Interleukin-17 acts in the hypothalamus reducing food intake

Nogueira, Guilherme; Solon, Carina; Carraro, Rodrigo S.; Engel, Daiane F.; Ramalho, Albina F.; Sidarta-Oliveira, Davi; Gaspar, Rodrigo S.; Bombassaro, Bruna; Vasques, Ana Carolina Junqueira; Geloneze, Bruno; Vinolo, Marco Aurélio Ramirez; Donato, José; Velloso, Lı́cio A.

doi:10.1016/j.bbi.2019.12.012

Cited by 29 publications

(22 citation statements)

References 80 publications

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“…22 One recent study also found that food intake increases IL-17 in human blood, and IL-17 promotes a rapid increase in hypothalamic anorexigenic pro-opiomelanocortin (POMC) neuron expression and reduces food intake in mice. 23 According to these observations, we may hypothesize that secukinumab may affect body weight by breaking the negative feedback loop of IL-17 in hypothalamus, and by interfering with adipogenesis in peripheral fat tissue. This may explain the weight gain in our patients since secukinumab inhibits the effects of IL-17.…”

Section: Discussionmentioning

confidence: 98%

Changes in metabolic parameters in psoriatic patients treated with secukinumab

Wang

Huang

2020

Therapeutic Advances in Chronic Disease

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Background: Psoriasis is associated with cardiovascular disease and metabolic syndrome but the effects of interleukin (IL)-17A inhibitor treatment on metabolic parameters are unknown. This study aimed to determine the effects of secukinumab on metabolic parameters based on the disease activity and treatment response in patients with psoriasis. Methods: In this retrospective study, we included 99 patients with moderate to severe psoriasis, who received IL-17 inhibitor (secukinumab) treatment for 24 weeks between January 2016 and February 2020. The disease activity [Psoriasis Area and Severity Index (PASI)] and metabolic parameters at baseline and after 12 or 24 weeks of treatment were collected. Results: The PASI improved with a significant reduction of high-sensitivity C-reactive protein (hs-CRP) at weeks 12 and 24 respectively. However, body weight and body mass index were significantly increased at week 12 and 24 of treatment. Triglycerides level and atherogenic index of plasma were significantly higher in week 24 in PASI-90 non-responders. The baseline hs-CRP level and PASI-90 non-response correlated with elevated triglyceride levels. Conclusion: Our results suggest that obesity and hypertriglyceridemia still existed in patients despite the improved disease activity after secukinumab treatment. Higher baseline hs-CRP level and PASI-90 non-response were predictors for elevated triglyceride levels after treatment. Therefore, patient education, regular screening of the lipid profile, and weight control are recommended during the treatment of secukinumab.

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Section: Discussionmentioning

confidence: 98%

Changes in metabolic parameters in psoriatic patients treated with secukinumab

Wang

Huang

2020

Therapeutic Advances in Chronic Disease

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“…These results may be relevant to IL‐17F since these two cytokines bind the same family of IL‐17 receptors, mediate overlapping inflammatory functions, and share 50% homology which is the highest among members of the IL‐17 family (Gaffen et al, 2014; Wright et al, 2008). IL‐17A induced an anorexigenic effect in rats that was attributed to a rapid increase in hypothalamic Pomc mRNA (Nogueira et al 2019). Npy was not altered in this study although Il ‐ 6 was induced, suggesting that IL‐17F induces inflammation but not Npy in mHypoE‐46 neurons.…”

Section: Discussionmentioning

confidence: 99%

Palmitate‐mediated induction of neuropeptide Y expression occurs through intracellular metabolites and not direct exposure to proinflammatory cytokines

Tran

Chen

et al. 2021

Journal of Neurochemistry

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A contributing factor to the development of obesity is the consumption of a diet high in saturated fatty acids, such as palmitate. These fats induce hypothalamic neuroinflammation, which dysregulates neuronal function and induces orexigenic neuropeptide Y (Npy) to promote food intake. An inflammatory cytokine array identified multiple candidates that could mediate palmitate-induced up-regulation of Npy mRNA levels. Of these, visfatin or nicotinamide phosphoribosyltransferase (NAMPT), macrophage migratory inhibitory factor (MIF), and IL-17F were chosen for further study. Direct treatment of the neuropeptide Y/agouti-related peptide (NPY/AgRP)-expressing mHypoE-46 neuronal cell line with the aforementioned cytokines demonstrated that visfatin could directly induce Npy mRNA expression. Preventing the intracellular metabolism of palmitate through long-chain acyl-CoA synthetase (ACSL) inhibition was sufficient to block the palmitate-mediated increase in Npy gene expression.Furthermore, thin-layer chromatography revealed that in neurons, palmitate is readily incorporated into ceramides and defined species of phospholipids. Exogenous C16 ceramide, dipalmitoyl-phosphatidylcholine, and dipalmitoyl-phosphatidylethanolamine were sufficient to significantly induce Npy expression. This study suggests that the intracellular metabolism of palmitate and elevation of metabolites, including ceramide and phospholipids, are responsible for the palmitate-mediated induction of the potent orexigen Npy. Furthermore, this suggests that the regulation of Npy expression is less reliant on inflammatory cytokines per se than palmitate metabolites in a model of NPY/AgRP neurons. These lipid species likely induce detrimental downstream cellular signaling events ultimately causing an increase in feeding, resulting in an overweight phenotype and/or obesity.

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“…As shown in the GSEA of KEGG pathways analysis, signaling through IL-17 is one of the most sensitive pathways activated in neurons after PA exposure. This signaling pathway belongs to the proin ammatory response well characterized mainly in T-cells and macrophages [43][44][45][46], as well as in hypothalamic neurons [47]. The family of transcription factors NF-κB have been implicated in the IL-17 signaling and in the regulation of other pathways and transcription factors such as p53, MAPK and PPAR [48][49][50][51].…”

Section: Discussionmentioning

confidence: 99%

Transcriptional profiles reveal deregulation of lipid metabolism and inflammatory pathways in neurons exposed to palmitic acid

Leon

Millman

Dominguez

et al. 2021

Preprint

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The effects of the consumption of high-fat diets (HFD) have been studied to unravel the molecular pathways they are altering in order to understand the link between increased caloric intake, metabolic diseases, and the risk of cognitive dysfunction. The saturated fatty acid, palmitic acid (PA), is the main component of HFD and it has been found increased in the circulation of obese and diabetic people. In the central nervous system, PA has been associated with inflammatory responses in astrocytes, but the effects on neurons exposed to it have not been largely investigated. Given that PA affect a variety of metabolic pathways, we aimed to analyze the transcriptomic profile activated by this fatty acid to shed light on the mechanisms of neuronal dysfunction. In the current study, we profiled the transcriptome response after PA exposition at non-toxic doses in primary hippocampal neurons. Gene ontology and Reactome pathway analysis revealed a pattern of gene expression which is associated with inflammatory pathways, and importantly, with the activation of lipid metabolism that is considered not very active in neurons. Validation by qRT-PCR of Hmgcs2, Angptl4, Ugt8 and Rnf145 support the results obtained by RNAsEq. Overall, these findings suggest that neurons are able to respond to saturated fatty acids changing the expression pattern of genes associated with inflammatory response and lipid utilization that may be involved in the neuronal damage associated with metabolic diseases.

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Interleukin-17 acts in the hypothalamus reducing food intake

Cited by 29 publications

References 80 publications

Changes in metabolic parameters in psoriatic patients treated with secukinumab

Changes in metabolic parameters in psoriatic patients treated with secukinumab

Palmitate‐mediated induction of neuropeptide Y expression occurs through intracellular metabolites and not direct exposure to proinflammatory cytokines

Transcriptional profiles reveal deregulation of lipid metabolism and inflammatory pathways in neurons exposed to palmitic acid

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