# Intersection of Exercise and Estrogen in Weight Regain After Weight Loss

> **NIH NIH U54** · UNIVERSITY OF COLORADO DENVER · 2023 · $683,477

## Abstract

Project 2 – Project Summary
Over 60% of adults are overweight or obese. Obesity is particularly problematic in women who experience
unique physiological changes over their lifespan (e.g., menopause). While many weight-loss strategies exist,
weight regain after weight loss remains the largest barrier to successfully treating obesity. Regular exercise is
one of the most potent strategies for preventing weight regain after weight loss. We previously developed a
preclinical model showing that regular exercise reduces caloric intake during weight regain after weight loss.
Importantly, the exercise-induced reduction in caloric intake is observed in males and ovariectomized females
but not in intact/cycling female rats. In males, we have shown that regular exercise suppresses the drive to
overeat and potentiates energy expenditure above and beyond the cost of the exercise bout. The overall
objective of this proposal is to determine how exercise counters the biological drive to regain weight
and elucidate the sexual dimorphic response. To achieve this objective, we propose to investigate known
mechanisms of appetite and energy expenditure regulation that are thought to mediate the sex differences and
explore a novel role for the tryptophan-kynurenine (TRP-KYN) pathway in regulating energy balance in this
context.
In Aim 1, we will examine sex differences, the effect of ovariectomy, and the impact of exercise on
post-prandial gut hormone responses and eating behaviors and during weight regain. We hypothesize
that exercise is modulating gut hormone peptides to exert beneficial feeding effects during weight regain after
weight loss and that the presence of estrogen interferes with this modulation in intact females to sustain weight
regain.
In Aim 2, we will determine the impact of ovariectomy and estrogen add-back on exercise-induced
energy expenditure during weight regain after weight loss. We hypothesize that the exercise-induced
increase in energy expenditure is linked to its ability to enhance the capacity to oxidize fat, which is inherently
higher in females due to estrogen. We suspect the presence of estrogen in intact females and ovariectomized
females with estrogen add-back will diminish the impact of exercise on dietary fat oxidation and energy
expenditure.
In addition to testing these hypotheses, our studies will provide valuable information about TRP-KYN pathway
metabolites and their role in mediating the effects of sex differences, the loss of ovarian function, and the
beneficial effects of exercise training. Observations from these studies will provide insight into the
mechanisms of the sexual dimorphic response to exercise during weight regain and identify novel targets and
strategies to facilitate weight loss maintenance more effectively.

## Key facts

- **NIH application ID:** 10712610
- **Project number:** 2U54AG062319-11
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** Paul S. Maclean
- **Activity code:** U54 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $683,477
- **Award type:** 2
- **Project period:** 2012-09-20 → 2028-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10712610

## Citation

> US National Institutes of Health, RePORTER application 10712610, Intersection of Exercise and Estrogen in Weight Regain After Weight Loss (2U54AG062319-11). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10712610. Licensed CC0.

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