# Rethinking Obesity and Cardiometabolic Health in Women: Using Evolutionarily Informed Hypotheses to Integrate Physiology and Behavior During Weight Loss

> **NIH NIH K01** · UNIVERSITY OF COLORADO DENVER · 2020 · $153,939

## Abstract

Project Summary/Abstract
Obesity is major modifiable risk factor for cardiometabolic disease that disproportionally
affects women. Current behavioral weight loss interventions produce only modest weight
loss with a high rate of recidivism, and are less likely to be successful in women.
Evolutionary considerations can help integrate separate lines of research on how
reproductive and metabolic physiology are related, and provide important insight into the
pathophysiology of obesity in women. Gonadotropins and ovarian hormones are
considered key regulators of energy homeostasis and body composition among women,
and suppression impacts energy intake and expenditure in ways that could inhibit weight
loss. Recently, a unique functional dysregulation of the hypothalamic pituitary ovarian
(HPO) axis has been observed in regularly cycling (eumennorheic) women with obesity,
resulting in lower levels of gonadotropins and ovarian hormones compared to normal
weight women. This dysregulation may be highly prevalent and is associated with
cardiometabolic risk factors and subfertility. While it has been presumed that this disorder
improves with weight loss, gonadotropins and ovarian hormones are suppressed in
normal weight women response to energy restriction. This suppression reflects an
adaptive response to strategically shift energy away from reproduction and toward
survival during resource scarcity. Therefore, restricting energy through behavioral weight
loss may prolong or induce HPO axis dysregulation in some women, which may in turn
inhibit weight loss. The proposed research seeks to fill gaps in knowledge regarding the
prevalence and etiology of obesity-related HPO axis dysregulation (Aim 1), examine the
extent to which it improves with a behavioral weight loss intervention (Aim 2), and explore
the impact of this disorder on energy intake and expenditure (including physical activity
and sedentary behavior), and weight loss (Aim 3). The study design is a prospective,
longitudinal, observational study of 40 eumemorhheic, pre-menopausal, obese women
enrolled in a NIH-funded 1-year randomized weight loss trial. Participants will undergo
measures of HPO axis function over complete menstrual cycles the month prior to and
the first 3 months of the behavioral weight loss intervention. Dr. Caldwell will perform
these measures and those that complement them obtained in the parent trial (changes in
weight, body composition, cardiometabolic parameters, energy intake, and energy
expenditure). The central premise is that a less metabolically healthy obese state is
associated with a greater degree of HPO axis dysregulation; that reducing energy
availability during behavioral weight loss will prolong or induce HPO axis dysregulation in
some women; and that the persistence or development of HPO axis dysregulation will
inhibit weight loss and promote weight gain. Dr. Caldwell will gain substantive career
development training through conducting this research and form criti...

## Key facts

- **NIH application ID:** 9903437
- **Project number:** 5K01HL143039-02
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** Ann Elizabeth Caldwell
- **Activity code:** K01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $153,939
- **Award type:** 5
- **Project period:** 2019-07-01 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9903437

## Citation

> US National Institutes of Health, RePORTER application 9903437, Rethinking Obesity and Cardiometabolic Health in Women: Using Evolutionarily Informed Hypotheses to Integrate Physiology and Behavior During Weight Loss (5K01HL143039-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9903437. Licensed CC0.

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