# Defining the Role of Renal Gluconeogenesis in Renal Cell Carcinoma

> **NIH NIH R37** · YALE UNIVERSITY · 2022 · $444,681

## Abstract

Project Summary
Renal cell carcinoma is the most common primary kidney cancer, representing 90-95% of primary renal
neoplasms. Obesity and diabetes are associated with an increased risk of renal cell carcinoma, but the
mechanisms by which systemic metabolic changes promote tumor progression are unknown. Although its
reputation as a glucose-producing organ has been dwarfed by that of the liver over the years, the kidney
possesses the same complement of gluconeogenic enzymes as the liver – with a higher concentration of
gluconeogenic proteins per gram of tissue in the kidney, suggesting that its gluconeogenic capacity may even
exceed the liver's. Glucose is well-known to be a crucial substrate for tumor growth; given the gluconeogenic
activity of the kidney, it is likely that increased renal gluconeogenesis may fuel tumor growth. However, this
phenomenon, and its mechanistic explanation, remains to be explored. We have recently found that fibroblast
growth factor-21 (FGF-21) promotes renal gluconeogenesis during starvation by activating intrarenal lipolysis
through a 2-adrenergic pathway, thereby activating pyruvate carboxylase flux in healthy rodents. Therefore,
this proposal will test the Overarching Hypothesis that in renal cell carcinoma, increased FGF-21 acts
through a similar mechanism to promote intrarenal lipolysis, pyruvate carboxylase activity, and as a result,
gluconeogenesis, and that this increased renal glucose supply fuels tumor growth. We will also examine the
utility of an FGF-21 neutralizing antibody against mice genetically prone to renal cell carcinoma, which we
anticipate will reduce renal gluconeogenesis and renal cell carcinoma progression. If the hypotheses are
confirmed, these data would identify FGF-21 – which is already being targeted in advanced clinical trials for
metabolism- and diabetes-related indications – as a potential therapeutic target in renal cell carcinoma.

## Key facts

- **NIH application ID:** 10360766
- **Project number:** 1R37CA258261-01A1
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** Rachel Jamison Perry
- **Activity code:** R37 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $444,681
- **Award type:** 1
- **Project period:** 2022-01-12 → 2026-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10360766

## Citation

> US National Institutes of Health, RePORTER application 10360766, Defining the Role of Renal Gluconeogenesis in Renal Cell Carcinoma (1R37CA258261-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10360766. Licensed CC0.

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