. Accordingly, we will test
our hypothesis with two specific aims. Aim 1. Determine the molecular mechanism by which NgBR regulates
LKB1-AMPK activation and adiponectin signaling pathway in the liver. Aim 2. Determine the molecular
mechanism by which NgBR regulates insulin signaling and hepatic gluconeogenesis. Successful completion of
studies proposed in this proposal will characterize NgBR as a resilience factor for preventing T2D and provide
novel insights for T2D prevention or treatment. Our studies will lead to many discoveries that will significantly
improve the health of US citizens and others suffering from T2D. Our studies will reveal new concepts and
ideas that can be used ...

## Key facts

- **NIH application ID:** 10827420
- **Project number:** 5R01DK132056-03
- **Recipient organization:** NEW YORK UNIVERSITY D/B/A NYU LONG ISLAND SCHOOL OF MEDICINE
- **Principal Investigator:** QING MIAO
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $574,937
- **Award type:** 5
- **Project period:** 2022-04-01 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10827420

## Citation

> US National Institutes of Health, RePORTER application 10827420, Role of NgBR in regulating hepatic gluconeogenesis and insulin resistance (5R01DK132056-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10827420. Licensed CC0.

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