T, Ryter SW, Chung HT. Carbon monoxide-releasing molecules reverse leptin resistance induced by endoplasmic reticulum stress. Am J Physiol Endocrinol Metab 304: E780 -E788, 2013. First published February 12, 2013 doi:10.1152/ajpendo.00466.2012.-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-2␣ 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)1␣ phosphorylation induced by ER stress. IRE1␣ knockdown rescued leptin resistance, whereas PERK knockdown blocked COdependent regulation of IRE1␣. 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.leptin; endoplasmic reticulum stress; carbon monoxide; leptin resistance; high fat diets LEPTIN, A CIRCULATING PROTEIN HORMONE, acts as a regulator of food intake and body weight through its actions in the brain (23). The leptin receptor (Ob-Rb) is the product of the diabetes (db) gene (30). Binding of leptin to Ob-Rb activates Janus kinase-2 (JAK2), which catalyzes the tyrosine phosphorylation of Ob-Rb. Subsequently, the signal transducer and activator of transcription 3 (STAT3) protein binds to phosphotyrosine (Tyr 1138 ) of Ob-Rb and as a result undergoes JAK2-dependent tyrosine phosphorylation. Activated STAT3 subsequently dissociates from the receptor, dimerizes in the cytoplasm, and then translocates to the nucleus to regulate gene transcription.