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IL-6-type Cytokine Signaling in Adipocytes Induces Intestinal GLP-1 Secretion

Published on Jan 1, 2018in Diabetes 7.27
· DOI :10.2337/db17-0637
Stephan Wueest15
Estimated H-index: 15
(Boston Children's Hospital),
Céline I. Laesser1
Estimated H-index: 1
(Boston Children's Hospital)
+ 6 AuthorsDaniel Konrad27
Estimated H-index: 27
(UZH: University of Zurich)
Abstract
We recently showed that interleukin (IL)-6-type cytokine signaling in adipocytes induces free fatty acid release from visceral adipocytes, thereby promoting obesity-induced hepatic insulin resistance and steatosis. In addition, IL-6-type cytokines may increase the release of leptin from adipocytes and by those means induce glucagon-like peptide 1 (GLP-1) secretion. We thus hypothesized that IL-6-type cytokine signaling in adipocytes may regulate insulin secretion. To this end, mice with adipocyte-specific knockout of gp130, the signal transducer protein of IL-6, were fed a high-fat diet for 12 weeks. Compared with control littermates, knockout mice showed impaired glucose tolerance and circulating leptin, GLP-1, and insulin levels were reduced. In line, leptin release from isolated adipocytes was reduced, and intestinal proprotein convertase subtilisin/kexin type 1 (Pcsk1) expression, the gene encoding PC1/3, which controls GLP-1 production, was decreased in knockout mice. Importantly, treatment with the GLP-1 receptor antagonist exendin 9-39 abolished the observed difference in glucose tolerance between control and knockout mice. Ex vivo, supernatant collected from isolated adipocytes of gp130 knockout mice blunted Pcsk1 expression and GLP-1 release from GLUTag cells. In contrast, glucose- and GLP-1-stimulated insulin secretion was not affected in islets of knockout mice. In conclusion, adipocyte-specific IL-6 signaling induces intestinal GLP-1 release to enhance insulin secretion, thereby counteracting insulin resistance in obesity.
  • References (43)
  • Citations (7)
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References43
Newest
Published on Jun 1, 2017in Nature Reviews Endocrinology 20.27
Huxing Cui14
Estimated H-index: 14
,
Miguel López48
Estimated H-index: 48
,
Kamal Rahmouni48
Estimated H-index: 48
In obesity, individuals develop resistance to leptin and ghrelin, which have important functions in the neuroendocrine control of energy homeostasis. Here, Cui and colleagues discuss the mechanisms that lead to leptin and ghrelin resistance, and how they might be exploited as targets for the management and treatment of obesity.
57 Citations Source Cite
Published on Apr 1, 2017in Cell Metabolism 20.57
Adam P. Chambers16
Estimated H-index: 16
(Novo Nordisk),
Joyce Sorrell11
Estimated H-index: 11
(UC: University of Cincinnati)
+ 9 AuthorsDavid A. D'Alessio61
Estimated H-index: 61
(Duke University)
Glucagon-like peptide 1 (GLP-1) is necessary for normal gluco-regulation, and it has been widely presumed that this function reflects the actions of GLP-1 released from enteroendocrine L cells. To test the relative importance of intestinal versus pancreatic sources of GLP-1 for physiological regulation of glucose, we administered a GLP-1R antagonist, exendin-[9-39] (Ex9), to mice with tissue-specific reactivation of the preproglucagon gene (Gcg). Ex9 impaired glucose tolerance in wild-type mice ...
50 Citations Source Cite
Published on Mar 1, 2017in Cell Reports 8.03
Shuyang Traub5
Estimated H-index: 5
(University of Basel),
Daniel T. Meier2
Estimated H-index: 2
(University of Basel)
+ 11 AuthorsValmir Makshana1
Estimated H-index: 1
(University of Basel)
Summary Pancreatic α cells may process proglucagon not only to glucagon but also to glucagon-like peptide-1 (GLP-1). However, the biological relevance of paracrine GLP-1 for β cell function remains unclear. We studied effects of locally derived insulin secretagogues on β cell function and glucose homeostasis using mice with α cell ablation and with α cell-specific GLP-1 deficiency. Normally, intestinal GLP-1 compensates for the lack of α cell-derived GLP-1. However, upon aging and metabolic stre...
21 Citations Source Cite
Published on Mar 1, 2017in International Journal of Obesity 5.16
Lisa Cole Burnett5
Estimated H-index: 5
,
Alicja A. Skowronski6
Estimated H-index: 6
+ 2 AuthorsRudolph L. Leibel76
Estimated H-index: 76
4 Citations Source Cite
Published on Apr 1, 2016in Journal of Diabetes Investigation 3.15
David A. D'Alessio61
Estimated H-index: 61
(Duke University)
Glucagon-like peptide-1 (GLP-1) is a product of proglucagon cleavage synthesized in L cells in the intestinal mucosa, α-cells in the pancreatic islet, and neurons in the nucleus of the solitary tract. GLP-1 is essential for normal glucose tolerance and acts through a specific GLP-1 receptor that is expressed by islet β-cells as well as other cell types. Because plasma concentrations of GLP-1 increase following meal ingestion it has been generally presumed that GLP-1 acts as a hormone, communicat...
12 Citations Source Cite
Published on Oct 1, 2015in Frontiers in Neuroendocrinology 6.88
Eglantine Balland9
Estimated H-index: 9
(Monash University, Clayton campus),
Michael A. Cowley46
Estimated H-index: 46
(Monash University, Clayton campus)
Abstract Leptin resistance is one of the main challenges of obesity. To date, two levels of resistance have been identified, first a decreased rate of leptin uptake into the brain and secondly a diminished central response to leptin. New findings have identified the mechanisms of leptin transport and demonstrated that it can be rescued in obesity, but it did not overcome the problem of central resistance. Alteration in the actions of leptin following diet-induced obesity (DIO) appears to be a mu...
40 Citations Source Cite
Published on Sep 17, 2015in Diabetes 7.27
Stephan Wueest15
Estimated H-index: 15
(Boston Children's Hospital),
Flurin Item8
Estimated H-index: 8
(Boston Children's Hospital)
+ 4 AuthorsDaniel Konrad27
Estimated H-index: 27
(UZH: University of Zurich)
Hepatic steatosis and insulin resistance are among the most prevalent metabolic disorders and tightly associated with obesity and type 2 diabetes. However, underlying mechanism linking obesity to hepatic lipid accumulation and insulin resistance are incompletely understood. Glycoprotein 130 (gp130) is the common signal transducer of all interleukin 6 (IL-6) cytokines. Herein, we provide evidence that gp130-mediated adipose tissue lipolysis promotes hepatic steatosis and insulin resistance. In ob...
30 Citations Source Cite
Published on Aug 1, 2015in Diabetologia 6.02
Tadasuke Komori13
Estimated H-index: 13
(Wakayama Medical University),
Minoru Tanaka24
Estimated H-index: 24
+ 3 AuthorsYoshihiro Morikawa31
Estimated H-index: 31
(Wakayama Medical University)
Aims/hypothesis Obesity and insulin resistance are closely associated with adipose tissue dysfunction caused by the abnormal recruitment of inflammatory cells, including macrophages. Oncostatin M (OSM), a member of the IL-6 family of cytokines, plays important roles in a variety of biological functions including the regulation of inflammatory responses. In previous reports, we have demonstrated that mice deficient in the OSM receptor β subunit show obesity, adipose tissue inflammation, insulin r...
13 Citations Source Cite
Published on May 4, 2015in PLOS ONE 2.77
Felicia Goldsmith4
Estimated H-index: 4
(Louisiana State University Agricultural Center),
Michael J. Keenan22
Estimated H-index: 22
(Louisiana State University Agricultural Center)
+ 7 AuthorsJianping Ye54
Estimated H-index: 54
(Pennington Biomedical Research Center)
Sitagliptin (SG) increases serum GLP-1 (Glucagon-like peptide-1) through inhibition of the hormone degradation. Resistant starch (RS) induces GLP-1 expression by stimulating L-cells in the intestine. Sitagliptin and resistant starch may have a synergistic interaction in the induction of GLP-1. This possibility was tested in current study in a mouse model of type 2 diabetes. Hyperglycemia was induced in the diet-induced obese mice by a signal injection of streptozotocin (STZ). Sitagliptin (0.4g/1...
8 Citations Source Cite
Published on Feb 1, 2015in Liver International 4.50
KanjiYamaguchi20
Estimated H-index: 20
(Kyoto Prefectural University of Medicine),
Takeshi Nishimura13
Estimated H-index: 13
(Kyoto Prefectural University of Medicine)
+ 12 AuthorsYoshio Sumida30
Estimated H-index: 30
(Kyoto Prefectural University of Medicine)
Background & Aims Mice fed high-fat diet (HFD) demonstrate obesity-related systemic insulin resistance (IR). Aim of this study is to clarify the role of interleukin (IL)-6 in IR in vivo focusing on skeletal muscle, adipose tissue and liver. Methods Plasma markers of IR and hepatic IL-6 signalling were examined in eight-week HFD feeding C57/BL6 mice. Furthermore, IR-related molecules in skeletal muscles, adipose tissues and livers were investigated following a single injection of anti- IL-6 recep...
20 Citations Source Cite
Cited By7
Newest
Saleh Afrasyabi (UI: University of Isfahan), Syed Mohamad Marandi (UI: University of Isfahan), Mehdi Kargarfard9
Estimated H-index: 9
(UI: University of Isfahan)
The connection between exercise and appetite has ramifications for acute energy balance and weight-management. Research would suggest that exercise training can transiently suppress appetite, particularly in overweight and T2D, healthy-weight individuals. However, the effect of such a transient appetite suppression on subsequent food intake may be restricted. The aim of this thesis was to investigate appetite responses to HIIT in obesity with T2D and to assess the effect of other exercise charac...
Source Cite
Published on Jun 1, 2019in Inflammation 2.88
Dufang Ma5
Estimated H-index: 5
(SDUTCM: Shandong University of Traditional Chinese Medicine),
Yong Wang (SDUTCM: Shandong University of Traditional Chinese Medicine)+ 2 AuthorsXiao Li4
Estimated H-index: 4
(SDUTCM: Shandong University of Traditional Chinese Medicine)
Source Cite
Published on May 23, 2019in Journal of Neuroendocrinology 3.39
Fredrik Anesten8
Estimated H-index: 8
(University of Gothenburg),
Adrià Dalmau Gasull1
Estimated H-index: 1
(University of Gothenburg)
+ 9 AuthorsZsolt Liposits45
Estimated H-index: 45
(MTA: Hungarian Academy of Sciences)
Source Cite
Published on Oct 11, 2018in Frontiers in Endocrinology 3.52
Silvano Paternoster1
Estimated H-index: 1
(Curtin University),
Marco Falasca38
Estimated H-index: 38
(Curtin University)
An aging world population exposed to a sedentary life style is currently plagued by chronic metabolic diseases, such as type-2 diabetes, that are spreading worldwide at an unprecedented rate. One of the most promising pharmacological approaches for the management of type 2 diabetes takes advantage of the peptide hormone glucagon-like peptide-1 (GLP-1) under the form of protease resistant mimetics, and DPP-IV inhibitors. Despite the improved quality of life, long-term treatments with these new cl...
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Published on Aug 29, 2018in International Journal of Molecular Sciences 3.69
María C. García15
Estimated H-index: 15
,
Patricia Pazos2
Estimated H-index: 2
+ 1 AuthorsCarlos Dieguez83
Estimated H-index: 83
Obesity rates and the burden of metabolic associated diseases are escalating worldwide Energy burning brown and inducible beige adipocytes in human adipose tissues (ATs) have attracted considerable attention due to their therapeutic potential to counteract the deleterious metabolic effects of nutritional overload and overweight. Recent research has highlighted the relevance of resident and recruited ATs immune cell populations and their signalling mediators, cytokines, as modulators of the therm...
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Published on Jul 3, 2018
Stephan Wueest15
Estimated H-index: 15
(Boston Children's Hospital),
Daniel Konrad27
Estimated H-index: 27
(UZH: University of Zurich)
ABSTRACTHigh secretion of interleukin (IL)-6 from white adipose tissue may contribute to metabolic complications in obesity. We have recently shown that IL-6-type cytokine signaling in adipocytes is involved in the development of obesity-associated hepatic insulin resistance and steatosis. In addition, we revealed that adipocyte-specific IL-6 signaling ameliorates glucose metabolism in obesity via enhancing insulin secretion. Mechanistically, IL-6 induces the release of free fatty acid (FFA) and...
1 Citations Source Cite
Published on Jul 1, 2018in Physiological Reports
Charlotte Bayer Christiansen6
Estimated H-index: 6
(UCPH: University of Copenhagen),
Sara J. Lind (UCPH: University of Copenhagen)+ 8 AuthorsNicolai J. Wewer Albrechtsen16
Estimated H-index: 16
(UCPH: University of Copenhagen)
Source Cite