Cholecystokinin and hypothalamic corticotrophin-releasing factor participate in endotoxin-induced hypophagia

Rorato, Rodrigo; Reis, Wagner Luis; Antunes‐Rodrigues, José; Elias, Lucila Leico Kagohara

doi:10.1113/expphysiol.2010.056465

Cited by 8 publications

(3 citation statements)

References 60 publications

(141 reference statements)

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“…Plasma corticosterone levels were determined by specific radioimmunoassays after extraction with ethanol, as previously described [ 69 ]. Plasma leptin (Millipore, Burlington, MA) and glucose (Doles Reagents, Goiania, Brazil) concentrations were measured using commercial kits.…”

Section: Methodsmentioning

confidence: 99%

Arcuate AgRP, but not POMC neurons, modulate paraventricular CRF synthesis and release in response to fasting

et al. 2022

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Background The activation of the hypothalamic–pituitary–adrenal (HPA) axis is essential for metabolic adaptation in response to fasting. However, the neurocircuitry connecting changes in the peripheral energy stores to the activity of hypothalamic paraventricular corticotrophin-releasing factor (CRFPVN) neurons, the master controller of the HPA axis activity, is not completely understood. Our main goal was to determine if hypothalamic arcuate nucleus (ARC) POMC and AgRP neurons can communicate fasting-induced changes in peripheral energy stores, associated to a fall in plasma leptin levels, to CRFPVN neurons to modulate the HPA axis activity in mice. Results We observed increased plasma corticosterone levels associate with increased CRFPVN mRNA expression and increased CRFPVN neuronal activity in 36 h fasted mice. These responses were associated with a fall in plasma leptin levels and changes in the mRNA expression of Agrp and Pomc in the ARC. Fasting-induced decrease in plasma leptin partially modulated these responses through a change in the activity of ARC neurons. The chemogenetic activation of POMCARC by DREADDs did not affect fasting-induced activation of the HPA axis. DREADDs inhibition of AgRPARC neurons reduced the content of CRFPVN and increased its accumulation in the median eminence but had no effect on corticosterone secretion induced by fasting. Conclusion Our data indicate that AgRPARC neurons are part of the neurocircuitry involved in the coupling of PVNCRF activity to changes in peripheral energy stores induced by prolonged fasting.

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Section: Methodsmentioning

confidence: 99%

Arcuate AgRP, but not POMC neurons, modulate paraventricular CRF synthesis and release in response to fasting

et al. 2022

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“…One of every fourth section was immunostained for p-STAT3 and Fos/ tyrosine hydroxylase (TH). Immunohistochemistry procedures were carried out as previously described (6,49). Briefly, sections were rinsed with buffer and incubated for 24 h at room temperature with rabbit anti-Fos antibody (Ab-5, 1:10,000, Calbiochem) or for 48 h at 4°C with rabbit anti-p-STAT3 antibody (1:1,000, Cell Signaling).…”

Section: Immunohistochemistrymentioning

confidence: 99%

High-fat diet induces site-specific unresponsiveness to LPS-stimulated STAT3 activation in the hypothalamus

Borges¹,

Rorato²,

Uchôa³

et al. 2014

American Journal of Physiology-Regulatory, Integrative and Comp

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Hypophagia induced by inflammation is associated with Janus kinase (JAK)-2/signal transducer and activator of transcription (STAT) 3 signaling pathway, and leptin-mediated hypophagia is also mediated by JAK2-STAT3 pathway. We have previously reported that lipopolysaccharide (LPS) did not reduce food intake in leptin-resistant high-fat diet (HFD) rats but maintained body weight loss. We investigated whether changes in p-STAT3 expression in the hypothalamus and brain stem could account for the desensitization of hypophagia in HFD animals after a low LPS dose (100 μg/kg). Wistar rats fed standard diet (3.95 kcal/g) or HFD (6.3 kcal/g) for 8 wk were assigned into control diet-saline, control diet-LPS, HFD-saline, and HFD-LPS groups. LPS reduced feeding in the control diet but not HFD. This group showed no p-STAT3 expression in the paraventricular nucleus (PVN) and ventromedial hypothalamic nucleus (VMH), but sustained, though lower than control, p-STAT3 in the nucleus of the solitary tract (NTS) and raphe pallidus (RPa). LPS decreased body weight in HFD rats and increased Fos expression in the NTS. LPS increased body temperature, oxygen consumption, and energy expenditure in both control diet and HFD rats, and this response was more pronounced in HFD-LPS group. Brown adipose tissue (BAT) thermogenesis and increased energy expenditure seem to contribute to body weight loss in HFD-LPS. This response might be related with increased brain stem activation. In conclusion, LPS activates STAT3-mediated pathway in the hypothalamus and brain stem, leading to hypophagia, however, LPS effects on food intake, but not body weight loss, are abolished by leptin resistance induced by HFD. The preserved STAT3 phosphorylation in the brain stem suggests that unresponsiveness to LPS on STAT3 activation under HFD might be selective to the hypothalamus.

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“…In our study, single or repeated LPS induced no changes in p-ERK expression in either the mediobasal hypothalamus extracts or in the parvocellular portion of the PVN. p-ERK can be induced in the parvocellular corticotropinreleasing factor (CRF)-expressing neurons in the PVN in response to insulin (22), whose levels may increase after infectious stimuli such as LPS (24,42,54). We have previously reported that a single LPS injection increased CRF mRNA and Fos-CRF expression in the parvocellular PVN (5,41).…”

Section: E45 Leptin Resistance Induced By Long-term Exposure To Lpsmentioning

confidence: 99%

Protein tyrosine phosphatase-1B contributes to LPS-induced leptin resistance in male rats

Borges

Rorato

Uchôa

et al. 2015

American Journal of Physiology-Endocrinology and Metabolism

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Borges BC, Rorato RC, Uchoa ET, Marangon PB, Elias CF, Antunes-Rodrigues J, Elias LL. Protein tyrosine phosphatase-1B contributes to LPS-induced leptin resistance in male rats. Am J Physiol Endocrinol Metab 308: E40 -E50, 2015. First published October 28, 2014 doi:10.1152/ajpendo.00094.2014.-Leptin resistance is induced by the feedback inhibitors tyrosine phosphatase-1B (PTP1B) and decreased Src homology 2 domain-containing tyrosine phosphatase-2 (SHP-2) signaling. To investigate the participation of PTP1B and SHP-2 in LPS-induced leptin resistance, we injected repeated (6-LPS) intraperitoneal LPS doses (100 g/kg ip) for comparison with a single (1-LPS) treatment and evaluated the expression of SHP-2, PTP1B, p-ERK1/2, and p-STAT3 in the hypothalamus of male Wistar rats. The single LPS treatment increased the expression of p-STAT3 and PTP1B but not SHP-2. The repeated LPS treatment reduced SHP-2, increased PTP1B, and did not change p-STAT3. We observed that the PTP1B expression induced by the endotoxin was highly colocalized with leptin receptor cells in the hypothalamus of LepRb-IRESCre-tdTomato reporter mice. The single, but not the repeated, LPS treatment decreased the food intake and body weight. Leptin had no stimulatory effect on the hypophagia, body weight loss, or pSTAT3 expression in 6-LPS rats, indicating leptin unresponsiveness. Notably, the PTP1B inhibitor (3.0 nmol/rat in 5 l icv) restored the LPSinduced hypophagia in 6-LPS rats and restored the ability of leptin to reduce food intake and body weight as well as to phosphorylate STAT3 in the arcuate, paraventricular, and ventromedial nuclei of the hypothalamus. The present data suggest that an increased PTP1B expression in the hypothalamus underlies the development of leptin resistance during repeated exposure to LPS. Our findings contribute to understanding the mechanisms involved in leptin resistance during low-grade inflammation as seen in obesity. leptin resistance; endotoxemia; protein tyrosine phosphatase-1B; Src homology 2 domain-containing tyrosine phosphatase-2; extracellular signal-regulated kinases INFLAMMATION HAS BEEN DEMONSTRATED to be a common underlying cause of many obesity-associated conditions, such as diabetes and atherosclerosis (13,30,37,48). Rodent models of the obesity induced by a fat-enriched diet show enhancement of inflammatory cytokine secretion (37) and increased hypothalamic inflammatory signaling (44). Changes in gut microbiota are crucial factors in the development of obesity. Cani et al. (9) reported that high-fat feeding in mice augments plasma lipopolysaccharide (LPS) from gram-negative bacteria at a concentration sufficient to increase body weight and inflammation. In rats, the inflammation triggered by LPS and the subsequent activation of Toll-like receptor 4 (TLR4) has a determinant role in the development of the obese phenotype in response to high-fat/high-calorie food intake (14). Interestingly, exogenous long-term LPS infusion (300 g·kg Ϫ1 ·day Ϫ1for 4 wk) in normal-diet-fed mice caused a metabolic response t...

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Cholecystokinin and hypothalamic corticotrophin-releasing factor participate in endotoxin-induced hypophagia

Cited by 8 publications

References 60 publications

Arcuate AgRP, but not POMC neurons, modulate paraventricular CRF synthesis and release in response to fasting

Arcuate AgRP, but not POMC neurons, modulate paraventricular CRF synthesis and release in response to fasting

High-fat diet induces site-specific unresponsiveness to LPS-stimulated STAT3 activation in the hypothalamus

Protein tyrosine phosphatase-1B contributes to LPS-induced leptin resistance in male rats

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