STAT3 phosphorylation in central leptin resistance

Abstract

Mechanism exploitation of energy homeostasis is urgently required because of the worldwide prevailing of obesity-related metabolic disorders in human being. Although it is well known that leptin plays a central role in regulating energy balance by suppressing food intake and promoting energy expenditure, the existence of leptin resistance in majority of obese individuals hampers the utilization of leptin therapy against these disorders. However, the mechanism of leptin resistance is largely unknown in spite of the globally enormous endeavors. Current theories to interpret leptin resistance include the impairment of leptin transport, attenuation of leptin signaling, chronic inflammation, ER tress, deficiency of autophagy, as well as leptin itself. Leptin-activated leptin receptor (LepRb) signals in hypothalamus via several pathways, in which JAK2-STAT3 pathway, the most extensively investigated one, is considered to mediate the major action of leptin in energy regulation. Upon leptin stimulation the phosphorylation of STAT3 is one of the key events in JAK2-STAT3 pathway, followed by the dimerization and nuclear translocation of this molecule. Phosphorylated STAT3 (p-STAT3), as a transcription factor, binds to and regulates its target gene such as POMC gene, playing the physiological function of leptin. Regarding POMC gene in hypothalamus however little is known about the detail of its interaction with STAT3. Moreover the status of p-STAT3 and its significance in hypothalamus of DIO mice needs to be well elucidated. This review comprehends literatures on leptin and leptin resistance and especially discusses what STAT3 phosphorylation would contribute to central leptin resistance.

Hypothalamic inflammation in metabolic disorders and aging

“…It has been reported that selective ablation of JNK1 from the mouse central nervous system (CNS) significantly reduces HFD-induced obesity [128,129]. Similarly, other signaling pathways, such as the Janus kinase 2 (JAK2)/signal transducer and activator of transcription-3 (STAT3) [130,131], forkhead box protein O1 (FOXO1) [132,133], and mechanistic target of rapamycin (mTOR) [134][135][136][137] might get dysregulated by inflammatory insults in the hypothalamus during obesity. This leads to an increase in the protein-tyrosine phosphatase 1B (PTP1B) and suppressor of cytokine signaling 3 (SOCS3) levels through the activation of IKKβ/NF-κB, thereby eventually causing aberrant energy balance and obesity [20,138].…”

SDF-1/CXCR4 axis promotes osteogenic differentiation of BMSCs through the JAK2/STAT3 pathway

“…After recruitment by JAK2, STAT3 dimerizes and translocates to the nucleus after Tyr705 phosphorylation. The activation of STAT3 signaling can induce changes in the expression of downstream molecules and regulate biological processes such as cell migration, proliferation, and apoptosis [20]. Previous studies have shown that the JAK2/STAT3 pathway is involved in the progression of colorectal cancer [18] and central nervous system diseases related to experimental cerebral ischemia [21].…”

A System-Level Mechanism of Anmyungambi Decoction for Obesity: A Network Pharmacological Approach

“…Leptin resistance is characterized by decreased satiety, excessive food consumption, and an increase in total body mass [ 33 ] and a significant issue in obesity. While controversial, enhanced STAT3 activation is regarded to ameliorate leptin resistance [ 34 ]. Indeed, STAT3 activity was considerably increased in the hypothalamus of diet-induced obesity mice, accompanied by lower pro-opiomelanocortin (POMC) expression and abnormal metabolic physiological behaviors, implying that increased STAT3 activity negatively affected leptin-mediated POMC expression in diet-induced obesity mice [ 34 ].…”

“…While controversial, enhanced STAT3 activation is regarded to ameliorate leptin resistance [ 34 ]. Indeed, STAT3 activity was considerably increased in the hypothalamus of diet-induced obesity mice, accompanied by lower pro-opiomelanocortin (POMC) expression and abnormal metabolic physiological behaviors, implying that increased STAT3 activity negatively affected leptin-mediated POMC expression in diet-induced obesity mice [ 34 ]. Moreover, excess STAT3 activity inhibited POMC expression in the hypothalamus of diet-induced obesity mice, implying that STAT3 inhibition may promote leptin signaling [ 35 ].…”