# Glucocorticoid and circadian clock coregulation of insulin sensitivity and metabolism

> **NIH NIH K01** · CINCINNATI CHILDRENS HOSP MED CTR · 2021 · $149,931

## Abstract

PROJECT SUMMARY/ABSTRACT
Circadian rhythm plays a central role in metabolic homeostasis and nutrient utilization in nearly all organisms
and virtually all tissues. Glucocorticoids are oscillatory regulators of metabolic function that act with cell and
tissue-type specificity. Glucocorticoid steroids like prednisone are used to treat a wide range of inflammatory
conditions, where their use is associated with prominent metabolic side effects. Chronic daily glucocorticoid
intake promotes insulin resistance and obesity, and therefore novel approaches are needed to reverse these
dysmetabolic effects. An important breakthrough in glucocorticoid-driven metabolic regulation stems from
recently published discoveries that steroid dosing frequency, i.e. daily versus pulsatile weekly, promotes
strikingly opposing effects on lean mass quality, exercise tolerance, and energy production. Contrary to daily
dosing, weekly glucocorticoids exposure improves nutrient uptake and metabolism, boosting muscle growth
and curtailing fat accrual. Specifically, I have uncovered that pulsatile glucocorticoids stimulate branched-chain
amino acid oxidative metabolism and insulin sensitivity through a glucocorticoid receptor-responsive
epigenomic program focusing on the transcriptional regulator Kruppel-like factor 15 (KLF15). Furthermore,
pulsatile glucocorticoids also activate BMAL1 and its molecular cascades. Each of these components, the
glucocorticoid receptor, KLF15 and BMAL1 are regulated by circadian oscillations in their metabolic effects.
However, it is still unclear whether and how the circadian clock and glucocorticoid cascades interact to
promote fuel utilization and favorable metabolic reprogramming, and whether environmental or genetic
challenges to this interaction will affect metabolic physiology. To address this question, I propose to (i) dissect
circadian regulation of glucocorticoid receptor activation and its effects on glucose and fatty acid utilization in
metabolically active tissues like muscle, liver and fat, and (ii) investigate the epigenomic cross-regulation
between BMAL1 and KLF15 in driving branched-chain amino acid metabolism and energy production.
Experiments will follow a basic-to-translational path from mice models to human cells using a multidisciplinary
approach encompassing epigenetic, molecular and metabolic studies. The overarching goal for this proposal is
to provide new actionable knowledge of cross-regulation between glucocorticoids and circadian clock, with
implications for the treatment of metabolic diseases like obesity and diabetes.

## Key facts

- **NIH application ID:** 10166838
- **Project number:** 5K01DK121875-04
- **Recipient organization:** CINCINNATI CHILDRENS HOSP MED CTR
- **Principal Investigator:** Mattia Quattrocelli
- **Activity code:** K01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $149,931
- **Award type:** 5
- **Project period:** 2019-07-01 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10166838

## Citation

> US National Institutes of Health, RePORTER application 10166838, Glucocorticoid and circadian clock coregulation of insulin sensitivity and metabolism (5K01DK121875-04). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10166838. Licensed CC0.

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