Obesity Induces Hypothalamic Endoplasmic Reticulum Stress and Impairs Proopiomelanocortin (POMC) Post-translational Processing

• Published in: The Journal of biological chemistry 2013-06, Vol.288 (24), p.17675-17688
• Main Authors: Çakir, Isin, Cyr, Nicole E., Perello, Mario, Litvinov, Bogdan Patedakis, Romero, Amparo, Stuart, Ronald C., Nillni, Eduardo A.
• Format: Article
• Language: English
• Subjects: Adrenocorticotropic Hormone - metabolism; alpha-MSH - metabolism; Animals; Arcuate Nucleus of Hypothalamus - metabolism; Arcuate Nucleus of Hypothalamus - pathology; Cell Line; Diet, High-Fat - adverse effects; eIF-2 Kinase - genetics; eIF-2 Kinase - metabolism; Endoplasmic Reticulum - metabolism; Endoplasmic Reticulum Stress; Energy Metabolism; Gene Expression Regulation; Hypothalamus; Leptin - physiology; Male; Metabolism; Mice; Neuropeptide; Obesity - etiology; Obesity - metabolism; Obesity - pathology; Pro-Opiomelanocortin - genetics; Pro-Opiomelanocortin - metabolism; Proprotein Convertase 2 - metabolism; Protein Processing; Protein Processing, Post-Translational; Protein Tyrosine Phosphatase, Non-Receptor Type 1 - genetics; Protein Tyrosine Phosphatase, Non-Receptor Type 1 - metabolism; Rats; Rats, Sprague-Dawley; Suppressor of Cytokine Signaling 3 Protein; Suppressor of Cytokine Signaling Proteins - genetics; Suppressor of Cytokine Signaling Proteins - metabolism
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M113.475343

It was shown previously that abnormal prohormone processing or inactive proconverting enzymes that are responsible for this processing cause profound obesity. Our laboratory demonstrated earlier that in the diet-induced obesity (DIO) state, the appetite-suppressing neuropeptide α-melanocyte-stimulating hormone (α-MSH) is reduced, yet the mRNA of its precursor protein proopiomelanocortin (POMC) remained unaltered. It was also shown that the DIO condition promotes the development of endoplasmic reticulum (ER) stress and leptin resistance. In the current study, using an in vivo model combined with in vitro experiments, we demonstrate that obesity-induced ER stress obstructs the post-translational processing of POMC by decreasing proconverting enzyme 2, which catalyzes the conversion of adrenocorticotropin to α-MSH, thereby decreasing α-MSH peptide production. This novel mechanism of ER stress affecting POMC processing in DIO highlights the importance of ER stress in regulating central energy balance in obesity. Background: The α-MSH peptide is essential in regulating food intake and energy expenditure. Results: ER stress induced by obesity reduces α-MSH, accumulates POMC, and decreases the enzyme PC2. Conclusion: There is a direct link between obesity and ER stress, resulting in altered POMC processing. Significance: These studies bring a new perspective to how ER stress can regulate energy balance by altering POMC processing.