# Beneficial reprogramming of lipid metabolism with intermittent fasting

> **NIH NIH R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2024 · $663,984

## Abstract

Caloric restriction is the most conserved behavioral intervention that prolongs lifespan in model organisms.
Capturing benefits of caloric restriction, either through dietary prescription or by identifying causal pathways that
can be manipulated pharmacologically, holds promise to improve cardiometabolic health. Testing whether the
life-prolonging effect is translatable to humans is challenging; however, multiple studies, with various approaches
to caloric restriction, have demonstrated benefits to surrogate endpoints such as weight loss, lipids, and glucose
homeostasis. One important question is the degree to which benefits of caloric restriction are due to weight
loss—i.e. would we all benefit from caloric restriction or are the benefits most applicable to patients who are
overweight? Moreover, long-term compliance with a diet requiring daily adherence is challenging. Intermittent
fasting has emerged as an alternative that does not require daily adherence and early studies suggest metabolic
benefit. Our multi-disciplinary research group has focused on studying fasting because there is theoretical benefit
independent of weight loss. Through coupling of clinical phenotyping with multi-omics analyses, we have defined
metabolic responses as a function of fasting duration and in relationship to key physiological events, such as
weight loss and changes in bone metabolism, as catabolic effects on bone are a consistent negative result of
caloric restriction with weight loss. We have discovered a marked fasting shift in lipid composition— sustained
even after re-feeding—characterized by reduced low carbon-content, saturated triglycerides and increased high-
carbon content, unsaturated triglycerides; a triglyceride shift shown in epidemiologic studies to protect against
future cardiometabolic disease and frailty. Remarkably, the beneficial shift in triglyceride quality is already evident
in the first fasting day, before weight loss or negative changes in bone turnover markers. Therefore, our central
hypothesis is that fasting drives cardiometabolic benefits independent of weight loss and the benefits can be
captured without negative effects to bone if each fasting dose is limited to one day. We propose a mechanistic
clinical study, randomizing volunteers at high risk of diabetes, to one of 3 groups: 1) Control group, 2) Fasting
one day per week for 3 months, or 3) Fasting one day per week with a caloric prescription to maintain body
weight. In Aim 1 we will perform metabolomics to test whether intermittent fasting beneficially reprograms lipid
metabolism, whether that reprogramming predicts improved insulin sensitivity and whether these changes occur
independent of weight loss. Recognizing that the most important negative consequence of any approach to
caloric restriction is the catabolic effect on bone, in Aim 2 we will assess the effects on bone, including state of
the art analyses of bone microarchitecture. If successful, this study will provide proof...

## Key facts

- **NIH application ID:** 10830426
- **Project number:** 5R01DK133578-02
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Pouneh Khadejeh Fazeli
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $663,984
- **Award type:** 5
- **Project period:** 2023-07-01 → 2028-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10830426

## Citation

> US National Institutes of Health, RePORTER application 10830426, Beneficial reprogramming of lipid metabolism with intermittent fasting (5R01DK133578-02). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10830426. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*