# Impact of  CREBRF and its obesity-risk variant on hypothalamic glucocorticoid  and neuroendocrine output using molecular, cellular, and physiological approaches.

> **NIH NIH K01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2020 · $148,403

## Abstract

PROJECT SUMMARY
Strong evidence links central hypothalamic neuroendocrine output to complex biological processes and
behaviors that control energy and metabolic homeostasis. Dr. Kershaw’s collaborative research group recently
identified a novel obesity-risk variant in a putative transcriptional regulator, CREBRF, that is highly expressed in
the hypothalamus. Although virtually nothing in know about CREBRF, it has been linked to glucocorticoid
signaling, raising that possibility that its energy and metabolic effects in humans is mediated, in part, by
influencing hypothalamic glucocorticoid and/or neuroendocrine output. The overarching goal of this proposal is
to determine how CREBRF and its obesity-risk variant contribute to the central regulation of energy homeostasis
and the stress response. The overall objective, which is the next step in the pursuit of this goal, is to characterize
the role of this gene/variant in central hypothalamic glucocorticoid and neuroendocrine output. The central
hypothesis is that CREBRF is expressed and regulated in key hypothalamic neurons and that the loss of
CREBRF or expression of its missense CrebrfR457Q will differentially impact the metabolic control transcriptome
and the chromatin landscape within the hypothalamus, thereby influences behavioral and metabolic outcomes.
This hypothesis is based on the following: 1) endogenous CREBRF is highly expressed in the central nervous
systems including the hypothalamus where it co-localizes with the glucocorticoid receptor (GR); 2) ectopic
expression of CREBRF in cells influences subnuclear GR targeting and stability; 3) global CrebrfKO mice have
dysregulated glucocorticoid signaling and abnormal postpartum maternal behavior; and 4) global CrebrfKO mice
have reduced body weight. The above hypothesis will be tested using molecular, cellular, and physiological
approaches with the following specific aims: 1) To characterize the impact of CREBRF and its obesity risk variant
(CREBRFR458Q) on hypothalamic output in vivo using murine models; and 2) to determine the function of
CREBRF and its obesity risk variant (CREBRFR458Q) on chromatin accessibility and cell-specific transcriptome
using murine models. This research is innovative because 1) it examines obesity in a murine model without the
complications of diabetes, 2) examine the mechanisms for the phenotype observed in Samoans and 3) will lay
the foundation for numerous avenues to pursue the potential therapeutic benefits of targeting central CREBRF.
This contribution will be significant because it will identify CREBRF expression, regulation, and function in
specific hypothalamic neuropeptide-containing neurons and HPA-axis output during defined stress conditions
and determine the impact of CREBRF and its obesity-linked variant on the genome-wide chromatin landscape
and single cell transcriptomes within the hypothalamus. Such findings are expected to have a broad translational
impact by improving strategies for prevention a...

## Key facts

- **NIH application ID:** 9994879
- **Project number:** 5K01DK115543-04
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Krystle Anne Frahm
- **Activity code:** K01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $148,403
- **Award type:** 5
- **Project period:** 2017-09-08 → 2022-09-07

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9994879

## Citation

> US National Institutes of Health, RePORTER application 9994879, Impact of  CREBRF and its obesity-risk variant on hypothalamic glucocorticoid  and neuroendocrine output using molecular, cellular, and physiological approaches. (5K01DK115543-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9994879. Licensed CC0.

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