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

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.

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

International Journal of Molecular Sciences ◽

10.3390/ijms22073443 ◽

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.

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TNF-α Up-Regulates Protein Level and Cell Surface Expression of the Leptin Receptor by Stimulating Its Export via a PKC-Dependent Mechanism

Endocrinology ◽

10.1210/en.2012-1510 ◽

2012 ◽

Vol 153 (12) ◽

pp. 5821-5833 ◽

Cited By ~ 37

Author(s):

Lixia Gan ◽

Kaiying Guo ◽

Maria Laura Cremona ◽

Timothy E. McGraw ◽

Rudolph L. Leibel ◽

...

Keyword(s):

Cell Surface ◽

Protein Level ◽

Leptin Receptor ◽

Surface Expression ◽

Cell Surface Expression ◽

Leptin Signaling ◽

Leptin Sensitivity ◽

Stat3 Phosphorylation ◽

Tnf Α ◽

Wide Range

Abstract Increasing evidence suggests that inflammation/cytokines may modulate hypothalamic responses to leptin, which is a key regulator of energy homeostasis and inflammatory/stress responses. We investigated a possible role of TNF-α, a key early mediator of inflammation, in regulating the expression and trafficking of the long-isoform leptin receptor (LEPRb), the primary mediator of leptin signaling, in cultured cells. We found that TNF-α in a wide range of concentrations up-regulated LEPRb protein level and soluble LEPR (sLEPR) release via ectodomain shedding of LEPRb in multiple cell types, including neuronal cells. TNF-α also acutely increased LEPRb cell surface expression and leptin-induced STAT3 phosphorylation. In contrast, TNF-α had no significant effects on the protein level or cell surface expression of several other transmembrane proteins, including the transferrin receptor and cadherin. The stimulatory effects of TNF-α on LEPRb cell surface expression and sLEPR release were not dependent on de novo protein synthesis or functional lysosomes but were blocked by brefeldin A, suggesting that an intact Golgi or continuous endoplasmic reticulum to Golgi transport of newly synthesized proteins is required for these effects. However, TNF-α did not increase the half-life of cell surface LEPRb. Protein kinase C (PKC) inhibitor GF109203X abrogated the effects of TNF-α, whereas the pan-PKC activator phorbol 12-myristate 13-acetate mimicked the TNF-α effects. Taken together, our results suggest that TNF-α, via activation of PKC, regulates anterograde trafficking and/or degradation of LEPRb in the biosynthetic pathway, leading to concomitant increases in LEPRb protein level, cell surface expression, and sLEPR production. The finding that LEPRb cell surface expression and sLEPR production, key modulators of leptin sensitivity and bioavailability, are direct targets of TNF-α signaling could have a potentially important implication in the regulation of leptin signaling activity in different pathophysiological conditions as diverse as obesity and sepsis.

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The Social Neuroscience of Cooperation

10.31234/osf.io/8kcd4 ◽

2018 ◽

Cited By ~ 1

Author(s):

Jay Joseph Van Bavel

Keyword(s):

Theoretical Models ◽

Brain Regions ◽

Review Literature ◽

Social Neuroscience ◽

Future Research ◽

A Value ◽

Group Cooperation ◽

Neural Processes ◽

The Social ◽

Cooperative Decision Making

We review literature from several fields to describe common experimental tasks used to measure human cooperation as well as the theoretical models that have been used to characterize cooperative decision-making, as well as brain regions implicated in cooperation. Building on work in neuroeconomics, we suggest a value-based account may provide the most powerful understanding the psychology and neuroscience of group cooperation. We also review the role of individual differences and social context in shaping the mental processes that underlie cooperation and consider gaps in the literature and potential directions for future research on the social neuroscience of cooperation. We suggest that this multi-level approach provides a more comprehensive understanding of the mental and neural processes that underlie the decision to cooperate with others.

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Multiple Sclerosis Biomarker Discoveries by Proteomics and Metabolomics Approaches

Biomarker Insights ◽

10.1177/11772719211013352 ◽

2021 ◽

Vol 16 ◽

pp. 117727192110133

Author(s):

Ameneh Jafari ◽

Amirhesam Babajani ◽

Mostafa Rezaei-Tavirani

Keyword(s):

Multiple Sclerosis ◽

Complex Disease ◽

Biomarker Discovery ◽

Response To Treatment ◽

Inflammatory Disorder ◽

Protein Marker ◽

Complex Disorders ◽

New Information ◽

The Central Nervous System ◽

Monitoring Treatment

Multiple sclerosis (MS) is an autoimmune inflammatory disorder of the central nervous system (CNS) resulting in demyelination and axonal loss in the brain and spinal cord. The precise pathogenesis and etiology of this complex disease are still a mystery. Despite many studies that have been aimed to identify biomarkers, no protein marker has yet been approved for MS. There is urgently needed for biomarkers, which could clarify pathology, monitor disease progression, response to treatment, and prognosis in MS. Proteomics and metabolomics analysis are powerful tools to identify putative and novel candidate biomarkers. Different human compartments analysis using proteomics, metabolomics, and bioinformatics approaches has generated new information for further clarification of MS pathology, elucidating the mechanisms of the disease, finding new targets, and monitoring treatment response. Overall, omics approaches can develop different therapeutic and diagnostic aspects of complex disorders such as multiple sclerosis, from biomarker discovery to personalized medicine.

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β-Elemene Suppresses Obesity-Induced Imbalance in the Microbiota-Gut-Brain Axis

Biomedicines ◽

10.3390/biomedicines9070704 ◽

2021 ◽

Vol 9 (7) ◽

pp. 704

Author(s):

Yingyu Zhou ◽

Wanyi Qiu ◽

Yimei Wang ◽

Rong Wang ◽

Tomohiro Takano ◽

...

Keyword(s):

Intestinal Microbiota ◽

High Fat Diet ◽

Brain Regions ◽

Cerebral Metabolites ◽

The Central Nervous System ◽

Cerebral Inflammation ◽

Regulatory Effects ◽

Induced Changes ◽

Pearson Correlations ◽

Glucose Cycle

As a kind of metabolically triggered inflammation, obesity influences the interplay between the central nervous system and the enteral environment. The present study showed that β-elemene, which is contained in various plant substances, had effects on recovering the changes in metabolites occurring in high-fat diet (HFD)-induced obese C57BL/6 male mice brains, especially in the prefrontal cortex (PFC) and hippocampus (HIP). β-elemene also partially reversed HFD-induced changes in the composition and contents of mouse gut bacteria. Furthermore, we evaluated the interaction between cerebral metabolites and intestinal microbiota via Pearson correlations. The prediction results suggested that Firmicutes were possibly controlled by neuron integrity, cerebral inflammation, and neurotransmitters, and Bacteroidetes in mouse intestines might be related to cerebral aerobic respiration and the glucose cycle. Such results also implied that Actinobacteria probably affected cerebral energy metabolism. These findings suggested that β-elemene has regulatory effects on the imbalanced microbiota-gut-brain axis caused by obesity and, therefore, would contribute to the future study in on the interplay between cerebral metabolites from different brain regions and the intestinal microbiota of mice.

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Comparison of the Safety of Standard and Triple Dose Gadodiamide Injection in MR Imaging of the Central Nervous System

Acta Radiologica ◽

10.1177/028418519403500416 ◽

1994 ◽

Vol 35 (4) ◽

pp. 396-399 ◽

Cited By ~ 4

Author(s):

M. G. Svaland ◽

T. Christensen ◽

E. Lundorf

Keyword(s):

Mr Imaging ◽

Adverse Events ◽

Contrast Enhancement ◽

Dose Group ◽

Serum Bilirubin ◽

Diagnostic Yield ◽

Blood Chemistry ◽

New Information ◽

Safety Parameters ◽

The Central Nervous System

Gadodiamide injection was administered intravenously to 49 patients with known or suspected CNS lesions undergoing MR imaging. Two parallel groups were used to evaluate the efficacy and safety of single doses of 0.1 (25 patients) and 0.3 (24 patients) mmol/kg b.w. The principal measures of efficacy were diagnostic yield of MR and the overall contrast enhancement. Adverse events and serum bilirubin were the main safety parameters. Contrast enhancement of the lesion was observed for 16 patients in each dose group. Thirteen patients in the 0.1 and 17 in the 0.3 mmol/kg group had their diagnosis amended following the postcontrast image, but only one patient in each dose group had their management affected by new information from the postcontrast image. The overall diagnostic utility of gadodiamide injection was good, but there were no differences between the 2 doses studied in this respect. No injection-associated discomfort or other adverse events were reported. No clinically important changes in serum bilirubin, or other parameters of blood chemistry, or hematology were observed. Overall, the safety profile of gadodiamide injection 0.3 mmol/kg b.w. in this study was similar to that of 0.1 mmol/kg b.w.

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p-Coumaric Acid Enhances Hypothalamic Leptin Signaling and Glucose Homeostasis in Mice via Differential Effects on AMPK Activation

International Journal of Molecular Sciences ◽

10.3390/ijms22031431 ◽

2021 ◽

Vol 22 (3) ◽

pp. 1431

Author(s):

Linh V. Nguyen ◽

Khoa D. A. Nguyen ◽

Chi-Thanh Ma ◽

Quoc-Thai Nguyen ◽

Huong T. H. Nguyen ◽

...

Keyword(s):

Glucose Homeostasis ◽

Blood Glucose Control ◽

Whole Body ◽

Ampk Activation ◽

Coumaric Acid ◽

Leptin Signaling ◽

Differential Effects ◽

Leptin Sensitivity ◽

Ampk Activity

AMP-activated protein kinase (AMPK) plays a crucial role in the regulation of energy homeostasis in both peripheral metabolic organs and the central nervous system. Recent studies indicated that p-Coumaric acid (CA), a hydroxycinnamic phenolic acid, potentially activated the peripheral AMPK pathway to exert beneficial effects on glucose metabolism in vitro. However, CA’s actions on central AMPK activity and whole-body glucose homeostasis have not yet been investigated. Here, we reported that CA exhibited different effects on peripheral and central AMPK activation both in vitro and in vivo. Specifically, while CA treatment promoted hepatic AMPK activation, it showed an inhibitory effect on hypothalamic AMPK activity possibly by activating the S6 kinase. Furthermore, CA treatment enhanced hypothalamic leptin sensitivity, resulting in increased proopiomelanocortin (POMC) expression, decreased agouti-related peptide (AgRP) expression, and reduced daily food intake. Overall, CA treatment improved blood glucose control, glucose tolerance, and insulin sensitivity. Together, these results suggested that CA treatment enhanced hypothalamic leptin signaling and whole-body glucose homeostasis, possibly via its differential effects on AMPK activation.

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Low concentrations of hydrogen sulphide alter monoamine levels in the developing rat central nervous system

Canadian Journal of Physiology and Pharmacology ◽

10.1139/y92-215 ◽

1992 ◽

Vol 70 (11) ◽

pp. 1515-1518 ◽

Cited By ~ 35

Author(s):

B. Skrajny ◽

R. S. Hannah ◽

S. H. Roth

Keyword(s):

Central Nervous System ◽

Nervous System ◽

Frontal Cortex ◽

Hydrogen Sulphide ◽

Chronic Exposure ◽

Brain Regions ◽

Target Organs ◽

Low Concentrations ◽

The Central Nervous System ◽

Developing Rat

The central nervous system is one of the primary target organs for hydrogen sulphide (H2S) toxicity; however, there are limited data on the neurotoxic effects of low-dose chronic exposure on the developing nervous system. Levels of serotonin and norepinephrine in the developing rat cerebellum and frontal cortex were determined following chronic exposure to 20 and 75 ppm H2S during perinatal development. Both monoamines were altered in rats exposed to 75 ppm H2S compared with controls; serotonin levels were significantly increased at days 14 and 21 postnatal in both brain regions, and norepinephrine levels were significantly increased at days 7, 14, and 21 postnatal in cerebellum and at day 21 in the frontal cortex. Exposure to 20 ppm H2S significantly increased the levels of serotonin in the frontal cortex at day 21, whereas levels of norepinephrine were significantly reduced in the frontal cortex at days 14 and 21, and at day 14 in the cerebellum.Key words: hydrogen sulphide, monoamines, serotonin, norepinephrine, neurotoxicity.

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Refining the Effects Observed in a Developmental Neurobehavioral Study of Ammonium Perchlorate Administered Orally in Drinking Water to Rats. II. Behavioral and Neurodevelopment Effects

International Journal of Toxicology ◽

10.1080/10915810500367094 ◽

2005 ◽

Vol 24 (6) ◽

pp. 451-467 ◽

Cited By ~ 11

Author(s):

Raymond G. York ◽

John Barnett ◽

Michael F. Girard ◽

David R. Mattie ◽

Marni V. K. Bekkedal ◽

...

Keyword(s):

Drinking Water ◽

Ammonium Perchlorate ◽

Brain Regions ◽

Male Rats ◽

Male Rat ◽

Sprague Dawley ◽

Continuous Access ◽

Brain Morphometry ◽

The Central Nervous System ◽

The Right

A developmental neurotoxicity study was conducted to generate additional data on the potential functional and morphological hazard to the central nervous system caused by ammonium perchlorate in offspring from in utero and lactation exposure. Female Sprague-Dawley rats (23 to 25/group) were given continuous access to 0 (carrier), 0.1, 1.0, 3.0, and 10.0 mg/kg-day perchlorate in the drinking water beginning 2 weeks prior to mating and continuing through day 10 of lactation for the behavioral function assessment or given continuous access to 0 (carrier), 0.1, 1.0, 3.0, and 30.0 mg/kg-day beginning on gestation day 0 and continuing through day 10 of lactation for neurodevelopment assessments. Motor activity was conducted on postpartum days 14, 18, and 22 and juvenile brain weights, neurohistopathological examinations, and regional brain morphometry were conducted on postpartum days 10 and 22. This research revealed a sexually dimorphic response, with some brain regions being larger in perchlorate-treated male rats than in comparable controls. Even so, there was no evidence of any obvious exposure-related effects on male rat brain weights or neuropathology. The most consistent exposure-related effect in the male pups was on the thickness of the corpus callosum, with both the right- and left-sided measures of the thickness of this white matter tract being significantly greater for the male pups in the 0.1 and 1.0 mg/kg-day exposure groups. The behavioral testing suggests prenatal exposure to ammonium perchlorate does not affect the development of gross motor movements in the pups.

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The development of central nervous system control of the gill withdrawal reflex evoked by siphon stimulation in Aplysia

Canadian Journal of Physiology and Pharmacology ◽

10.1139/y79-148 ◽

1979 ◽

Vol 57 (9) ◽

pp. 987-997 ◽

Cited By ~ 10

Author(s):

Ken Lukowiak

Keyword(s):

Central Nervous System ◽

Nervous System ◽

Abdominal Ganglion ◽

System Control ◽

Reflex Amplitude ◽

Withdrawal Reflex ◽

Reflex Latency ◽

Neural Processes ◽

The Central Nervous System ◽

Cns Control

In older Aplysia, the central nervous system (CNS) (abdominal ganglion) exerts suppressive and facilitatory control over the peripheral nervous system (PNS) which initially mediates the gill withdrawal reflex and its subsequent habituation evoked by tactile stimulation of the siphon. In young animals, both the suppressive and facilitatory CNS control were found to be absent. In older animals, removal of branchial nerve (Br) input to the gill resulted in a significantly reduced reflex latency and, with ctenidial (Ct) and siphon (Sn) nerves intact, a significantly increased reflex amplitude and an inability of the reflex to habituate with repeated siphon stimulation. In young animals, removal of Br had no effect on reflex latency and with Ct and Sn intact, the reflex amplitude latency was not increased and the reflex habituated. Older animals can easily discriminate between different intensity stimuli applied to the siphon as evidenced by differences in reflex amplitude, rates of habituation, and evoked neural activity. On the other hand, young animals cannot discriminate well between different stimulus intensities. The lack of CNS control in young animals was found to be due to incompletely developed neural processes within the abdominal ganglion and not the PNS. The lack of CNS control in young Aplysia results in gill reflex behaviours being less adaptive in light of changing stimulus conditions, but may be of positive survival value in that the young will not habituate as easily. The fact that CNS control is present in older animals strengthens the idea that in any analysis of the underlying neural mechanisms of habituation the entire integrated CNS–PNS must be taken into account.

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