scholarly journals Angiopoietin-Like Growth Factor Involved in Leptin Signaling in the Hypothalamus

2021 ◽  
Vol 22 (7) ◽  
pp. 3443
Author(s):  
Yunseon Jang ◽  
Jun Young Heo ◽  
Min Joung Lee ◽  
Jiebo Zhu ◽  
Changjun Seo ◽  
...  
Keyword(s):  
Growth Factor ◽  
Brain Regions ◽  
Whole Body ◽  
Signal Transducers ◽  
Leptin Signaling ◽  
Stat3 Phosphorylation ◽  
Hypothalamic Regulation ◽  
Induced Signal ◽  
Body Energy ◽  
Transcription 3

The hypothalamic regulation of appetite governs whole-body energy balance. Satiety is regulated by endocrine factors including leptin, and impaired leptin signaling is associated with obesity. Despite the anorectic effect of leptin through the regulation of the hypothalamic feeding circuit, a distinct downstream mediator of leptin signaling in neuron remains unclear. Angiopoietin-like growth factor (AGF) is a peripheral activator of energy expenditure and antagonizes obesity. However, the regulation of AGF expression in brain and localization to mediate anorectic signaling is unknown. Here, we demonstrated that AGF is expressed in proopiomelanocortin (POMC)-expressing neurons located in the arcuate nucleus (ARC) of the hypothalamus. Unlike other brain regions, hypothalamic AGF expression is stimulated by leptin-induced signal transducers and activators of transcription 3 (STAT3) phosphorylation. In addition, leptin treatment to hypothalamic N1 cells significantly enhanced the promoter activity of AGF. This induction was abolished by the pretreatment of ruxolitinib, a leptin signaling inhibitor. These results indicate that hypothalamic AGF expression is induced by leptin and colocalized to POMC neurons.

scholarly journals Systemic leptin dose-dependently increases STAT3 phosphorylation within hypothalamic and hindbrain nuclei

2014 ◽  
Vol 306 (8) ◽  
pp. R576-R585 ◽  
Author(s):  
James W. Maniscalco ◽  
Linda Rinaman
Keyword(s):  
Brain Regions ◽  
Neural Population ◽  
Leptin Signaling ◽  
Leptin Sensitivity ◽  
New Information ◽  
Stat3 Phosphorylation ◽  
Neural Processes ◽  
The Central Nervous System ◽  
Glucagon Like Peptide 1 ◽  
Cellular Phenotypes

Leptin released peripherally acts within the central nervous system (CNS) to modulate numerous physiological and behavioral functions. Histochemical identification of leptin-responsive CNS cells can reveal the specific cellular phenotypes and neural circuits through which leptin signaling modulates these functions. Leptin signaling elicits phosphorylation of signal transducer and activator of transcription 3 (pSTAT3), making pSTAT3-immunoreactivity (ir) a useful proxy for identifying leptin-responsive cells. Relatively low systemic doses of leptin (i.e., 10–130 μg/kg body wt) are sufficient to decrease food intake, inhibit gastric emptying, and increase sympathetic activity, but there are no histological reports of central pSTAT3-ir following leptin doses within this range. Considering this, we quantified central pSTAT3-ir in rats after intraperitoneal injections of leptin at doses ranging from 50 to 800 μg/kg body wt. Tissue sections were processed to identify pSTAT3-ir alone or in combination with immunolabeling for cocaine- and amphetamine-regulated transcript (CART), glucagon-like peptide-1 (GLP-1), prolactin-releasing peptide (PrRP), or dopamine-β-hydroxylase (DβH). Leptin doses as low as 50, 100, and 200 μg/kg body wt significantly increased the number of pSTAT3-ir cells in the arcuate nucleus of the hypothalamus (ARC), nucleus of the solitary tract (NTS), and ventromedial nucleus of the hypothalamus, respectively, and also led to robust pSTAT3 labeling in neural processes. The differential dose-dependent increases in pSTAT3-ir across brain regions provide new information regarding central leptin sensitivity. Within the ARC, CART-ir and pSTAT3-ir were often colocalized, consistent with evidence of leptin sensitivity in this neural population. Conversely, within the NTS, pSTAT3 only rarely colocalized with PrRP and/or DβH, and never with GLP-1.

Effect of IL-6 on the insulin sensitivity in patients with type 2 diabetes

2014 ◽  
Vol 306 (7) ◽  
pp. E769-E778 ◽  
Author(s):  
N. M. Harder-Lauridsen ◽  
R. Krogh-Madsen ◽  
J. J. Holst ◽  
P. Plomgaard ◽  
L. Leick ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Glucose Metabolism ◽  
Glucose Uptake ◽  
Whole Body ◽  
Cytokine Signaling ◽  
Contributing Factors ◽  
Stat3 Phosphorylation ◽  
Socs3 Expression ◽  
Body Energy

Elevated interleukin-6 (IL-6) levels are associated with type 2 diabetes, but its role in glucose metabolism is controversial. We investigated the effect of IL-6 on insulin-stimulated glucose metabolism in type 2 diabetes patients and hypothesized that an acute, moderate IL-6 elevation would increase the insulin-mediated glucose uptake. Men with type 2 diabetes not treated with insulin [ n = 9, age 54.9 ± 9.7 (mean ± SD) yr, body mass index 34.8 ± 6.1 kg/m2, HbA1c7.0 ± 1.0%] received continuous intravenous infusion with either recombinant human IL-6 (rhIL-6) or placebo. After 1 h with placebo or rhIL-6, a 3-h hyperinsulinemic-isoglycemic clamp was initiated. Whole body glucose metabolism was measured using stable isotope-labeled tracers. Signal transducer and activator of transcription 3 (STAT3) phosphorylation and suppressor of cytokine signaling 3 (SOCS3) expression were measured in muscle biopsies. Whole body energy expenditure was measured using indirect calorimetry. In response to the infusion of rhIL-6, circulating levels of IL-6 ( P < 0.001), neutrophils ( P < 0.001), and cortisol ( P < 0.001) increased while lymphocytes decreased ( P < 0.01). However, IL-6 infusion did not change glucose infusion rate, rate of appearance, or rate of disappearance during the clamp. While IL-6 enhanced phosphorylation of STAT3 in skeletal muscle ( P = 0.041), the expression of SOCS3 remained unchanged. Whole body oxygen uptake ( P < 0.01) and expired carbon dioxide ( P < 0.01) increased during rhIL-6 infusion. In summary, although IL-6 induced local and systemic responses, the insulin-stimulated glucose uptake was not affected. While different contributing factors may be involved, our results are in contrast to our hypothesis and previous findings in young, healthy men.

scholarly journals Disruption of Peripheral Leptin Signaling in Mice Results in Hyperleptinemia without Associated Metabolic Abnormalities

Endocrinology ◽  
2007 ◽  
Vol 148 (8) ◽  
pp. 3987-3997 ◽  
Author(s):  
Kaiying Guo ◽  
Julie E. McMinn ◽  
Thomas Ludwig ◽  
Yi-Hao Yu ◽  
Guoqing Yang ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Energy Metabolism ◽  
Food Intake ◽  
Leptin Receptor ◽  
Feedback Regulation ◽  
Whole Body ◽  
Negative Feedback Regulation ◽  
Leptin Signaling ◽  
Relative Contribution ◽  
Body Energy

Although central leptin signaling appears to play a major role in the regulation of food intake and energy metabolism, the physiological role of peripheral leptin signaling and its relative contribution to whole-body energy metabolism remain unclear. To address this question, we created a mouse model (Cre-Tam mice) with an intact leptin receptor in the brain but a near-complete deletion of the signaling domain of leptin receptor in liver, adipose tissue, and small intestine using a tamoxifen (Tam)-inducible Cre-LoxP system. Cre-Tam mice developed marked hyperleptinemia (∼4-fold; P &lt; 0.01) associated with 2.3-fold increase (P &lt; 0.05) in posttranscriptional production of leptin. Whereas this is consistent with the disruption of a negative feedback regulation of leptin production in adipose tissue, there were no discernable changes in energy balance, thermoregulation, and insulin sensitivity. Hypothalamic levels of phosphorylated signal transducer and activator of transcription 3, neuropeptide expression, and food intake were not changed despite hyperleptinemia. The percentage of plasma-bound leptin was markedly increased (90.1–96 vs. 41.8–74.7%; P &lt; 0.05), but plasma-free leptin concentrations remained unaltered in Cre-Tam mice. We conclude from these results that 1) the relative contribution to whole-body energy metabolism from peripheral leptin signaling is insignificant in vivo, 2) leptin signaling in adipocyte constitutes a distinct short-loop negative feedback regulation of leptin production that is independent of tissue metabolic status, and 3) perturbation of peripheral leptin signaling alone, although increasing leptin production, may not be sufficient to alter the effective plasma levels of leptin because of the counter-regulatory increase in the level of leptin binding protein(s).

scholarly journals AICAR activates AMPK to regulate STAT3 nuclear translocation and phosphorylation and iNOS expression in inflammatory pain

2020 ◽  
Author(s):  
Hongchun Xiang ◽  
Guo-Wei Cai ◽  
Liang Hu ◽  
He Zhu ◽  
Lixue Lin ◽  
...  
Keyword(s):  
Inflammatory Pain ◽  
Nuclear Translocation ◽  
Mitochondrial Damage ◽  
Ros Generation ◽  
Ampk Activation ◽  
Signal Transducers ◽  
Stat3 Phosphorylation ◽  
Ros Accumulation ◽  
Amp Activated Protein Kinase ◽  
Transcription 3

Abstract Background: AMP-activated protein kinase (AMPK) activators can improve inflammatory pain and neuropathic pain. Inflammation translocate signal transducers and activators of transcription 3 (STAT3) to the nuclei of activated macrophages, and STAT3 phosphorylation promotes the expression of inducible nitric oxide synthetase (iNOS). In this study, we determined whether AMPK activation alleviate inflammatory pain via STAT3 nuclear translocation and phosphorylation. Methods: Immunoblotting was used to measure the expression of p-AMPK, and iNOS. Immunoblotting and immunofluorescence were used to detect the nuclear translocation of p-STAT3(Ser727) and STAT3 in macrophages of local inflammatory tissues. Flow cytometry was used to measure reactive oxygen species (ROS) accumulation and mitochondrial damage.Results: AMPK activation with AICAR significantly alleviated pain hypersensitivity and inhibited the expression of iNOS in complete Freund's adjust (CFA)-induced inflamed skin tissues. CFA caused nuclear translocation of STAT3 and p-STAT3(Ser727) in macrophages of inflamed skin tissues. AICAR inhibited nuclear translocation of STAT3 and p-STAT3(Ser727) and promoted the phosphorylation of STAT3(Ser727) in the cytoplasm of macrophages. AICAR also inhibited the expression of iNOS and nuclear translocation of STAT3 and p-STAT3(Ser727), and promoted the phosphorylation of STAT3(Ser727) in NR8383 macrophages treated with CFA. AMPK activation also inhibited the ROS generation and the mitochondrial damage of NR8383 macrophages caused by CFA. In addition, transfection of STAT3 S727D decreased ROS and alleviated mitochondrial damage.Conclusions: Activation of AMPK attenuates inflammatory pain and suppresses STAT3 nuclear translocation and phosphorylation of STAT3(Ser727) in macrophages, resulting in reduced iNOS. Activation of AMPK also promotes phosphorylation of STAT3(Ser727) in the cytoplasm of macrophages to alleviate ROS accumulation and mitochondrial damage associated with inflammation.

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