# The role of phosphodiesterase 9 in the regulation of adipocyte thermogenesis and obesity-related diseases

> **NIH NIH F32** · VANDERBILT UNIVERSITY MEDICAL CENTER · 2020 · $69,306

## Abstract

PROJECT SUMMARY
 Obesity presents a major health concern as it is often a predisposing factor for multiple diseases, most
notably heart disease and diabetes. There are two types of adipose tissue: white adipose tissue (WAT) which
stores triglycerides and brown adipose tissue (BAT) which is an important site of non-shivering thermogenesis.
Cells in the WAT depot can increase a population of cells, called “beige” or “brite” adipocytes, that have elevated
levels of mitochondria, express uncoupling protein-1 (UCP1), and are more thermogenic. Increasing energy
expenditure by increasing the amounts of beige and BAT is a potential anti-obesity therapeutic. Natriuretic
peptides (NP) and nitric oxide (NO) can increase UCP1 expression and thermogenesis in adipocytes by
activating cyclic guanosine monophosphate (cGMP)-protein kinase G (PKG) signaling. Phosphodiesterase
(PDE) enzymes break the phosphodiester bond in cyclic nucleotides rendering them inactive. PDE 5, 6, and 9
are specific to cGMP and, of these, PDE9 has the highest affinity for and is the most selective for cGMP. Inhibition
of PDE9 will be investigated as a potential anti-obesity therapeutic target. Mice with a targeted gene deletion of
Pde9 and PDE9 specific antagonists will be investigated for their potential to increase thermogenesis in
adipocytes. The specific aims of this project are to:
(1) Test the hypothesis that the cGMP-specific phosphodiesterase 9 modulates adipocyte metabolism
and 'thermogenic' gene expression.
 In these studies the ability of the cGMP-specific phosphodiesterase 9 (PDE9) to regulate adipocyte
metabolism will be investigated in vitro. The response to ANP for cGMP generation, glucose and fatty acid
uptake, and energy utilization will be determined. Mitochondrial biogenesis, UCP1 expression, and cellular
respiration will be measured as functional readouts of browning of adipose tissue in vitro.
(2) Establish the impact of phosphodiesterase 9 on obesity and the diabetic/insulin resistant phenotype
using mouse models.
 The role of PDE9 in adipose tissue will be investigated in vivo. Diet-induced and genetic models of obesity
will be examined to test the hypothesis that pharmacological blockade of PDE9 or Pde9 gene knockout in mice
will diminish weight gain, reduce insulin resistance, and improve glucose homeostasis. Studies will ascertain
whether changes in the metabolic phenotype of these mice are due to thermogenesis via increased brown
adipose tissue activity and/or expansion of UCP1-expressing cells in white adipose depots.

## Key facts

- **NIH application ID:** 9915903
- **Project number:** 5F32DK116520-04
- **Recipient organization:** VANDERBILT UNIVERSITY MEDICAL CENTER
- **Principal Investigator:** Ryan Patrick Ceddia
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $69,306
- **Award type:** 5
- **Project period:** 2018-05-01 → 2021-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9915903

## Citation

> US National Institutes of Health, RePORTER application 9915903, The role of phosphodiesterase 9 in the regulation of adipocyte thermogenesis and obesity-related diseases (5F32DK116520-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9915903. Licensed CC0.

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