Interleukin-18 Activates Skeletal Muscle AMPK and Reduces Weight Gain and Insulin Resistance in Mice

Lindegaard, Birgitte; Matthews, Vance B.; Brandt, Claus; Højman, Pernille; Allen, Tamara L; Estévez, Emma; Watt, Matthew J.; Bruce, Clinton R.; Mortensen, Ole Hartvig; Syberg, Susanne; Rudnicka, Caroline; Abildgaard, Julie; Pilegaard, Henriette; Hidalgo, Juan; Ditlevsen, Susanne; Alsted, Thomas J.; Madsen, Andreas Nygaard; Pedersen, Bente Klarlund; Febbraio, Mark A.

doi:10.2337/db12-1095

Cited by 79 publications

(91 citation statements)

References 34 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…It suggests the involvement of AMPK activation in the protecting effects of IL-37 against adipose tissue expansion on HFD feeding. Interestingly, recent data revealed that IL-18 signalling enhances FA oxidation via activation of AMPK signalling 45 . As both IL-37 and IL-18 bind to the same IL-18 receptor a chain (IL-18ra) 24 , our findings suggest that IL-37 can activate AMPK signalling via similar mechanisms, leading to increased FA oxidation and alleviation from development of obesity.…”

Section: Discussionmentioning

confidence: 99%

IL-37 protects against obesity-induced inflammation and insulin resistance

et al. 2014

View full text Add to dashboard Cite

Cytokines of the IL-1 family are important modulators of obesity-induced inflammation and the development of systemic insulin resistance. Here we show that IL-1 family member IL-37, recently characterized as an anti-inflammatory cytokine, ameliorates obesity-induced inflammation and insulin resistance. Mice transgenic for human IL-37 (IL-37tg) exhibit reduced numbers of adipose tissue macrophages, increased circulating levels of adiponectin and preserved glucose tolerance and insulin sensitivity after 16 weeks of HFD. In vitro treatment of adipocytes with recombinant IL-37 reduces adipogenesis and activates AMPK signalling. In humans, elevated steady-state IL-37 adipose tissue mRNA levels are positively correlated with insulin sensitivity and a lower inflammatory status of the adipose tissue. These findings reveal IL-37 as an important anti-inflammatory modulator during obesityinduced inflammation and insulin resistance in both mice and humans, and suggest that IL-37 is a potential target for the treatment of obesity-induced insulin resistance and type 2 diabetes.

show abstract

Section: Discussionmentioning

confidence: 99%

IL-37 protects against obesity-induced inflammation and insulin resistance

et al. 2014

View full text Add to dashboard Cite

show abstract

“…An in vitro study also revealed that exendin-4 inhibited MC multiplication and expression of transforming growth factor-β1 and connective tissue growth factor, both of which induced ECM accumulation [15]. Exendin-4 induced phosphorylation of AMPK, which reduced weight gain and insulin resistance in mice with high-fat diets [16]. Additionally, phosphorylated AMPK was down-regulated in the kidneys of db/db mice [17,18].…”

Section: Introductionmentioning

confidence: 99%

Exendin-4 Alleviates High Glucose-Induced Rat Mesangial Cell Dysfunction through the AMPK Pathway

Guan

Zheng

et al. 2014

Cell Physiol Biochem

View full text Add to dashboard Cite

Background/Aims: Glucagon-like peptide-1 (GLP-1), which counteracts insulin resistance in humans with type 2 diabetes, has been shown to ameliorate diabetic nephropathy in experimental models. However, the mechanisms through which GLP-1 modulates renal function remained illdefined. The present study investigated the putative mechanisms underlying effects of exendin-4, a GLP-1 analog, on mesangial cell proliferation and fibronectin. Methods: Rat mesangial cells (MCs) were treated with exendin-4 under high glucose conditions. AMP-activated protein kinase (AMPK) inhibitors (compound C) and agonists (AICAR) were used to analyze the role of this kinase. Cell proliferation was measured using a MTT assay. Fibronectin expression and AMPK-signaling pathway activity were assessed using ELISA and Western blotting, respectively. The production of matrix metalloproteinase (MMP)-2 and tissue inhibitors of metalloproteinases (TIMP)-2 was evaluated using quantitative real-time RT-PCR. Results: Exendin-4 inhibited cell proliferation and fibronectin secretion in high glucose-induced MCs. It also caused phosphorylation of AMPK and subsequently increased the ratio of MMP-2 to TIMP-2, which resulted in the degradation of fibronectin. Exendin-4 reversed extracellular signal-regulated kinase (ERK) phosphorylation and enhanced expression of mammalian target of rapamycin (mTOR) in MCs. Moreover, the activation of the AMPK pathway by exendin-4 was induced by AICAR, which was inhibited by compound C. Conclusion: Exendin-4 exerts an inhibitory effect on cell proliferation and fibronectin secretion in rat MCs, partly through AMPK activation. These results may explain some of the beneficial effects of exendin-4 on the kidney.

show abstract

“…Moreover, plasma IL-18 has also been positively associated with increased risk of insulin resistance and type 2 diabetes mellitus (T2DM) (Ahmad et al, 2013;Lindegaard et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

Inhibition of the Inflammasome NLRP3 by Arglabin Attenuates Inflammation, Protects Pancreatic -Cells from Apoptosis, and Prevents Type 2 Diabetes Mellitus Development in ApoE2Ki Mice on a Chronic High-Fat Diet

Abderrazak

Hadri

Bosc

et al. 2016

Journal of Pharmacology and Experimental Therapeutics

View full text Add to dashboard Cite

Intraperitoneal injection of arglabin (2.5 ng/g of body weight, twice daily, 13 weeks) into female human apolipoprotein E 2 gene knock-in (ApoE 2 Ki) mice fed a high-fat Western-type diet (HFD) reduced plasma levels of glucose and insulin by ∼20.0% 6 3.5% and by 50.0% 6 2.0%, respectively, in comparison with vehicletreated mice. Immunohistochemical analysis revealed the absence of active caspase-3 in islet sections from ApoE 2 Ki mice fed a HFD and treated with arglabin. In addition, arglabin reduced interleukin-1b (IL-1b) production in a concentration-dependent manner in Langerhans islets isolated from ApoE 2 Ki mice treated with lipopolysaccharide (LPS) and with cholesterol crystals. This inhibitory effect is specific for the inflammasome NOD-like receptor family, pyrin domain-containing 3 (NLRP3) because IL-1b production was abolished in Langerhans islets isolated from Nlrp3 2/2 mice. In the insulin-secreting INS-1 cells, arglabin inhibited, in a concentration-dependent manner, the maturation of pro-IL-1b into biologically active IL-1b probably through the inhibition of the maturation of procaspase-1 into active capsase-1. Moreover, arglabin reduced the susceptibility of INS-1 cells to apoptosis by increasing Bcl-2 levels. Similarly, autophagy activation by rapamycin decreased apoptosis susceptibility while autophagy inhibition by 3-methyladenin treatment promoted apoptosis. Arglabin further increased the expression of the autophagic markers Bcl2-interacting protein (Beclin-1) and microtubule-associated protein 1 light chain 3 II (LC3-II) in a concentration-dependent manner. Thus, arglabin reduces NLRP3-dependent inflammation as well as apoptosis in pancreatic b-cells in vivo and in the INS-1 cell line in vitro, whereas it increases autophagy in cultured INS-1 cells, indicating survival-promoting properties of the compound in these cells. Hence, arglabin may represent a new promising compound to treat inflammation and type 2 diabetes mellitus development.

show abstract

Interleukin-18 Activates Skeletal Muscle AMPK and Reduces Weight Gain and Insulin Resistance in Mice

Cited by 79 publications

References 34 publications

IL-37 protects against obesity-induced inflammation and insulin resistance

IL-37 protects against obesity-induced inflammation and insulin resistance

Exendin-4 Alleviates High Glucose-Induced Rat Mesangial Cell Dysfunction through the AMPK Pathway

Inhibition of the Inflammasome NLRP3 by Arglabin Attenuates Inflammation, Protects Pancreatic -Cells from Apoptosis, and Prevents Type 2 Diabetes Mellitus Development in ApoE2Ki Mice on a Chronic High-Fat Diet

Contact Info

Product

Resources

About