# Regulation of Hepatic Gluconeogenesis by the CREB:TORC2 Pathway

> **NIH NIH R01** · SALK INSTITUTE FOR BIOLOGICAL STUDIES · 2020 · $725,348

## Abstract

Project Summary/Abstract
The transcription factor CREB (cAMP response element-binding protein) regulates metabolic gene expression
in response to increases in cAMP signaling. CREB is thought to promote the expression of up to 5000 genes in
the mammalian genome, but mechanisms by which CREB activates different sets of target genes in different
contexts remain unclear. To address this problem, the Montminy lab will analyze CREB signaling output in the
liver and pancreatic islets, as CREB activity in these two tissues is essential for glucose homeostasis. During
periods of fasting, increases in circulating glucagon trigger the expression of gluconeogenic genes in the liver
via induction of the CREB pathway. During feeding, intestinal enteroendocrine cells secrete glucagon like
peptide 1 (GLP1), which stimulates insulin secretion and promotes beta cell viability, also via a CREB-
dependent mechanism. Balancing these two opposing CREB-mediated physiological processes appears
critical for glucose homeostasis. CREB activity is stimulated by the histone acetyl-transferase coactivators CBP
and P300, and by a family of cAMP regulated transcriptional coactivators (CRTCs), which associate with
CREB in response to cAMP. Here, the roles of different CRTCs and transcriptional co-factors in modulating
CREB/CRTC activity to elicit tissue-specific responses (i.e., hepatic vs. pancreatic islet) will be examined. The
overall hypothesis is that the CREB pathway functions as a central regulator of hepatic glucose production and
pancreatic insulin secretion. Aim 1 will focus on CREB-mediated glucose production by the liver in response to
fasting. The Montminy lab will generate mice lacking CRTC2 and CRTC3 (alone and in combination)
specifically in hepatocytes and assess effects on glucose output. The lab will then examine roles played by the
transcription factor FOXO1 and the epigenetic regulator BRD4 in facilitating CRTC recruitment to a subset of
fasting-induced genes in hepatocytes. Aim 2 will explore the role of CRTC1 and CRTC2 in mediating the
effects of glucose and GLP1 on insulin secretion and beta cell viability. The lab will generate mice lacking
CRTC1 and CRTC2 (alone and in combination) specifically in pancreatic islet beta cells and assess the effects
on insulin secretion and CREB target gene selection. The lab will characterize roles played by the beta cell-
specific transcription factor NeuroD1 and the cAMP-regulated non-coding RNA, LINC00473, in potentiating
CREB/CRTC signaling in the pancreas. The proposed studies will uncover how interactions between CREB,
CRTCs, and their cofactors (e.g., lineage-specific transcription factors and epigenetic regulators) promote
glucose homeostasis by differentially activating specific subsets of CREB target genes in liver and pancreatic
islets. Targeting these cofactors via chemical inhibitors may provide therapeutic benefit to individuals with type
II diabetes.

## Key facts

- **NIH application ID:** 9875458
- **Project number:** 5R01DK083834-36
- **Recipient organization:** SALK INSTITUTE FOR BIOLOGICAL STUDIES
- **Principal Investigator:** MARC R MONTMINY
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $725,348
- **Award type:** 5
- **Project period:** 2019-02-18 → 2023-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9875458

## Citation

> US National Institutes of Health, RePORTER application 9875458, Regulation of Hepatic Gluconeogenesis by the CREB:TORC2 Pathway (5R01DK083834-36). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9875458. Licensed CC0.

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