Peripheral sgp130-mediated<i>trans</i>-signaling blockade induces obesity and insulin resistance in mice via PPARα suppression

Lanton, Tali; Levkovitch-Siany, Orr; Udi, Shiran; Tam, Joseph; Abramovich, Rinat; Perles, S; Williams, Evan G.; Rachmilewitz, Jacob; Mor, Uria; Elinav, Eran; Schmidt-Arras, D; Rehman, Ateequr; Rosenstiel, Philip; Giannou, Anastasios D.; Huber, Samuel; Rose–John, Stefan; Galun, Eithan; Axelrod, Jonathan H.

doi:10.1101/2020.09.24.309716

Cited by 3 publications

(2 citation statements)

References 52 publications

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“…Lanton et al . showed that sgp130 transgenic mice would induce obesity by suppressing PPARα [ 37 ], which is consistent with the novel phenomenon of an increased preradiation F/B ratio. However, in our study group, sgp130 transgenic mice were the most radioresistant; therefore, the substantial decrease in their post-radiation F/B ratio is a question that needs further investigation.…”

Section: Discussionsupporting

confidence: 72%

Role of microbiota in radiation-induced small-bowel damage

Chen,

Li,

Huang

2023

Journal of Radiation Research

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Radiation-induced gastrointestinal damage is a common acute radiation syndrome. Previous studies have highlighted that Galectin-1 and Interleukin-6 (IL-6) are associated with flaking of small intestinal villi and intestinal radioresistance. Therefore, our goal is to study whether gut bacteria regulated by galectin-1 or IL-6 can mitigate radiation-induced small intestine damage. In this study, differences between galectin-1, sgp130-regulated and wild-type (WT) mice were analyzed by microbiome array. The effects of the Firmicutes/Bacteroidetes (F/B) ratio and the proportion of bacterial distribution at the phylum level were observed after 18 Gy whole abdomen radiation. Fecal microbiota transplantation was used to implant radioresistant gut flora into WT mice, and the number of viable small intestinal crypt foci was observed by immunohistochemistry. Fecal transplantation from galectin-1 knockout and sgp130 transgenic mice, with higher radiation resistance, into WT mice significantly increased the number of surviving small intestinal crypts. This radiation resistance, generated through gene regulation, was not affected by the F/B ratio. We initially found that the small intestinal villi of WT mice receiving radioresistant mouse fecal bacteria demonstrated better repair outcomes after radiation exposure. These results indicate the need for a focus on the identification and application of superior radioresistant bacterial strains. In our laboratory, we will further investigate specific radioresistant bacterial strains to alleviate acute side effects of radiation therapy to improve the patients’ immune ability and postoperative quality of life.

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Section: Discussionsupporting

confidence: 72%

Role of microbiota in radiation-induced small-bowel damage

Chen,

Li,

Huang

2023

Journal of Radiation Research

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“…This finding could be indicative of a compensatory anti-inflammatory mechanism to prevent overt inflammation induced by IL-6 trans-signaling [ 211 , 212 ]. Moreover, animal studies reveal that the blockade of peripheral IL-6 trans-signaling by recombinant sgp130, induces mature-onset obesity, glucose intolerance and IR [ 260 ].…”

Section: Il-6 and Il-8 In Selected Pregnancy Pathologiesmentioning

confidence: 99%

IL-6 and IL-8: An Overview of Their Roles in Healthy and Pathological Pregnancies

Vilotić

Nacka-Aleksić

Pirković

et al. 2022

IJMS

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Interleukin-6 (IL-6) is an acknowledged inflammatory cytokine with a pleiotropic action, mediating innate and adaptive immunity and multiple physiological processes, including protective and regenerative ones. IL-8 is a pro-inflammatory CXC chemokine with a primary function in attracting and activating neutrophils, but also implicated in a variety of other cellular processes. These two ILs are abundantly expressed at the feto-maternal interface over the course of a pregnancy and have been shown to participate in numerous pregnancy-related events. In this review, we summarize the literature data regarding their role in healthy and pathological pregnancies. The general information related to IL-6 and IL-8 functions is followed by an overview of their overall expression in cycling endometrium and at the feto-maternal interface. Further, we provide an overview of their involvement in pregnancy establishment and parturition. Finally, the implication of IL-6 and IL-8 in pregnancy-associated pathological conditions, such as pregnancy loss, preeclampsia, gestational diabetes mellitus and infection/inflammation is discussed.

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IL-6 Trans-Signaling Is Increased in Diabetes, Impacted by Glucolipotoxicity, and Associated With Liver Stiffness and Fibrosis in Fatty Liver Disease

Gunes,

Schmitt,

Bilodeau

et al. 2023

Diabetes

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Many people living with diabetes also have non-alcoholic fatty liver disease (NAFLD). Interleukin-6 (IL-6) is involved in both diseases, interacting with both membrane-bound (classical) and circulating soluble receptors (trans-signaling). We investigated whether secretion of IL-6 trans-signaling co-receptors are altered in NAFLD by diabetes, and whether this might associate with the severity of fatty liver disease. Secretion patterns were investigated using human hepatocyte, stellate and monocyte cell lines. Associations with liver pathology were investigated in two patient cohorts: 1) biopsy-confirmed NASH and 2) class 3 obesity. We found that exposure of stellate cells to high glucose and palmitate increased IL-6 and sgp130 secretion. In line with this, plasma sgp130 in both patient cohorts positively correlated with HbA1c, and subjects with diabetes had higher circulating levels of IL-6 and trans-signaling co-receptors. Plasma sgp130 strongly correlated with liver stiffness and was significantly increased in subjects with F4 fibrosis stage. Monocyte activation was associated with reduced sIL-6R secretion. These data suggest that the hyperglycemia and hyperlipidemia can directly impact IL-6 trans-signaling, and that this may be linked to enhanced severity of NAFLD in patients with concomitant diabetes.

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Peripheral sgp130-mediatedtrans-signaling blockade induces obesity and insulin resistance in mice via PPARα suppression

Cited by 3 publications

References 52 publications

Role of microbiota in radiation-induced small-bowel damage

Role of microbiota in radiation-induced small-bowel damage

IL-6 and IL-8: An Overview of Their Roles in Healthy and Pathological Pregnancies

IL-6 Trans-Signaling Is Increased in Diabetes, Impacted by Glucolipotoxicity, and Associated With Liver Stiffness and Fibrosis in Fatty Liver Disease

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