# Mechanisms of Metabolic Regulation by Dietary Methionine Restriction

> **NIH NIH R01** · LSU PENNINGTON BIOMEDICAL RESEARCH CTR · 2020 · $370,000

## Abstract

Dietary methionine restriction (MR) produces a highly integrated series of biochemical and
physiological responses that reduce adiposity, improve biomarkers of metabolic health and
enhance insulin sensitivity. Our data make a compelling case that dietary MR acts through both
centrally-mediated effects on energy balance, and direct effects on peripheral tissues that
remodel white adipose tissue, activate thermogenesis in brown adipose tissue, and enhance
insulin sensitivity. We hypothesize that sensing of dietary MR is coupled to these responses
through hepatic sensing of reduced methionine through a glutathione-dependent mechanism
that activates CREBH and the eIF2 kinase, PERK. The activation of CREBH and PERK results
in activation eIF2α- and NRF2-dependent transcriptional programs that increase hepatic
expression and release of FGF21. We hypothesize that the increase in FGF21 acts through
direct and centrally-mediated mechanisms to activate thermogenesis, increase energy
expenditure, reduce fat deposition, and enhance overall insulin sensitivity. We will use a
combination of in vivo metabolic phenotyping and ex vivo biochemical analysis with loss of
function animal models to examine the role of essential amino acid sensing in the respective
responses to dietary MR. The goal of this work is to identify the nutrient sensing and signaling
systems which detect the restriction of methionine and translate this dietary modification into a
highly integrated and beneficial set of physiological responses.

## Key facts

- **NIH application ID:** 9896807
- **Project number:** 5R01DK096311-08
- **Recipient organization:** LSU PENNINGTON BIOMEDICAL RESEARCH CTR
- **Principal Investigator:** Thomas W Gettys
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $370,000
- **Award type:** 5
- **Project period:** 2012-07-01 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9896807

## Citation

> US National Institutes of Health, RePORTER application 9896807, Mechanisms of Metabolic Regulation by Dietary Methionine Restriction (5R01DK096311-08). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9896807. Licensed CC0.

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