# Interrogating Fatty Acid Metabolism Impairment andClinical Correlates in Males with Klinefelter Syndrome

> **NIH NIH R01** · UNIVERSITY OF COLORADO DENVER · 2023 · $311,000

## Abstract

ABSTRACT
Klinefelter syndrome (KS) is a genetic condition affecting 1 in 600 males who have an additional X
chromosome (47,XXY) associated with multisystem manifestations and increased mortality secondary to
disorders of insulin resistance. One of the hallmark features of KS is primary testicular failure resulting in
hypogonadism, and to date androgen treatment has been the only therapeutic intervention studied in these
individuals. However, insulin resistance and abnormal metabolism have been observed in youth with KS prior
to the onset of testicular hypogonadism. Furthermore, testosterone replacement does not ameliorate these
cardiometabolic deficits that the majority of these individuals experience. The underlying molecular
mechanisms for the high prevalence of insulin resistance and exercise intolerance observed in KS are
unknown. This application proposes that the additional X chromosome leads to metabolic aberrations that can
be targeted for therapeutic intervention. Peroxisome proliferator-activated receptor alpha (PPAR-α) is
transcription factor that regulates the expression of genes controlling fatty acid metabolism, inflammation, and
oxidative stress. Low PPAR-α activity is associated with cardiometabolic profiles similar to that observed in KS,
including adiposity, dyslipidemia, and exercise intolerance. Our preliminary data have shown a metabolome
and transcriptome consistent with insufficient activity of the PPAR-α complex in males with KS. The central
hypothesis of this study is that lower PPAR-α activity contributes to the cardiometabolic phenotype in KS and
that increasing PPAR-α activity via PPAR-α agonist treatment will result in upregulation of gene transcription
that will improve cardiometabolic physiology. In this proof-of-concept trial, we will first compare expression of
PPAR-α-regulated genes from whole blood and skeletal muscle in adolescent and young adult males with and
without KS, as well as systemic fat oxidation during submaximal prolonged exercise and tissue-specific
mitochondrial ß-oxidation. Resting energy expenditure, metabolite concentrations, and patient-centered
outcomes will also be obtained and compared between groups. The KS cohort will then receive intervention
with a PPAR- α agonist (fenofibrate) for one month, and all outcomes will be reassessed. This study will lay the
foundation for future investigation of the first ever non-androgen treatment to improve insulin resistance and
exercise intolerance in males with KS. The study aims support the mission and priority areas of the NIDDK and
are expected to have direct clinical implications for individuals with KS.

## Key facts

- **NIH application ID:** 10646288
- **Project number:** 5R01DK133292-02
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** Shanlee Davis
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $311,000
- **Award type:** 5
- **Project period:** 2022-07-01 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10646288

## Citation

> US National Institutes of Health, RePORTER application 10646288, Interrogating Fatty Acid Metabolism Impairment andClinical Correlates in Males with Klinefelter Syndrome (5R01DK133292-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10646288. Licensed CC0.

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