Guided by the notion that late onset chronic diseases are the consequence of prolonged overworking of various tissues that have genetic and epigenetic vulnerabilities, I assert that it is the cellular energy metabolism of the different tissues that determines their health and longevity and consequently that of the entire organism. Based on my previous and ongoing work, I hypothesize that a small set of neurons in the hypothalamus, which produce Agouti-related protein (AgRP), act as the master regulator of energy utilization by all tissues, and hence, these hypothalamic neurons determine healthy tissue function and longevity. We will selectively up- or down-regulate the activity of hypothalamic AgRP neurons and test the effect of these perturbations on normal physiology of peripheral tissues and that of the brain. I suggest that these changes in peripheral tissue function by altered AgRP neuronal functioning will have critical impact on higher brain functions as well, including learning and memory and the ability of the brain to withstand stress during neurodegeneration induced either by normal aging or by pathological processes, such as Alzheimer's and Parkinson's disease. This project is uniquely suited for the NDPA program because it is unconventional and represents an approach in biomedical research that is nonexistent. It is a high risk avenue, but, if successful, would have great benefits in that it could immediately lead to novel treatments for various chronic diseases.
Late onset chronic diseases, such as dementias, Alzheimers and Parkinsons disease, diabetes, cardiovascular disorders and tissue malignancies, are the leading causes of morbidity and mortality in the U.S., creating the greatest emotional and financial burden on the individual and society. As the size of the aging population continues to grow, late onset chronic diseases are predicted to further dominate the attention of biomedicine and society at large. This proposal aims to deliver paradigm shifting discoveries that will achieve a decline in the prevalence of chronic diseases.
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|Koch, Marco; Varela, Luis; Kim, Jae Geun et al. (2015) Hypothalamic POMC neurons promote cannabinoid-induced feeding. Nature 519:45-50|
|Vogt, Merly C; Paeger, Lars; Hess, Simon et al. (2014) Neonatal insulin action impairs hypothalamic neurocircuit formation in response to maternal high-fat feeding. Cell 156:495-509|
|Ruan, Hai-Bin; Dietrich, Marcelo O; Liu, Zhong-Wu et al. (2014) O-GlcNAc transferase enables AgRP neurons to suppress browning of white fat. Cell 159:306-17|
|Seli, Emre; Babayev, Elnur; Collins, Stephen C et al. (2014) Minireview: Metabolism of female reproduction: regulatory mechanisms and clinical implications. Mol Endocrinol 28:790-804|
|Kim, Jae Geun; Suyama, Shigetomo; Koch, Marco et al. (2014) Leptin signaling in astrocytes regulates hypothalamic neuronal circuits and feeding. Nat Neurosci 17:908-10|
|Matarese, Giuseppe; Procaccini, Claudio; Menale, Ciro et al. (2013) Hunger-promoting hypothalamic neurons modulate effector and regulatory T-cell responses. Proc Natl Acad Sci U S A 110:6193-8|
|Dietrich, Marcelo O; Liu, Zhong-Wu; Horvath, Tamas L (2013) Mitochondrial dynamics controlled by mitofusins regulate Agrp neuronal activity and diet-induced obesity. Cell 155:188-99|
|Oury, Franck; Khrimian, Lori; Denny, Christine A et al. (2013) Maternal and offspring pools of osteocalcin influence brain development and functions. Cell 155:228-41|
|Schneeberger, Marc; Dietrich, Marcelo O; SebastiÃ¡n, David et al. (2013) Mitofusin 2 in POMC neurons connects ER stress with leptin resistance and energy imbalance. Cell 155:172-87|
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