# Role of peroxisome proliferation in leptin resistance

> **NIH NIH R01** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2020 · $337,540

## Abstract

Previous data from our and others' laboratories (Andrews et al., 2008; Benani et al., 2007; Anderson et al.,
2009; Jaillard et al., 2009; Campanucci et al., 2010; Diano et al., 2011; Dietrich et al., 2013; Long et al.,
2014) showed that reactive oxygen species (ROS) generation is not merely a by-product of substrate
oxidation, but it plays a crucial role in modulating cellular responses involved in the regulation of energy
metabolism. We have observed that suppression of ROS levels diminish pro-opiomelanocortin (POMC) cell
activation and promote the activity of neuropeptide Y- (NPY)/ agouti related peptide- (AgRP) neurons and
feeding, whereas ROS activates POMC neurons and reduces feeding. Mitochondria are primary organelles
in the generation of ROS and mitochondrial dynamics, i.e. fission and fusion, alters the production of
mitochondrial ROS, with mitochondrial fission decreasing and mitochondrial fusion increasing ROS
production. Furthermore, uncoupling protein 2 (UCP2), a mitochondrial protein inducing proton leak and
highly expressed in the arcuate nucleus, reduces ROS production. Our published (Coppola et al., 2007;
Andrews et al., 2008; Diano et al., 2011; Dietrich et al., 2013; Long et al., 2014) and preliminary data
generated during this funding period showed that mitochondrial size in AgRP and POMC neurons changes
according to the metabolic state of the organism: while during negative energy balance, characterized by
increased AgRP and decreased POMC neuronal activities, mitochondrial size decreases (fission), during
positive energy balance (fed state) mitochondrial size increases in AgRP and POMC (fusion). Thus, we
hypothesize that the activity levels of POMC and NPY/AgRP neurons require UCP2-mediated mitochondrial
dynamics. UCP2-induced mitochondrial fission, by decreasing ROS production, inhibits POMC neurons
while activates NPY/AgRP neurons. Furthermore, we hypothesize that fuel availability drives mitochondrial
dynamics a more specifically low glucose levels drives fission, while high glucose availability drives fusion.
To test our hypothesis that fuel regulation of UCP2-mediated mitochondrial dynamics is an
important component in the central regulation of metabolism, 3 Aims are proposed:
Aim 1 will test the hypothesis that UCP2-mediated mitochondrial fission inactivates POMC neurons.
Aim 2 will test the hypothesis that UCP2-mediated mitochondrial fission activates NPY/AgRP
neurons.
Aim 3 will test the hypothesis that fuel availability drives mitochondrial dynamics in AgRP and
POMC neurons. Specifically we hypothesize that low glucose and high fatty acid environment
(negative energy balance) drives fission, while high glucose availability drives fusion.
The execution of these studies will deliver novel insights into central regulation of whole body glucose
metabolism and offer novel avenues to combat diabetes by targeting brain mitochondrial dynamics.

## Key facts

- **NIH application ID:** 10320591
- **Project number:** 7R01DK097566-09
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** Sabrina Diano
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $337,540
- **Award type:** 7
- **Project period:** 2020-09-01 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10320591

## Citation

> US National Institutes of Health, RePORTER application 10320591, Role of peroxisome proliferation in leptin resistance (7R01DK097566-09). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10320591. Licensed CC0.

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