Alterations in the metabolic control of lipid and glucose homeostasis predispose an individual to develop cardiometabolic diseases, such as obesity, type 2-diabetes (T2D) and cardiovascular dysfunction. The Central Nervous System (CNS) plays a critical role in regulating cardiometabolic homeostasis. Within the CNS, the melanocortin system has been shown to be a major component in modulating cardiometabolic homeostasis. This system consists of 3 components: 1) neurons expressing Neuropeptide Y/Agouti related peptide (NPY/AgRP), 2) neurons expressing pro-opiomelanocortin (POMC) and 3) neurons expressing melanocortin receptors, including MC3R and MC4R. The POMC gene encodes several peptides that are the products of a complex post-translational process. Among these peptides, alpha-melanocyte stimulating hormone (?-MSH) has been shown to play a fundamental role in metabolism. Although its production has been largely studied, its degradation process has been unknown for a long time. In 2009, we demonstrated that prolyl carboxypeptidase (PRCP) is a peptidase responsible for the degradation of ?-MSH. We have showed that ?-MSH1-13 is indeed a substrate of PRCP, which cleaves ?-MSH1-13 to inactive ?-MSH1-12. Through anatomical, biochemical, pharmacological and genetic tools, we have demonstrated that central PRCP is an important regulator of melanocortin action. In this application, we aim to further elucidate on the role of PRCP in specific neuronal populations in the regulation of cardiometabolism and on role of neuronal activity in PRCP release and action.
Four specific aims are proposed:
Aim 1 will determine whether PRCP expression in NPY/AgRP neurons is necessary to modulate food intake.
Aim 2 will determine whether PRCP in the hypothalamic dorsomedial nucleus (DMH) is necessary in the regulation of blood pressure and energy expenditure (EE).
Aim 3 will determine whether PRCP release is promoted by neuronal activity. Because PRCP plays a pivotal role in homeostasis by regulating central melanocortin signaling, PRCP represents a potential new therapeutic target to treat cardiometabolic disorders such as obesity, type 2 diabetes and cardiovascular dysfunction. Thus, the execution of these studies will further unmask the role of central PRCP in metabolism regulation and will help us to better develop new classes of tissue-specific PRCP inhibitors needed to translate PRCP genetics and biochemistry for treatments of cardiometabolic disorders.

Public Health Relevance

To understand the etiology of cardiometabolic disorders, including obesity, type II diabetes, and cardiovascular dysfunction, it is essential that we gain better insight into the mechanisms used by the central nervous system to regulate neuronal circuitry related to metabolism. We have identified an enzyme, prolyl carboxypeptidase (PRCP), responsible for the degradation of the anorexigenic neuropeptide alpha-melanocyte stimulating hormone, and thus responsible for modulating melanocortin signaling. To better understand its role in the central nervous system is important to further dissect mechanistic contributes of central PRCP in energy metabolism and cardiovascular function; the experiments proposed in this application will further unmask the role of central PRCP in metabolism regulation and cardiovascular function and will help us to better develop new classes of tissue specific PRCP inhibitors needed to translate PRCP genetics and biochemistry for treatments of metabolic disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK105571-04
Application #
9607079
Study Section
Integrative Physiology of Obesity and Diabetes Study Section (IPOD)
Program Officer
Hyde, James F
Project Start
2015-12-01
Project End
2019-11-30
Budget Start
2018-12-01
Budget End
2019-11-30
Support Year
4
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Yale University
Department
Obstetrics & Gynecology
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
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
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:
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