IL-6 Indirectly Modulates the Induction of Glyceroneogenic Enzymes in Adipose Tissue during Exercise

Wan, Zhongxiao; Ritchie, Ian R. W.; Beaudoin, Marie-Soleil; Castellani, L; Chan, Catherine B.; Wright, David C.

doi:10.1371/journal.pone.0041719

Cited by 40 publications

(42 citation statements)

References 38 publications

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“…In support of this, in whole body IL-6 knockout mice, the glucose lowering effects of CL were indistinguish- able from those in WT animals measured at multiple time points postinjection, and this occurred independently of differences in plasma fatty acid levels. Although it has recently been shown that fasting-induced increases in plasma fatty acids are reduced in IL-6-deficient mice (37), this could likely be attributed to reductions in circulating catecholamine levels in these mice (30), as the data from the current study and previous work from our laboratory (32) demonstrate that both in vivo and ex vivo lipolytic responsiveness is intact in IL-6 knockout mice. In addition to normal reductions in blood glucose in response to CL treatment in IL-6-deficient mice, we demonstrate a clear temporal dissociation between increases in plasma IL-6 concentrations and reductions in blood glucose levels following CL treatment.…”

Section: Discussioncontrasting

confidence: 55%

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Evidence for fatty acids mediating CL 316,243-induced reductions in blood glucose in mice

MacPherson

Castellani

Beaudoin

et al. 2014

American Journal of Physiology-Endocrinology and Metabolism

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MacPherson RE, Castellani L, Beaudoin M, Wright DC. Evidence for fatty acids mediating CL 316,243-induced reductions in blood glucose in mice. Am J Physiol Endocrinol Metab 307: E563-E570, 2014. First published August 5, 2014; doi:10.1152 doi:10. /ajpendo.00287.2014, a ␤ 3-adrenergic agonist, was developed as an antiobesity and diabetes drug and causes rapid decreases in blood glucose levels in mice. The mechanisms mediating this effect have not been fully elucidated; thus, the purpose of the current study was to examine the role of fatty acids and interleukin-6, reputed mediators of insulin secretion, in this process. To address this question, we used physiological and pharmacological approaches in combination with knockout mouse models. CL 316,243 treatment in male C57BL6 mice increased plasma fatty acids, glycerol, interleukin-6, and insulin and reduced blood glucose concentrations 2 h following injections. The ability of CL 316,243 to increase insulin and fatty acids and reduce glucose was preserved in interleukin-6-deficient mice. CL 316,243-induced drops in blood glucose occurred in parallel with increases in circulating fatty acids but prior to increases in plasma interleukin-6. CL 316,243-mediated increases in plasma insulin levels and reductions in blood glucose were attenuated when mice were pretreated with the lipase inhibitor nicotinic acid or in whole body adipose tissue triglyceride lipase knockout mice. Collectively, our findings demonstrate an important role for fatty acids in mediating the effects of CL 316,243 in mice. Not only do our results provide new insight into the mechanisms of action of CL 316,243, but they also hint at an unappreciated aspect of adipose tissue -pancreas cross-talk.CL 316,243 (CL) IS A SPECIFIC ␤ 3 -adrenergic agonist originally developed as an antiobesity and antidiabetic drug (1). Treating obese, insulin-resistant rodents with this compound for several weeks leads to improvements in glucose homeostasis and insulin sensitivity (7,8,31) that are likely related to CLmediated decreases in food intake (7, 9), increases in energy expenditure (9), and subsequent reductions in adipose tissue mass (7,8,31). In contrast, in lean human subjects, CL treatment results in increases in insulin-mediated glucose disposal (36) independent of changes in body composition, suggesting a direct effect of this compound on insulin sensitivity. In addition to these longer-term effects, CL rapidly (i.e., within minutes) increases insulin secretion and reduces blood glucose levels in mice in vivo (9). The whole body deletion of ␤ 3 -adrenergic receptors abolishes CL-mediated reductions in blood glucose and this is prevented when ␤ 3 -adrenergic receptors are reintroduced into white and brown adipocytes (9). However, when ␤ 3 -adrenergic receptors are reintroduced into brown adipoyctes only, the glucose lowering effects of CL are not recovered (9), providing evidence that a factor secreted from white adipocytes mediates the effects of CL on insulin secretion and reductions in blood glucose. At th...

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Section: Discussioncontrasting

confidence: 55%

“…Changes in mRNA expression of IL-6 were determined using real-time qPCR as described in detail previously by our laboratory (32,33). RNA was isolated from epididymal white adipose tissue using an RNeasy kit according to the manufacturer's instructions.…”

Section: Real-time Pcrmentioning

confidence: 99%

Evidence for fatty acids mediating CL 316,243-induced reductions in blood glucose in mice

MacPherson

Castellani

Beaudoin

et al. 2014

American Journal of Physiology-Endocrinology and Metabolism

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“…Interestingly, BCAA catabolism can regulate muscular fatty acid β-oxydation via the glyceroneogenesis pathway [67], whose ratelimiting step is the conversion of oxaloacetate to phosphoenolpyruvate by phosphoenolpyruvate carboxykinase. As the expression of the phosphoenolpyruvate carboxykinase gene is strongly inhibited by IL-6 in liver and adipose tissue [68,69], IL-6 blockade could interfere with plasmatic concentrations of glycerol, serine, and branched chain amino acids, as observed in the present study.…”

Section: Moderate Effect On Metabolismsupporting

confidence: 63%

Combined Metabolomics and Transcriptomics Approaches to Assess the IL-6 Blockade as a Therapeutic of ALS: Deleterious Alteration of Lipid Metabolism

et al. 2016

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In amyotrophic lateral sclerosis (ALS), motor neuron degeneration occurs simultaneously with systemic metabolic impairment and neuroinflammation. Playing an important role in the regulation of both phenomena, interleukin (IL)-6, a major cytokine of the inflammatory response has been proposed as a target for management of ALS. Although a pilot clinical trial provided promising results in humans, another recent preclinical study showed that knocking out the IL-6 gene in mice carrying ALS did not improve clinical outcome. In this study, we aimed to determine the relevance of the IL-6 pathway blockade in a mouse model of ALS by using a pharmacological antagonist of IL-6, a murine surrogate of tocilizumab, namely MR16-1. We analyzed the immunological and metabolic effects of IL-6 blockade by cytokine measurement, blood cell immunophenotyping, targeted metabolomics, and transcriptomics. A deleterious clinical effect of MR16-1 was revealed, with a speeding up of weight loss (p = 0.0041) and decreasing body weight (p < 0.05). A significant increase in regulatory T-cell count (p = 0.0268) and a decrease in C-X-C ligand-1 concentrations in plasma (p = 0.0479) were observed. Metabolomic and transcriptomic analyses revealed that MR16-1 mainly affected branchedchain amino acid, lipid, arginine, and proline metabolism. IL-6 blockade negatively affected body weight, despite a moderated anti-inflammatory effect. Metabolic effects of IL-6 were mild compared with metabolic disturbances observed in ALS, but a modification of lipid metabolism by

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“…Tissue in each dish was minced into 5-10 mg fragments and placed into 4.5 mL M199 supplemented with 1% antibiotic/antimycotic, 50 mU insulin and 2.5 nM dexamethasone. Samples were left to equilibrate for 24 hours at 37 C, at which point the media was removed and changed to M199 supplemented with the same doses of antibiotic and dexamethasone, 2.5% bovine serum albumin (BSA) and no insulin. For the 2-8 hour time course experiment, one dish per depot was treated with each of the following conditions: i) sterile H 2 O (control), ii) 1 mM CL 316,243, iii) 10 nM 17-b-estradiol, or iv) 1 mM CL 316,243 plus 10 nM 17-b-estradiol.…”

Section: Adipose Tissue Organ Culturementioning

confidence: 99%

“…37,38 Insulin and estradiol ELISAs Serum samples from saline-injected SHAM, OVX and OVX E2 rats were analyzed for insulin concentration in duplicate, using a commercially available kit (Millipore EZMRI-13K), as described previously. 39,40 Accuracy and intra-assay comparisons were validated using 2 quality control standards (run in triplicate) provided with each kit.…”

Section: Free Fatty Acid and Glycerol Concentrationsmentioning

confidence: 99%

Estradiol does not directly regulate adipose lipolysis

et al. 2017

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The mechanisms by which estradiol modulates adipose lipolysis are poorly understood. We sought to measure basal and b 3 -stimulated indices of lipoysis (FFAs, glycerol) in vivo in E2 deficient or supplemented rats, and ex vivo with direct acute E2 exposure. For 2 weeks, ovariectomized (OVX) and OVX rats treated with a daily oral dose of E2 (OVX E2) were pairfed to SHAM controls (n D 12 per group). Adipocyte size was modestly (»40%) increased in OVX rats, but did not reach significance (p D 0.2). After 2 weeks, half of the animals in each group received an in vivo injection of saline or 1 mg/kg of the b3 agonist CL 316, 243. Serum FFA concentrations, but not glycerol, were lower in OVX and OVX E2 rats compared with SHAM controls (p D 0.02). A significant CL response was present in all groups (p<0.001) and HSL activation was unaffected by OVX or OVX E2 in retroperitoneal (r.p.) or inguinal (iWAT) adipose depots in vivo. Ex vivo, CL increased FFA and glycerol accumulation in the media as well as HSL phosphorylation by several fold in r.p. and iWAT explants, but responses from OVX and OVX E2 rats were comparable to SHAMs. To assess whether E2 can directly affect lipolysis, r.p. and iWAT tissue was treated with E2, CL or E2 C CL for 2, 4 or 8 hours using adipose tissue organ culture. CL stimulated FFA release (p<0.001), but was unaffected by E2. Overall, our results indicate that E2 does not directly regulate adipose tissue lipolysis.

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IL-6 Indirectly Modulates the Induction of Glyceroneogenic Enzymes in Adipose Tissue during Exercise

Cited by 40 publications

References 38 publications

Evidence for fatty acids mediating CL 316,243-induced reductions in blood glucose in mice

Evidence for fatty acids mediating CL 316,243-induced reductions in blood glucose in mice

Combined Metabolomics and Transcriptomics Approaches to Assess the IL-6 Blockade as a Therapeutic of ALS: Deleterious Alteration of Lipid Metabolism

Estradiol does not directly regulate adipose lipolysis

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