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Hypothalamic glucagon signaling inhibits hepatic glucose production

Nature Medicine volume 19, pages 766–772 (2013)Cite this article

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Abstract

Glucagon activates hepatic protein kinase A (PKA) to increase glucose production1,2, but the gluco-stimulatory effect is transient even in the presence of continuous intravenous glucagon infusion3,4,5. Continuous intravenous infusion of insulin, however, inhibits glucose production through its sustained actions in both the liver6 and the mediobasal hypothalamus (MBH)7,8. In a pancreatic clamp setting, MBH infusion with glucagon activated MBH PKA and inhibited hepatic glucose production (HGP) in rats, as did central glucagon infusion in mice. Inhibition of glucagon receptor–PKA signaling in the MBH and hepatic vagotomy each negated the effect of MBH glucagon in rats, whereas the central effect of glucagon was diminished in glucagon receptor knockout mice. A sustained rise in plasma glucagon concentrations transiently increased HGP, and this transiency was abolished in rats with negated MBH glucagon action. In a nonclamp setting, MBH glucagon infusion improved glucose tolerance, and inhibition of glucagon receptor–PKA signaling in the MBH enhanced the ability of intravenous glucagon injection to increase plasma glucose concentrations. We also detected a similar enhancement of glucose concentrations that was associated with a disruption in MBH glucagon signaling in rats fed a high-fat diet. We show that hypothalamic glucagon signaling inhibits HGP and suggest that hypothalamic glucagon resistance contributes to hyperglycemia in diabetes and obesity.

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Figure 1: MBH glucagon infusion inhibits HGP.
Figure 2: Activation of the glucagon receptor and PKA signaling pathway are required for MBH glucagon to lower HGP.
Figure 3: Glucagon action in the MBH lowers HGP through the hepatic vagus and mediates glucagon's transient stimulatory effect on HGP.
Figure 4: Disruption of glucagon action in the MBH enhances the ability of i.

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Acknowledgements

We thank P.Y.T. Wang for technical assistance and D.J. Drucker from the Samuel Lunenfeld Research Institute for providing the Gcgr−/− and Gcgr+/+ mice. This work was supported by a research grant from the Canadian Diabetes Association. P.I.M. was supported by an Ontario Graduate Scholarship and a scholarship from the University of Toronto Banting and Best Diabetes Centre (BBDC). J.T.Y.Y. is supported by a BBDC and University Health Network postdoctoral fellowship. M.A.A. is supported by a BBDC scholarship. M.C. was supported by an Ontario Graduate scholarship and a BBDC scholarship. C.K.L.L. and C.S.Y. were supported by graduate scholarships from the Canadian Institute of Health Research and the BBDC. T.K.T.L. holds the John Kitson McIvor (1915–1942) Endowed Chair in Diabetes Research and the Canada Research Chair in Obesity at the Toronto General Research Institute and the University of Toronto.

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  1. Patricia I Mighiu and Jessica T Y Yue: These authors contributed equally to this work.

Authors and Affiliations

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

    Patricia I Mighiu, Jessica T Y Yue, Beatrice M Filippi, Mona A Abraham, Madhu Chari, Carol K L Lam, Clair S Yang, Nikita R Christian & Tony K T Lam

  2. Department of Physiology, University of Toronto, Toronto, Ontario, Canada

    Patricia I Mighiu, Mona A Abraham, Madhu Chari, Carol K L Lam, Clair S Yang, Nikita R Christian & Tony K T Lam

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

    Jessica T Y Yue, Beatrice M Filippi & Tony K T Lam

  4. Department of Biochemistry, Albert Einstein College of Medicine, Bronx, New York, USA

    Maureen J Charron

  5. Department of Medicine, Albert Einstein College of Medicine, Bronx, New York, USA

    Maureen J Charron

  6. Banting and Best Diabetes Centre, University of Toronto, Toronto, Ontario, Canada

    Tony K T Lam

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Contributions

P.I.M. and J.T.Y.Y. conducted and designed experiments, performed data analyses and wrote the manuscript. B.M.F. assisted in experiments involving molecular biology techniques. M.A.A., M.C., C.K.L.L., C.S.Y. and N.R.C. assisted in in vivo experiments. M.J.C. generated and provided the Gcgr−/− mice. T.K.T.L. supervised the project, designed experiments and edited the manuscript.

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Correspondence to Tony K T Lam.

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Mighiu, P., Yue, J., Filippi, B. et al. Hypothalamic glucagon signaling inhibits hepatic glucose production. Nat Med 19, 766–772 (2013). https://doi.org/10.1038/nm.3115

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