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Pten deletion in RIP-Cre neurons protects against type 2 diabetes by activating the anti-inflammatory reflex

Nature Medicine volume 20, pages 484–492 (2014)Cite this article

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Abstract

Inflammation has a critical role in the development of insulin resistance. Recent evidence points to a contribution by the central nervous system in the modulation of peripheral inflammation through the anti-inflammatory reflex. However, the importance of this phenomenon remains elusive in type 2 diabetes pathogenesis. Here we show that rat insulin-2 promoter (Rip)-mediated deletion of Pten, a gene encoding a negative regulator of PI3K signaling, led to activation of the cholinergic anti-inflammatory pathway that is mediated by M2 activated macrophages in peripheral tissues. As such, Rip-cre+ Ptenflox/flox mice showed lower systemic inflammation and greater insulin sensitivity under basal conditions compared to littermate controls, which were abolished when the mice were treated with an acetylcholine receptor antagonist or when macrophages were depleted. After feeding with a high-fat diet, the Pten-deleted mice remained markedly insulin sensitive, which correlated with massive subcutaneous fat expansion. They also exhibited more adipogenesis with M2 macrophage infiltration, both of which were abolished after disruption of the anti-inflammatory efferent pathway by left vagotomy. In summary, we show that Pten expression in Rip+ neurons has a critical role in diabetes pathogenesis through mediating the anti-inflammatory reflex.

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Figure 1: Rip-cre–mediated Pten deletion leads to PI3K activation and neuronal activation in hypothalamic and brainstem nuclei.
Figure 2: Rip-cre+ Ptenflox/flox mice exhibit predominant M2 macrophage polarization and decreased inflammation.
Figure 3: Rip-cre+ Ptenflox/flox mice have enhanced whole-body and metabolic tissue insulin sensitivity on chow and HFD.
Figure 4: Improved insulin sensitivity in Rip-cre+ Ptenflox/flox mice is dependent on cholinergic activation and is present after HFD.
Figure 5: HFD-fed Rip-cre+ Ptenflox/flox mice demonstrate greater M2 macrophage infiltration and adipogenesis in the visceral compartment.
Figure 6: Macrophage depletion or vagotomy attenuates visceral adipogenesis and peripheral insulin sensitivity.

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Acknowledgements

We thank Y. Dor (Department of Developmental Biology and Cancer Research, The Institute for Medical Research Israel-Canada, The Hebrew University-Hadassah Medical School) for providing the Pdx1-Cre-ER mice. This work was supported by grants to M.W. from the Canadian Institutes of Health Research (CIHR; MOP-93707) and the Canadian Diabetes Association (CDA). M.W. holds a Canada Research Chair in Signal Transduction in Diabetes Pathogenesis. M.G.M.Jr. was supported by a grant from the US National Institutes of Health (DK57768). Support was also received from grants to D.A.W. from the CIHR (MOP-119414) and CDA. L.W. was supported by Frederick Banting and Charles Best Canada Graduate Scholarship from CIHR, a Novo Nordisk Graduate Scholarship from the Banting and Best Diabetes Centre, a Canada Graduate Scholarship from the Natural Sciences and Engineering Research Council of Canada (NSERC) and a Comprehensive Research Experience for Medical Students (CREMS) Scholarship from the Faculty of Medicine, University of Toronto. S.T. was supported by a Toronto General Research Institute Postdoctoral Fellowship. C.T.L. is supported by the Eliot Phillipson Clinician Scientist Training Program and a Banting and Best Diabetes Centre Postdoctoral Fellowship.

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Authors and Affiliations

  1. Toronto General Research Institute, University Health Network, Toronto, Ontario, Canada

    Linyuan Wang, Sue Tsai, Cynthia T Luk, Stephanie A Schroer, Daniel A Winer & Minna Woo

  2. Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada

    Linyuan Wang, Christopher J Paige, Tak W Mak & Minna Woo

  3. Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada

    Linyuan Wang, Cynthia T Luk & Minna Woo

  4. Department of Molecular and Integrative Physiology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA

    Darren Opland, Margaret B Allison & Martin G Myers Jr

  5. Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada

    Cynthia T Luk & Minna Woo

  6. The Campbell Family Institute for Breast Cancer Research, Toronto, Ontario, Canada

    Andrew J Elia & Tak W Mak

  7. Ontario Cancer Institute, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada

    Andrew J Elia, Caren Furlonger, Christopher J Paige & Tak W Mak

  8. Division of Cancer Genetics, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan

    Akira Suzuki

  9. Department of Immunology, University of Toronto, Toronto, Ontario, Canada

    Christopher J Paige, Tak W Mak & Daniel A Winer

  10. Department of Pathology, University Health Network, University of Toronto, Toronto, Ontario, Canada

    Daniel A Winer

  11. Division of Endocrinology and Metabolism, Department of Medicine, University Health Network, University of Toronto, Toronto, Ontario, Canada

    Daniel A Winer & Minna Woo

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Contributions

L.W. performed experiments, analyzed data, wrote the manuscript and contributed to the study concept. D.O., S.T., M.B.A., A.J.E. and C.F. performed experiments, analyzed data and prepared data for presentation. C.T.L. analyzed data and edited the manuscript. S.A.S. developed methods and animal models and performed experiments. A.S. and T.W.M. developed animal models. C.J.P., D.A.W. and M.G.M.Jr. contributed to study design, discussion and the manuscript. M.W. supervised the project, developed the study concept and edited the manuscript.

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Correspondence to Minna Woo.

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Wang, L., Opland, D., Tsai, S. et al. Pten deletion in RIP-Cre neurons protects against type 2 diabetes by activating the anti-inflammatory reflex. Nat Med 20, 484–492 (2014). https://doi.org/10.1038/nm.3527

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