# The role of adipocyte KLF14 in Metabolic Syndrome

> **NIH NIH R01** · UNIVERSITY OF VIRGINIA · 2020 · $479,945

## Abstract

PROJECT SUMMARY
 Metabolic syndrome (MetSyn) is a group of metabolic conditions that occur together and promote the
development of cardiovascular disease (CVD) and type 2 diabetes. Although various criteria for defining
MetSyn exist, disease conditions include abdominal obesity, insulin resistance, elevated serum triglyceride
levels, depressed serum high-density lipoprotein (HDL) levels, elevated blood glucose levels and hypertension.
The incidence of MetSyn is predicted to increase as obesity has become a worldwide epidemic. This increase
may have detrimental effects and may actually reverse the trend of decreasing CVD in the US. Heritability
estimates for individual components of MetSyn vary between 40% to 70%, suggesting a strong contribution of
genetic components to disease pathology. Recent genome-wide association studies (GWAS) have identified
over 600 genomic loci that are associated with obesity, diabetes, CVD and cardiometabolic traits. However,
most of the underlying genes and the related mechanisms of how these loci contribute to the disease process
remain unknown. One of the Type 2 Diabetes GWAS signals at chromosome 7q32.3 has pleiotropic effects as
it is also associated with serum HDL levels and body fat distribution. The effects of the genetic variants appear
to be stronger in females than in males. This signal maps to a 45kb recombination interval, extending from 3kb
upstream of the transcription factor KLF14. Using gene expression data from subcutaneous adipose tissue
biopsies collected from participants of the Metabolic Syndrome in Men (METSIM) cohort, we showed that
KLF14 is the likely cis-effector gene for this locus and revealed it to be a master trans-regulator of a program of
adipose tissue expression. Our results indicated that lower expression of KLF14 was associated with
detrimental metabolic profiles in humans. Therefore, we hypothesized that induction of KLF14 abundance and
resulting changes in its targets in adipocytes would result in a beneficial metabolic profile. To test this
hypothesis, this proposal outlines a multilayered approach to define the trancriptional targets of KLF14 in
adipocytes, the impact of the modulation of KLF14 expression on adipocyte function, and explore the
therapeutic benefits of adipocyte-specific induction of KLF14 expression in transgenic mice. We will use
primary adipocytes, adipocyte cell lines, primary tissues, and transgenic mice to dissect the effects of KLF14
on gene expression and metabolic phenotypes.

## Key facts

- **NIH application ID:** 9935903
- **Project number:** 5R01DK118287-03
- **Recipient organization:** UNIVERSITY OF VIRGINIA
- **Principal Investigator:** Mete Civelek
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $479,945
- **Award type:** 5
- **Project period:** 2018-07-25 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9935903

## Citation

> US National Institutes of Health, RePORTER application 9935903, The role of adipocyte KLF14 in Metabolic Syndrome (5R01DK118287-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9935903. Licensed CC0.

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