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.

Public Health Relevance

To understand the etiology of metabolic disorders, including obesity and type II diabetes, it is essential that we gain better insight into the mechanisms used by the central nervous system to regulate neuronal circuitry related to glucose metabolism. The experiments proposed in this application will unmask the role of UCP2 and mitochondrial dynamics in the central regulation of energy and glucose homeostasis and will help us to better develop strategy for the treatment of obesity and type II diabetes.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Integrative Physiology of Obesity and Diabetes Study Section (IPOD)
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Hyde, James F
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Yale University
Obstetrics & Gynecology
Schools of Medicine
New Haven
United States
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Jin, Sungho; Diano, Sabrina (2018) Mitochondrial Dynamics and Hypothalamic Regulation of Metabolism. Endocrinology 159:3596-3604
Bruschetta, Giuseppe; Jin, Sungho; Kim, Jung Dae et al. (2018) Prolyl carboxypeptidase in Agouti-related Peptide neurons modulates food intake and body weight. Mol Metab 10:28-38
Santoro, Anna; Campolo, Michela; Liu, Chen et al. (2017) DRP1 Suppresses Leptin and Glucose Sensing of POMC Neurons. Cell Metab 25:647-660
Toda, Chitoku; Santoro, Anna; Kim, Jung Dae et al. (2017) POMC Neurons: From Birth to Death. Annu Rev Physiol 79:209-236
Kim, Jung Dae; Toda, Chitoku; Ramírez, Cristina M et al. (2017) Hypothalamic Ventromedial Lin28a Enhances Glucose Metabolism in Diet-Induced Obesity. Diabetes 66:2102-2111
Suyama, Shigetomo; Ralevski, Alexandra; Liu, Zhong-Wu et al. (2017) Plasticity of calcium-permeable AMPA glutamate receptors in Pro-opiomelanocortin neurons. Elife 6:
Dotolo, Raffaele; Kim, Jung Dae; Pariante, Paolo et al. (2016) Prolyl Endopeptidase (PREP) is Associated With Male Reproductive Functions and Gamete Physiology in Mice. J Cell Physiol 231:551-7
Toda, Chitoku; Kim, Jung Dae; Impellizzeri, Daniela et al. (2016) UCP2 Regulates Mitochondrial Fission and Ventromedial Nucleus Control of Glucose Responsiveness. Cell 164:872-83
Kim, Jae Geun; Sun, Ben-Hua; Dietrich, Marcelo O et al. (2015) AgRP Neurons Regulate Bone Mass. Cell Rep 13:8-14
Koch, Marco; Varela, Luis; Kim, Jae Geun et al. (2015) Hypothalamic POMC neurons promote cannabinoid-induced feeding. Nature 519:45-50

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