Obesity predisposes humans to diabetes and cardiovascular disease and is a universal threat to health. Fat storage is dynamically controlled by orchestrated hormonal, neural and metabolic signals between brain and periphery. Proopiomelanocortin (POMC) neurons that synthesize melanocortin peptides are a primary integrative site for these diverse signals related to energy homeostasis. In the past funding cycles, we made significant progress towards explaining how Pomc transcription is restricted to a subset of hypothalamic neurons. A modular locus comprised of two evolutionarily distinct enhancers directs neuron-specific Pomc expression. Targeted deletion of the individual nPE1, nPE2 or combined elements revealed that they act synergistically during hypothalamic development and additively in adult life to maintain sufficiently robust Pomc transcription to avoid obesity. A bioinformatic analysis of core nucleotide sequence motifs within the enhancers combined with anatomic and functional interrogation of candidate homeodomain transcription factors (TFs) in animal models identified a major contribution of Isl1 and Nkx2.1 in directing the unique temporal and spatial patterns of Pomc expression in the arcuate nucleus. Although necessary, these two factors alone are not sufficient to fully account for the complexities of neuronal Pomc regulation. Therefore, we propose the following specific aims for this project renewal: 1) Decipher the transcriptional code that controls hypothalamic Pomc expression through the functional identification of the entire set of TFs that control the embryonic development, identity and maintenance of the POMC neuronal phenotype using complementary mouse and zebrafish molecular genetics; 2) Identify the entire set of cis-acting regulatory elements in the neuronal enhancers that control hypothalamic Pomc expression and investigate their interactions to assemble a fully functional transcriptional locus; and 3) Dissect the physiological roles of nPE1, nPE2, and their cognate TFs on Pomc expression and metabolic regulation associated with leptin signaling and the energy demands of pregnancy and lactation. These studies will provide fundamental knowledge about a gene essential for regulating body mass and possibly identify novel genetic or signaling pathways that can be exploited for therapeutic purposes.

Public Health Relevance

Among the greatest current threats to public health are the continually increasing rates of obesity, diabetes, and the metabolic syndrome. Complex neural circuits integrate the balance between caloric demand and utilization with the behavioral and psychological processes related to feeding. This project centers on a key molecular component of the brain's feeding circuits, POMC, and regulation of its gene in hypothalamic neurons in response to combinations of specific transcription factors and metabolic signals such as leptin and estrogen.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK068400-12
Application #
9015801
Study Section
Integrative Physiology of Obesity and Diabetes Study Section (IPOD)
Program Officer
Hyde, James F
Project Start
2004-08-01
Project End
2019-02-28
Budget Start
2016-03-01
Budget End
2017-02-28
Support Year
12
Fiscal Year
2016
Total Cost
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Physiology
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Steyn, Frederik J; Ngo, Shyuan T; Chen, Vicky Ping et al. (2018) 17?-estradiol acts through hypothalamic pro-opiomelanocortin expressing neurons to reduce feeding behavior. Aging Cell 17:
Zhou, Yan; Rubinstein, Marcelo; Low, Malcolm J et al. (2018) V1b Receptor Antagonist SSR149415 and Naltrexone Synergistically Decrease Excessive Alcohol Drinking in Male and Female Mice. Alcohol Clin Exp Res 42:195-205
Burke, Luke K; Ogunnowo-Bada, Emmanuel; Georgescu, Teodora et al. (2017) Lorcaserin improves glycemic control via a melanocortin neurocircuit. Mol Metab 6:1092-1102
Rubinstein, Marcelo; Low, Malcolm J (2017) Molecular and functional genetics of the proopiomelanocortin gene, food intake regulation and obesity. FEBS Lett 591:2593-2606
Zhou, Y; Rubinstein, M; Low, M J et al. (2017) Hypothalamic-specific proopiomelanocortin deficiency reduces alcohol drinking in male and female mice. Genes Brain Behav 16:449-461
Chhabra, Kavaljit H; Morgan, Donald A; Tooke, Benjamin P et al. (2017) Reduced renal sympathetic nerve activity contributes to elevated glycosuria and improved glucose tolerance in hypothalamus-specific Pomc knockout mice. Mol Metab 6:1274-1285
Omary, M Bishr; Cohen, David E; El-Omar, Emad M et al. (2016) Not All Mice Are the Same: Standardization of Animal Research Data Presentation. Cell Mol Gastroenterol Hepatol 2:391-393
Burke, Luke K; Doslikova, Barbora; D'Agostino, Giuseppe et al. (2016) Sex difference in physical activity, energy expenditure and obesity driven by a subpopulation of hypothalamic POMC neurons. Mol Metab 5:245-52
Chhabra, Kavaljit H; Adams, Jessica M; Fagel, Brian et al. (2016) Hypothalamic POMC Deficiency Improves Glucose Tolerance Despite Insulin Resistance by Increasing Glycosuria. Diabetes 65:660-72
Low, Malcolm J (2016) Neuroendocrinology: New hormone treatment for obesity caused by POMC-deficiency. Nat Rev Endocrinol 12:627-628

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