Inducible‐NOS but not neuronal‐NOS participate in the acute effect of TNF‐α on hypothalamic insulin‐dependent inhibition of food intake

Moraes, João Carlos Silos; Amaral, Maria Esméria Corezola do; Picardi, Paty Karoll; Calegari, Vivian C.; Romanatto, Talita; Echeverry, Marcela Bermúdez; Chiavegatto, Silvana; Saad, Mário José Abdalla; Velloso, Lı́cio A.

doi:10.1016/j.febslet.2006.07.042

Cited by 22 publications

(15 citation statements)

References 41 publications

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“…Studies performed in the last 15 yr have provided strong evidence to support a mechanistic role of inflammation in the pathogenesis of insulin resistance and type 2 diabetes mellitus (3,5,6,10,11). Cytokines produced by the adipose tissue of obese subjects can activate systemic proinflammatory signaling (7,8,25).…”

Section: Discussionmentioning

confidence: 97%

Infliximab Restores Glucose Homeostasis in an Animal Model of Diet-Induced Obesity and Diabetes

et al. 2007

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TNF-alpha plays an important role in obesity-linked insulin resistance and diabetes mellitus by activating at least two serine kinases capable of promoting negative regulation of key elements of the insulin signaling pathway. Pharmacological inhibition of TNF-alpha is currently in use for the treatment of rheumatoid and psoriatic arthritis, and some case reports have shown clinical improvement of diabetes in patients treated with the TNF-alpha blocking monoclonal antibody infliximab. The objective of this study was to evaluate the effect of infliximab on glucose homeostasis and insulin signal transduction in an animal model of diabetes. Diabetes was induced in Swiss mice by a fat-rich diet. Glucose and insulin homeostasis were evaluated by glucose and insulin tolerance tests and by the hyperinsulinemic-euglycemic clamp. Signal transduction was evaluated by immunoprecipitation and immunoblotting assays. Short-term treatment with infliximab rapidly reduced blood glucose and insulin levels and glucose and insulin areas under the curve during a glucose tolerance test. Furthermore, infliximab increased the glucose decay constant during an insulin tolerance test and promoted a significant increase in glucose infusion rate during a hyperinsulinemic-euglycemic clamp. In addition, the clinical outcomes were accompanied by improved insulin signal transduction in muscle, liver, and hypothalamus, as determined by the evaluation of insulin-induced insulin receptor, insulin receptor substrate-1, and receptor substrate-2 tyrosine phosphorylation and Akt and forkhead box protein O1 serine phosphorylation. Thus, pharmacological inhibition of TNF-alpha may be an attractive approach to treat severely insulin-resistant patients with type 2 diabetes mellitus.

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Section: Discussionmentioning

confidence: 97%

Infliximab Restores Glucose Homeostasis in an Animal Model of Diet-Induced Obesity and Diabetes

et al. 2007

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“…Human CELF1 is 88% identical to the Xenopus homolog embryo deadenylation element binding protein (EDEN-BP) and can functionally replace it, binding to the EDEN element to control poly(A) tail length and aiding in rapid deadenylation of maternal mRNAs after fertilization (Paillard et al 2003). CELF1 interacts with poly(A)-specific ribonuclease (PARN) in HeLa cell extracts to promote deadenylation of FOS and TNF transcripts (Moraes et al 2006). Furthermore, siRNA-mediated knockdown of CELF1 in HeLa cells and myoblasts led to the stabilization of a set of normally rapidly degraded transcripts bound by CELF at GU-rich elements (GREs) and GU-repeats Ji et al 2009;Lee et al 2010;Rattenbacher et al 2010).…”

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confidence: 99%

Antagonistic regulation of mRNA expression and splicing by CELF and MBNL proteins

et al. 2015

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RNA binding proteins of the conserved CUGBP1, Elav-like factor (CELF) family contribute to heart and skeletal muscle development and are implicated in myotonic dystrophy (DM). To understand their genome-wide functions, we analyzed the transcriptome dynamics following induction of CELF1 or CELF2 in adult mouse heart and of CELF1 in muscle by RNA-seq, complemented by crosslinking/immunoprecipitation-sequencing (CLIP-seq) analysis of mouse cells and tissues to distinguish direct from indirect regulatory targets. We identified hundreds of mRNAs bound in their 3 ′ UTRs by both CELF1 and the developmentally induced MBNL1 protein, a threefold greater overlap in target messages than expected, including messages involved in development and cell differentiation. The extent of 3 ′ UTR binding by CELF1 and MBNL1 predicted the degree of mRNA repression or stabilization, respectively, following CELF1 induction. However, CELF1's RNA binding specificity in vitro was not detectably altered by coincubation with recombinant MBNL1. These findings support a model in which CELF and MBNL proteins bind independently to mRNAs but functionally compete to specify down-regulation or localization/stabilization, respectively, of hundreds of mRNA targets. Expression of many alternative 3 ′ UTR isoforms was altered following CELF1 induction, with 3 ′ UTR binding associated with down-regulation of isoforms and genes. The splicing of hundreds of alternative exons was oppositely regulated by these proteins, confirming an additional layer of regulatory antagonism previously observed in a handful of cases. The regulatory relationships between CELFs and MBNLs in control of both mRNA abundance and splicing appear to have evolved to enhance developmental transitions in major classes of heart and muscle genes.[Supplemental material is available for this article.] CELF RNA binding proteins (RBPs) play roles in early embryonic development, heart, and skeletal muscle functions. They are also thought to contribute to DM pathogenesis (Timchenko et al. 1996) and have been suggested to contribute to other diseases (Ladd 2013). The six family members present in mammals can be divided into two subfamilies: CELF1-2, which are expressed most highly in heart, skeletal muscle, and brain, and CELF3-6, which exhibit more restricted expression (Dasgupta and Ladd 2012). The CELF proteins contain two N-terminal RNA recognition motifs (RRMs) and one C-terminal RRM, with which they bind GU-rich RNAs, and a linker region termed the "divergent domain" that separates RRM2 and RRM3 and is involved in the regulation of alternative pre-mRNA splicing and mRNA decay (Han and Cooper 2005;.During normal development, CELF1 and CELF2 proteins are highly expressed in early embryonic stages and are then down-regulated more than 10-fold in skeletal muscle (Ladd et al. 2005) and the heart (Kalsotra et al. 2008) during post-natal development, remaining at low levels in adult tissues. This developmental downregulation occurs through multiple mechanisms, including repression by microRNAs (m...

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“…Furthermore, mice lacking TNF-R2 are fully responsive to murine TNFα (Palin et al 2007), which strongly supports signaling through TNF-R1 as a requirement for TNFα-induced sickness behavior. Recent findings support the hypothesis that TNFα-induced JNK activation via TNF-R1 likely plays an important role in neuroinflammation (Borsello et al 2003;Bubici et al 2004;Waetzig et al 2005), the reduction in food intake (Moraes et al 2006) and altered learning and memory (Medeiros et al 2007). Collectively, these data suggest that TNFα-induced sickness behavior is mediated by TNF-R1 and might be blocked by inhibitors of JNK in the brain.…”

Section: Introductionmentioning

confidence: 54%

“…In addition to its involvement in sickness behavior, JNK is frequently implicated in central events associated with TNFα signaling. For example, TNFα acts within the hypothalamus to depress food intake, and this physiologic response requires nitric oxide synthesis which is associated with an elevation in JNK activity (Moraes et al 2006). Furthermore, inhibition of JNK activity diminishes excitotoxic neuronal loss associated with ischemic brain insults (Borsello et al 2003;Repici et al 2007).…”

Section: Discussionmentioning

confidence: 99%

Tumor necrosis factor-α-induced sickness behavior is impaired by central administration of an inhibitor of c-jun N-terminal kinase

Palin¹,

McCusker²,

Strle³

et al. 2008

Psychopharmacology

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Rationale-Tumor necrosis factor-α (TNFα) acts within the brain to induce sickness behavior, but the molecular mechanisms are still unknown. TNFα binding induces receptor trimerization, activation of c-Jun N-terminal kinase (JNK), and induction of downstream transcription factors.Objectives-We hypothesized that TNFα-induced sickness behavior can be blocked by a novel JNK inhibitor.Methods-To test this idea, we used a bipartite protein consisting of a ten-amino-acid sequence of the trans-activating domain of the viral TAT protein (D-TAT) linked to a 19-amino-acid peptide that specifically inhibits JNK activation (D-JNKI-1). C57BL/6J mice were pre-treated intracerebroventricularly (i.c.v.) with D-JNKI-1 or the control peptide containing only the protein transduction domain, D-TAT. Mice were then injected centrally with an optimal amount of TNFα (50 ng/ mouse) to induce sickness behavior. Sickness was assessed as a decrease in social exploration of a novel juvenile, an increase in duration of immobility and loss of body weight. NIH Public AccessAuthor Manuscript Psychopharmacology (Berl). Author manuscript; available in PMC 2010 August 20. Conclusions-These findings demonstrate that D-JNKI-1 can abrogate TNFα-induced sickness behavior and suggest a potential therapeutic target for treating major depressive disorders that develop on a background of cytokine-induced sickness behavior.

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Inducible‐NOS but not neuronal‐NOS participate in the acute effect of TNF‐α on hypothalamic insulin‐dependent inhibition of food intake

Cited by 22 publications

References 41 publications

Infliximab Restores Glucose Homeostasis in an Animal Model of Diet-Induced Obesity and Diabetes

Infliximab Restores Glucose Homeostasis in an Animal Model of Diet-Induced Obesity and Diabetes

Antagonistic regulation of mRNA expression and splicing by CELF and MBNL proteins

Tumor necrosis factor-α-induced sickness behavior is impaired by central administration of an inhibitor of c-jun N-terminal kinase

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