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. Public Health Relevance: Late onset chronic diseases, such as dementias, Alzheimer's and Parkinson's 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 pr

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
NIH Director’s Pioneer Award (NDPA) (DP1)
Project #
Application #
Study Section
Special Emphasis Panel (ZGM1-NDPA-B (01))
Program Officer
Hyde, James F
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Yale University
Veterinary Sciences
Schools of Medicine
New Haven
United States
Zip Code
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
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
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
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
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; Sebastián, David et al. (2013) Mitofusin 2 in POMC neurons connects ER stress with leptin resistance and energy imbalance. Cell 155:172-87
Dietrich, Marcelo O; Horvath, Tamas L (2013) Hypothalamic control of energy balance: insights into the role of synaptic plasticity. Trends Neurosci 36:65-73

Showing the most recent 10 out of 23 publications