Obesity is a chronic metabolic disorder characterized by an excess of body fat. Obesity results from prolonged positive energy balance (i.e. energy intake exceeding energy expenditure). Although the cause of the excessive positive energy balance in obesity has not been clearly defined, key components reside in the hypothalamus, specifically in the arcuate nucleus. The arcuate nucleus (ARC) of the hypothalamus is critical for regulation of energy balance and is considered to play a key integrative role between the initial afferent signals from the periphery and CNS responses. The hypothalamic melanocortinergic system, composed of proopiomelanocortin (POMC) and agouti-related peptide (AgRP) neurons located within the ARC and melanocortin receptor type 4 (MC4R)-expressing neurons throughout the neuraxis, is a major regulator of energy homeostasis. Anorexigenic POMC neurons of the ARC respond to circulating signals and contribute to the regulation of energy expenditure by releasing the anorexigenic melanocyte-stimulating hormones. Recent studies have demonstrated that POMC neurons can be divided, at least, into two subpopulations in terms of the neurotransmitter phenotype and the expression of receptors, including leptin and insulin receptors. We hypothesize that these phenotypic distinctions reflect important functional differences and that it is the interplay between two phenotypically distinct populations of POMC neurons that is required for integration of peripheral and central signaling molecules, thus controlling the anorexigenic outcome of POMC neurons. In this proposal, we will determine how novel interactions between distinct populations of POMC neurons contribute to the control of hypothalamic neurophysiology and the regulation of energy homeostasis. We will provide an entirely novel perspective on the cellular mechanisms regulating energy balance in 3 specific aims.
Aim 1 : Determine the extent of POMC neuron heterogeneity in the ARC.
Aim 2 : Determine the physiological interactions between two of the distinct subsets of POMC neurons.
Aim 3 : Determine the network effect of POMC neuron heterogeneity and interaction. The information that we will thereby obtain will provide novel insight into the physiological consequences of POMC-POMC neuron interactions. Our studies will also lend support to the idea that the establishment of POMC heterogeneity during early stages of hypothalamic development is a critical factor for overall energy balance. Hence the proposed studies will provide novel insights into the neurobiology of melanocortin system in general and its specific role in the control of energy balance in particular.

Public Health Relevance

These studies have the potential to reveal entirely novel physiological interactions between two proposed distinct POMC neuronal populations within the arcuate neural circuit. We propose that the positive energy balance that leads to obesity is a result of disruption of the balance in melanocortin signaling. In view of the rampant increase in obesity and the consequent morbidity and mortality of the obesity epidemic in the US, understanding the underlying cellular pathogenesis of the metabolic disorders is crucial to the mission of the national institutes of health.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
Project #
Application #
Study Section
Neuroendocrinology, Neuroimmunology, Rhythms and Sleep Study Section (NNRS)
Program Officer
Hyde, James F
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Albert Einstein College of Medicine
Internal Medicine/Medicine
Schools of Medicine
United States
Zip Code
Jeong, Jae Hoon; Woo, Young Jae; Chua Jr, Streamson et al. (2016) Single-Cell Gene Expression Analysis of Cholinergic Neurons in the Arcuate Nucleus of the Hypothalamus. PLoS One 11:e0162839
Lee, Dong Kun; Jeong, Jae Hoon; Oh, Seunghoon et al. (2015) Apelin-13 enhances arcuate POMC neuron activity via inhibiting M-current. PLoS One 10:e0119457
Jeong, Jae Hoon; Lee, Dong Kun; Blouet, Clemence et al. (2015) Cholinergic neurons in the dorsomedial hypothalamus regulate mouse brown adipose tissue metabolism. Mol Metab 4:483-92
Lee, Dong Kun; Jeong, Jae Hoon; Chun, Sung-Kun et al. (2015) Interplay between glucose and leptin signalling determines the strength of GABAergic synapses at POMC neurons. Nat Commun 6:6618
Marcelin, Geneviève; Jo, Young-Hwan; Li, Xiaosong et al. (2014) Central action of FGF19 reduces hypothalamic AGRP/NPY neuron activity and improves glucose metabolism. Mol Metab 3:19-28
Jo, Young-Hwan; Buettner, Christoph (2014) Why leptin keeps you warm. Mol Metab 3:779-80
Lu, Zhonglei; Marcelin, Genevieve; Bauzon, Frederick et al. (2013) pRb is an obesity suppressor in hypothalamus and high-fat diet inhibits pRb in this location. EMBO J 32:844-57
Jo, Young-Hwan; Chua Jr, Streamson C (2013) The brain-liver connection between BDNF and glucose control. Diabetes 62:1367-8
Groessl, Florian; Jeong, Jae Hoon; Talmage, David A et al. (2013) Overnight fasting regulates inhibitory tone to cholinergic neurons of the dorsomedial nucleus of the hypothalamus. PLoS One 8:e60828
Blouet, Clemence; Liu, Shun-Mei; Jo, Young-Hwan et al. (2012) TXNIP in Agrp neurons regulates adiposity, energy expenditure, and central leptin sensitivity. J Neurosci 32:9870-7