Canna~Fangled Abstracts

Activation of the Nlrp3 inflammasome in infiltrating macrophages by endocannabinoids mediates beta cell loss in type 2 diabetes.

By August 22, 2013No Comments
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Activation of the Nlrp3 inflammasome in infiltrating macrophages byendocannabinoids mediates beta cell loss in type 2 diabetes.

Source

Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism, US National Institutes of Health, Bethesda, Maryland.

Abstract

Type 2 diabetes mellitus (T2DM) progresses from compensated insulin resistance to beta cell failure resulting in uncompensated hyperglycemia, a process replicated in the Zucker diabetic fatty (ZDF) rat. The Nlrp3 inflammasome has been implicated in obesity-induced insulin resistance and beta cell failure.Endocannabinoids contribute to insulin resistance through activation of peripheral CB1 receptors (CB1Rs) and also promote beta cell failure. Here we show that beta cell failure in adult ZDF rats is not associated with CB1R signaling in beta cells, but rather in M1 macrophages infiltrating into pancreatic islets, and that this leads to activation of the Nlrp3-ASC inflammasome in the macrophages. These effects are replicated in vitro by incubating wild-type human or rodent macrophages, but not macrophages from CB1R-deficient (Cnr1-/-) or Nlrp3-/- mice, with the endocannabinoid anandamide. Peripheral CB1R blockade, in vivo depletion of macrophages or macrophage-specific knockdown of CB1R reverses or prevents these changes and restores normoglycemia and glucose-induced insulin secretion. These findings implicate endocannabinoids and inflammasome activation in beta cell failure and identify macrophage-expressed CB1R as a therapeutic target in T2DM.
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 23955712
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At a glance

Figures

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  1. Effects of peripheral CB1R blockade on body weight, adiposity, hepatic lipogenesis and glycemic control in ZDF rats.
    Figure 1
  2. The effect of chronic JD5037 treatment on beta cell survival and function in ZDF rats.
    Figure 2
  3. Macrophage content and Nlrp3 expression in islets of lean and diabetic rats.
    Figure 3
  4. Effects of macrophage depletion on glycemic control and proinflammatory signaling in islets of ZDF rats.
    Figure 4
  5. Effects of macrophage-selective siRNA knockdown of CB1R in ZDF rats.
    Figure 5
  6. Proinflammatory gene and protein expression in human macrophages and rat and human isolated islets treated with AEA, IL-1[beta] or high glucose.
    Figure 6

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Author information

Affiliations

  1. Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism, US National Institutes of Health, Bethesda, Maryland.

    • Tony Jourdan,
    • Grzegorz Godlewski,
    • Resat Cinar,
    • Gergő Szanda,
    • Jie Liu,
    • Joseph Tam,
    • Tiffany Han,
    • Bani Mukhopadhyay &
    • George Kunos

  2. Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, US National Institutes of Health, Bethesda, Maryland.

    • Adeline Bertola

  3. Diabetes, Endocrinology and Obesity Branch, National Institute of Diabetes and Digestive and Kidney Diseases, US National Institutes of Health, Bethesda, Maryland.

    • Monica C Skarulis

  4. Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, Colorado.

    • Cynthia Ju

  5. Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts.

    • Myriam Aouadi &
    • Michael P Czech

Contributions

T.J. and G.K. designed and carried out experiments, analyzed results and wrote the manuscript. G.G. performed the surgery and the clamp experiments, R.C. conducted liquid chromatography–tandem mass spectrometry endocannabinoid measurements, A.B. did some of the immunohistochemistry and FACS analyses, G.S. did western blotting and PCR assays, J.L., J.T. and B.M. assisted with cell culture experiments, T.H. did the work on macrophage depletion, M.C.S. provided human blood samples, C.J. provided clodronate liposomes, T.J. and M.A. designed and tested the GeRPs, and M.A. and M.P.C. provided GeRPs. All authors had access to the manuscript and agreed with the final version.

Competing financial interests

The authors declare no competing financial interests.

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