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Hypothalamic glucagon signaling inhibits hepatic glucose production

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.

References

  1. Beale, E., Andreone, T., Koch, S., Granner, M. & Granner, D. Insulin and glucagon regulate cytosolic phosphoenolpyruvate carboxykinase (GTP) mRNA in rat liver. Diabetes 33, 328–332 (1984).

    CAS  PubMed  Article  Google Scholar 

  2. Lok, S. et al. The human glucagon receptor encoding gene: structure, cDNA sequence and chromosomal localization. Gene 140, 203–209 (1994).

    CAS  PubMed  Article  Google Scholar 

  3. Bomboy, J.D. Jr., Lewis, S.B., Lacy, W.W., Sinclair-Smith, B.C. & Liljenquist, J.E. Transient stimulatory effect of sustained hyperglucagonemia on splanchnic glucose production in normal and diabetic man. Diabetes 26, 177–184 (1977).

    CAS  PubMed  Article  Google Scholar 

  4. Eigler, N., Sacca, L. & Sherwin, R.S. Synergistic interactions of physiologic increments of glucagon, epinephrine, and cortisol in the dog: a model for stress-induced hyperglycemia. J. Clin. Invest. 63, 114–123 (1979).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  5. Felig, P., Wahren, J. & Hendler, R. Influence of physiologic hyperglucagonemia on basal and insulin-inhibited splanchnic glucose output in normal man. J. Clin. Invest. 58, 761–765 (1976).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  6. Cherrington, A.D. Banting lecture 1997. Control of glucose uptake and release by the liver in vivo. Diabetes 48, 1198–1214 (1999).

    CAS  PubMed  Article  Google Scholar 

  7. Könner, A.C. et al. Insulin action in AgRP-expressing neurons is required for suppression of hepatic glucose production. Cell Metab. 5, 438–449 (2007).

    PubMed  Article  CAS  Google Scholar 

  8. Pocai, A. et al. Hypothalamic K(ATP) channels control hepatic glucose production. Nature 434, 1026–1031 (2005).

    CAS  PubMed  Article  Google Scholar 

  9. Sherwin, R.S., Fisher, M., Hendler, R. & Felig, P. Hyperglucagonemia and blood glucose regulation in normal, obese and diabetic subjects. N. Engl. J. Med. 294, 455–461 (1976).

    CAS  PubMed  Article  Google Scholar 

  10. Ferrannini, E., DeFronzo, R.A. & Sherwin, R.S. Transient hepatic response to glucagon in man: role of insulin and hyperglycemia. Am. J. Physiol. 242, E73–E81 (1982).

    CAS  PubMed  Google Scholar 

  11. Cherrington, A.D., Lacy, W.W. & Chiasson, J.L. Effect of glucagon on glucose production during insulin deficiency in the dog. J. Clin. Invest. 62, 664–677 (1978).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  12. Liljenquist, J.E. et al. Evidence for an important role of glucagon in the regulation of hepatic glucose production in normal man. J. Clin. Invest. 59, 369–374 (1977).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  13. Unger, R.H. & Cherrington, A.D. Glucagonocentric restructuring of diabetes: a pathophysiologic and therapeutic makeover. J. Clin. Invest. 122, 4–12 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  14. Inokuchi, A., Oomura, Y., Shimizu, N. & Yamamoto, T. Central action of glucagon in rat hypothalamus. Am. J. Physiol. 250, R120–R126 (1986).

    CAS  PubMed  Google Scholar 

  15. Hoosein, N.M. & Gurd, R.S. Identification of glucagon receptors in rat brain. Proc. Natl. Acad. Sci. USA 81, 4368–4372 (1984).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  16. Wetsel, W.C., Eraly, S.A., Whyte, D.B. & Mellon, P.L. Regulation of gonadotropin-releasing hormone by protein kinase-A and -C in immortalized hypothalamic neurons. Endocrinology 132, 2360–2370 (1993).

    CAS  PubMed  Article  Google Scholar 

  17. Langhans, W., Duss, M. & Scharrer, E. Decreased feeding and supraphysiological plasma levels of glucagon after glucagon injection in rats. Physiol. Behav. 41, 31–35 (1987).

    CAS  PubMed  Article  Google Scholar 

  18. Banks, W.A. & Kastin, A.J. Peptides and the blood-brain barrier: lipophilicity as a predictor of permeability. Brain Res. Bull. 15, 287–292 (1985).

    CAS  PubMed  Article  Google Scholar 

  19. Reaven, G.M., Chen, Y.D., Golay, A., Swislocki, A.L. & Jaspan, J.B. Documentation of hyperglucagonemia throughout the day in nonobese and obese patients with noninsulin-dependent diabetes mellitus. J. Clin. Endocrinol. Metab. 64, 106–110 (1987).

    CAS  PubMed  Article  Google Scholar 

  20. Brand, C.L. et al. Immunoneutralization of endogenous glucagon with monoclonal glucagon antibody normalizes hyperglycaemia in moderately streptozotocin-diabetic rats. Diabetologia 37, 985–993 (1994).

    CAS  PubMed  Article  Google Scholar 

  21. Johnson, D.G., Goebel, C.U., Hruby, V.J., Bregman, M.D. & Trivedi, D. Hyperglycemia of diabetic rats decreased by a glucagon receptor antagonist. Science 215, 1115–1116 (1982).

    CAS  PubMed  Article  Google Scholar 

  22. Coll, A.P., Farooqi, I.S. & O'Rahilly, S. The hormonal control of food intake. Cell 129, 251–262 (2007).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  23. Flier, J.S. Obesity wars: molecular progress confronts an expanding epidemic. Cell 116, 337–350 (2004).

    CAS  PubMed  Article  Google Scholar 

  24. Lam, T.K. Neuronal regulation of homeostasis by nutrient sensing. Nat. Med. 16, 392–395 (2010).

    CAS  PubMed  Article  Google Scholar 

  25. Yue, J.T. & Lam, T.K. Lipid sensing and insulin resistance in the brain. Cell Metab. 15, 646–655 (2012).

    CAS  PubMed  Article  Google Scholar 

  26. Zhang, X. et al. Hypothalamic IKKβ/NF-κB and ER stress link overnutrition to energy imbalance and obesity. Cell 135, 61–73 (2008).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  27. Breen, D.M. et al. Jejunal nutrient sensing is required for duodenal-jejunal bypass surgery to rapidly lower glucose concentrations in uncontrolled diabetes. Nat. Med. 18, 950–955 (2012).

    CAS  PubMed  Article  Google Scholar 

  28. Muse, E.D., Lam, T.K., Scherer, P.E. & Rossetti, L. Hypothalamic resistin induces hepatic insulin resistance. J. Clin. Invest. 117, 1670–1678 (2007).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  29. Singhal, N.S., Lazar, M.A. & Ahima, R.S. Central resistin induces hepatic insulin resistance via neuropeptide Y. J. Neurosci. 27, 12924–12932 (2007).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  30. Honda, K. et al. The mechanism underlying the central glucagon-induced hyperglycemia and anorexia in chicks. Comp. Biochem. Physiol. A Mol. Integr. Physiol. 163, 260–264 (2012).

    CAS  PubMed  Article  Google Scholar 

  31. Gelling, R.W. et al. Lower blood glucose, hyperglucagonemia, and pancreatic alpha cell hyperplasia in glucagon receptor knockout mice. Proc. Natl. Acad. Sci. USA 100, 1438–1443 (2003).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  32. Parker, J.C., Andrews, K.M., Allen, M.R., Stock, J.L. & McNeish, J.D. Glycemic control in mice with targeted disruption of the glucagon receptor gene. Biochem. Biophys. Res. Commun. 290, 839–843 (2002).

    CAS  PubMed  Article  Google Scholar 

  33. Geary, N. & Smith, G.P. Pancreatic glucagon and postprandial satiety in the rat. Physiol. Behav. 28, 313–322 (1982).

    CAS  PubMed  Article  Google Scholar 

  34. Inokuchi, A., Oomura, Y. & Nishimura, H. Effect of intracerebroventricularly infused glucagon on feeding behavior. Physiol. Behav. 33, 397–400 (1984).

    CAS  PubMed  Article  Google Scholar 

  35. Sheriff, S. et al. Hypothalamic administration of cAMP agonist/PKA activator inhibits both schedule feeding and NPY-induced feeding in rats. Peptides 24, 245–254 (2003).

    CAS  PubMed  Article  Google Scholar 

  36. Morton, G.J., Cummings, D.E., Baskin, D.G., Barsh, G.S. & Schwartz, M.W. Central nervous system control of food intake and body weight. Nature 443, 289–295 (2006).

    CAS  PubMed  Article  Google Scholar 

  37. Day, J.W. et al. A new glucagon and GLP-1 co-agonist eliminates obesity in rodents. Nat. Chem. Biol. 5, 749–757 (2009).

    CAS  PubMed  Article  Google Scholar 

  38. Pocai, A. et al. Glucagon-like peptide 1/glucagon receptor dual agonism reverses obesity in mice. Diabetes 58, 2258–2266 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  39. Béguin, P., Nagashima, K., Nishimura, M., Gonoi, T. & Seino, S. PKA-mediated phosphorylation of the human K(ATP) channel: separate roles of Kir6.2 and SUR1 subunit phosphorylation. EMBO J. 18, 4722–4732 (1999).

    PubMed  PubMed Central  Article  Google Scholar 

  40. Neelands, P.J. & Clandinin, M.T. Diet fat influences liver plasma-membrane lipid composition and glucagon-stimulated adenylate cyclase activity. Biochem. J. 212, 573–583 (1983).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  41. Chari, M., Lam, C.K., Wang, P.Y. & Lam, T.K. Activation of central lactate metabolism lowers glucose production in uncontrolled diabetes and diet-induced insulin resistance. Diabetes 57, 836–840 (2008).

    CAS  PubMed  Article  Google Scholar 

  42. Yang, C.S. et al. Hypothalamic AMP-activated protein kinase regulates glucose production. Diabetes 59, 2435–2443 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  43. Inokuchi, A., Oomura, Y. & Nishimura, H. Effect of intracerebroventricularly infused glucagon on feeding behavior. Physiol. Behav. 33, 397–400 (1984).

    CAS  PubMed  Article  Google Scholar 

  44. Brand, C.L. et al. Immunoneutralization of endogenous glucagon with monoclonal glucagon antibody normalizes hyperglycaemia in moderately streptozotocin-diabetic rats. Diabetologia 37, 985–993 (1994).

    CAS  PubMed  Article  Google Scholar 

  45. Unson, C.G., Gurzenda, E.M. & Merrifield, R.B. Biological activities of des-His1[Glu9]glucagon amide, a glucagon antagonist. Peptides 10, 1171–1177 (1989).

    CAS  PubMed  Article  Google Scholar 

  46. van den Hoek, A.M. et al. Intracerebroventricular neuropeptide Y infusion precludes inhibition of glucose and VLDL production by insulin. Diabetes 53, 2529–2534 (2004).

    CAS  PubMed  Article  Google Scholar 

  47. Filippi, B.M., Yang, C.S., Tang, C. & Lam, T.K. Insulin activates Erk1/2 signaling in the dorsal vagal complex to inhibit glucose production. Cell Metab. 16, 500–510 (2012).

    CAS  PubMed  Article  Google Scholar 

  48. Wang, P.Y. et al. Upper intestinal lipids trigger a gut-brain-liver axis to regulate glucose production. Nature 452, 1012–1016 (2008).

    CAS  PubMed  Article  Google Scholar 

  49. Young, A.A., Cooper, G.J., Carlo, P., Rink, T.J. & Wang, M.W. Response to intravenous injections of amylin and glucagon in fasted, fed, and hypoglycemic rats. Am. J. Physiol. 264, E943–E950 (1993).

    CAS  PubMed  Google Scholar 

  50. Chari, M. et al. Glucose transporter-1 in the hypothalamic glial cells mediates glucose sensing to regulate glucose production in vivo. Diabetes 60, 1901–1906 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  51. Jaskolski, F., Mulle, C. & Manzoni, O.J. An automated method to quantify and visualize colocalized fluorescent signals. J. Neurosci. Methods 146, 42–49 (2005).

    CAS  PubMed  Article  Google Scholar 

  52. Livak, K.J. & Schmittgen, T.D. Analysis of relative gene expression data using real-time quantitative PCR and the 2−ΔΔC(T) method. Methods 25, 402–408 (2001).

    CAS  PubMed  Google Scholar 

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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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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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