# In vivo hepato-renal metabolic flux dysregulation in obesity

> **NIH NIH K01** · VANDERBILT UNIVERSITY · 2024 · $120,591

## Abstract

Project Summary
The liver and kidney are the major organs where glucose biosynthesis is coupled to mitochondrial
metabolism. Previous studies demonstrate that overnutrition accelerates whole-body gluconeogenesis
(GNG) and citric acid cycle (CAC) activity in vivo. A limitation of prior research is that the unique
contributions of the liver and kidney to whole-body GNG and CAC fluxes have been difficult to disentangle
in vivo. The inability to discern hepatic from renal metabolic fluxes represents a significant gap in
knowledge, as obesity may not only cause an ectopic accumulation of lipid but also an “ectopic
redistribution” of gluconeogenic function that disproportionately stresses the kidney. We hypothesize that
renal GNG and CAC activity are disproportionately elevated in obesity, which contributes to the
dysregulation of whole-body glucose metabolism and promotes mitochondrial dysfunction and oxidative
tissue damage in the kidney. The scientific aims of this proposal are to (i) determine whether the
progressive development of obesity disproportionately impacts renal gluconeogenic and oxidative
metabolism, (ii) assess whether gluconeogenic overload on the kidney accelerates oxidative metabolism
and stress during obesity, and (iii) identify metabolic mechanism(s) by which SGLT2 inhibitor treatment
reduces hepato-renal lipotoxicity in vivo. The aims of our project will be accomplished using a novel,
metabolic flux modeling system that simultaneously determines gluconeogenic and oxidative metabolic
fluxes in the liver and kidney in vivo. This work is innovative because it examines the etiology and
treatment of metabolic disease through the lens of multi-organ fluxomics while focusing on an
understudied aspect of gluco(dys)regulation. It is significant because it will identify organ-specific
metabolic nodes that may be better targeted to improve glycemic control and reduce damage in the kidney
and liver. Results from this K01 project, the unique expertise of each member of my mentoring committee,
and the diabetes research infrastructure at Vanderbilt University will be leveraged to achieve my career
objective of an independent career studying metabolic regulation in diabetic kidney disease and
hypoglycemic counter-regulation. As such, this project integrates a career development plan with the
training needed to bolster my disease-state expertise, grantsmanship, and expand my analytical
capabilities to ensure a smooth transition toward research independence.

## Key facts

- **NIH application ID:** 10813775
- **Project number:** 5K01DK135924-02
- **Recipient organization:** VANDERBILT UNIVERSITY
- **Principal Investigator:** Clinton Michael Hasenour
- **Activity code:** K01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $120,591
- **Award type:** 5
- **Project period:** 2023-04-01 → 2027-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10813775

## Citation

> US National Institutes of Health, RePORTER application 10813775, In vivo hepato-renal metabolic flux dysregulation in obesity (5K01DK135924-02). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10813775. Licensed CC0.

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