# Hexosamine biosynthetic pathway activation and leptin resistance

> **NIH NIH R01** · AUGUSTA UNIVERSITY · 2021 · $380,000

## Abstract

The adipokine leptin is released in proportion to the size of body fat stores and is a key
contributor to the control of food intake and maintenance of metabolic homeostasis in normal
weight animals and humans. A failure to fully activate leptin signaling proteins results in leptin
resistance, which is a predisposing factor for obesity. Approximately 34% of US adults and 17%
of children are obese and consumption of sugar sweetened beverages has been implicated in this
epidemic of obesity. Rats consuming 30% sucrose solution develop peripheral and central leptin
resistance faster than those fed formulated high-fat or high-sucrose diets. Leptin resistance is
traditionally associated with a failure increase phosphorylation of the transcription factor signal
transducer and activator of transcription 3 (pSTAT3) in areas of the brain that control food
intake and energy expenditure. In leptin resistant sucrose-drinking rats basal hypothalamic
pSTAT3 is increased and leptin does not increase pSTAT3 or inhibit food intake. Preliminary in
vivo and in vitro data provide compelling evidence that increased glucose availability increases
activity of the hexosamine biosynthetic pathway (HBP), increases pSTAT3 and causes leptin
resistance. HBP activity results in O-GlcNAc modification of hundreds of proteins including
enzymes and transcription factors. Basal HBP activity is crucial for many regulatory cell
processes, but chronic activation disrupts signaling cascades and promotes cancer,
cardiovascular disease and insulin resistance. Rats drink sucrose throughout the day and we
hypothesize that the resultant surges in blood glucose chronically activate the HBP and inhibit
leptin signaling due to O-GlcNAc modification of the key leptin signaling protein STAT3. Three
Specific Aims will test this hypothesis. The first Aim will test whether consumption of liquid
sucrose results in repeated excursions of blood glucose that stimulate the HBP, promote protein
O-GlcNAc modification and cause leptin resistance. The second Aim will use in vitro studies to
investigate the mechanism by which activation of the HBP modifies STAT3 phosphorylation and
interferes with leptin signaling. The third Aim will use in vivo rodent studies to test the
physiologic impact of HBP activation in the hypothalamus on leptin responsiveness. These Aims
will provide significant new information on a mechanism that links consumption of sweetened
beverages with increased risk for obesity.

## Key facts

- **NIH application ID:** 9918883
- **Project number:** 5R01DK109997-04
- **Recipient organization:** AUGUSTA UNIVERSITY
- **Principal Investigator:** Ruth B Harris
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $380,000
- **Award type:** 5
- **Project period:** 2017-05-01 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9918883

## Citation

> US National Institutes of Health, RePORTER application 9918883, Hexosamine biosynthetic pathway activation and leptin resistance (5R01DK109997-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9918883. Licensed CC0.

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