Carbon monoxide-releasing molecules reverse leptin resistance induced by endoplasmic reticulum stress.

Abstract

Leptin, a circulating hormone, regulates food intake and body weight. While leptin resistance represents a major cause of obesity, the underlying mechanisms remain unclear. Endoplasmic reticulum (ER) stress can contribute to leptin resistance. Carbon monoxide (CO), a gaseous molecule, exerts antiapoptotic and anti-inflammatory effects in animal models of tissue injury. We hypothesized that CO could inhibit leptin resistance during ER stress. Thapsigargin or tunicamycin was used to induce ER stress in human cells expressing the leptin receptor. These agents markedly inhibited leptin-induced STAT3 phosphorylation, confirming that ER stress induces leptin resistance. The CO-releasing molecule CORM-2 blocked the ER stress-dependent inhibition of leptin-induced STAT3 phosphorylation. CORM-2 treatment induced the phosphorylation of protein kinase R-like endoplasmic reticulum kinase (PERK), and eukaryotic translation initiation factor-2α and enhanced PERK phosphorylation during ER stress. Furthermore, CORM-2 inhibited X-box binding protein-1 expression, activating transcription factor-6 cleavage, and inositol-requiring enzyme (IRE)1α phosphorylation induced by ER stress. IRE1α knockdown rescued leptin resistance, whereas PERK knockdown blocked CO-dependent regulation of IRE1α. In vivo, CO inhalation normalized body weight in animals fed high-fat diets. Furthermore, CO modulated ER stress pathways and rescued leptin resistance in vivo. In conclusion, the pathological mechanism of leptin resistance may be ameliorated by the pharmacological application of CO.

• Authors: Min Zheng, Qinggao Zhang, Yeonsoo Joe, Seul-Ki Kim, Md Jamal Uddin, Hyunyul Rhew, Taeksang Kim, Stefan W Ryter, Hun Taeg Chung
• Journal: American journal of physiology. Endocrinology and metabolism (Am J Physiol Endocrinol Metab) Vol. 304 Issue 7 Pg. E780-8 (Apr 01 2013) ISSN: 1522-1555 [Electronic] United States
• PMID: 23403944 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Anti-Bacterial Agents
• Antimetabolites
• Enzyme Inhibitors
• Leptin
• Organometallic Compounds
• Receptors, Leptin
• STAT3 Transcription Factor
• tricarbonyldichlororuthenium (II) dimer
• Tunicamycin
• Thapsigargin
• Carbon Monoxide
• ERN1 protein, human
• PERK kinase
• Protein Serine-Threonine Kinases
• eIF-2 Kinase
• Endoribonucleases

Topics

• Animals
• Anti-Bacterial Agents (pharmacology)
• Antimetabolites (pharmacology)
• CHO Cells
• Carbon Monoxide (pharmacology)
• Cell Line, Tumor
• Cricetinae
• Cricetulus
• Diet, High-Fat
• Endoplasmic Reticulum (drug effects, metabolism)
• Endoplasmic Reticulum Stress (drug effects, physiology)
• Endoribonucleases (genetics, metabolism)
• Enzyme Inhibitors (pharmacology)
• Humans
• Leptin (metabolism)
• Mice
• Organometallic Compounds (pharmacology)
• Phosphorylation (drug effects)
• Protein Serine-Threonine Kinases (genetics, metabolism)
• Receptors, Leptin (metabolism)
• STAT3 Transcription Factor (metabolism)
• Signal Transduction (drug effects)
• Thapsigargin (pharmacology)
• Tunicamycin (pharmacology)
• eIF-2 Kinase (metabolism)