Skip to main content

Advertisement

SpringerLink
Log in

Glucagon and lipid signaling in the hypothalamus

  • Published:
Mammalian Genome Aims and scope Submit manuscript

Abstract

Hyperglycemia, caused in part by elevated hepatic glucose production (GP), is a hallmark feature of diabetes and obesity. The hypothalamus responds to hormones and nutrients to regulate hepatic GP and glucose homeostasis. This invited perspective focuses on the molecular signaling and biochemical pathways involved in the gluco-regulatory action of hypothalamic glucagon signaling and lipid sensing in health and disease. Recent evidence generated via genetic, molecular and chemical experimental approaches indicates that glucagon and lipid signaling independently trigger complementary hypothalamic mechanisms to lower GP. Thus, targeting hypothalamic glucagon or lipid signaling may have therapeutic potential in diabetes and obesity.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  • Abraham MA, Yue JT, LaPierre MP, Rutter GA, Light PE, Filippi BM, Lam TK (2014) Hypothalamic glucagon signals through the KATP channels to regulate glucose production. Mol Metab 3:202–208

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Abu-Elheiga L, Matzuk MM, Abo-Hashema KA, Wakil SJ (2001) Continuous fatty acid oxidation and reduced fat storage in mice lacking acetyl-CoA carboxylase 2. Science 291:2613–2616

    Article  PubMed  CAS  Google Scholar 

  • Acosta-Martínez M, Levine JE (2007) Regulation of KATP channel subunit gene expression by hyperglycemia in the mediobasal hypothalamus of female rats. Am J Physiol Endocrinol Metab 292:E1801–E1807

    Article  PubMed  Google Scholar 

  • Agarwala GC, Bapat SK (1977) Effect of centrally administered glucagon on blood glucose levels in dogs. Indian J Med Res 66:323–330

    CAS  Google Scholar 

  • Agarwala GC, Mishra R, Jaiswal G, Bapat V (1989) Effect of centrally administered glucagon on liver glycogen & enzymes in anaesthetised dogs. Indian J Med Res 90:372–378

    PubMed  CAS  Google Scholar 

  • Amatruda JM, Livingston JN (2003) Glucagon. In: Porte D, Sherwin RS, Baron A, Ellenberg M, Rifkin H (eds) Ellenberg and Rifkin’s diabetes mellitus, 6th edn. McGraw-Hill, Ann Arbor, pp 97–115

    Google Scholar 

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

    Article  PubMed  PubMed Central  Google Scholar 

  • Belgardt BF, Okamura T, Brüning JC (2009) Hormone and glucose signalling in POMC and AgRP neurons. J Physiol 587:5305–5314

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Bomboy JD, Lewis SB, Lacy WW, Sinclair-Smith BC, Liljenquist JE (1977) Transient stimulatory effect of sustained hyperglucagonemia on splanchnic glucose production in normal and diabetic man. Diabetes 26:4–177

    Article  Google Scholar 

  • Brand CL, Rolin B, Jørgensen PN, Svendsen I, Kristensen JS, Holst JJ (1994) Immunoneutralization of endogenous glucagon with monoclonal glucagon antibody normalizes hyperglycaemia in moderately streptozotocin-diabetic rats. Diabetologia 37:985–993

    Article  PubMed  CAS  Google Scholar 

  • Choi CS, Savage DB, Abu-Elheiga L, Liu Z-X, Kim S, Kulkarni A, Distefano A, Hwang Y-J, Reznick RM, Codella R, Zhang D, Cline GW, Wakil SJ, Shulman GI (2007) Continuous fat oxidation in acetyl-CoA carboxylase 2 knockout mice increases total energy expenditure, reduces fat mass, and improves insulin sensitivity. Proc Natl Acad Sci USA 104:16480–16485

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Damm E, Buech TRH, Gudermann T, Breit A (2012) Melanocortin-induced PKA activation inhibits AMPK activity via ERK-1/2 and LKB-1 in hypothalamic GT1-7 cells. Mol Endocrinol 26:643–654

    Article  PubMed  CAS  Google Scholar 

  • Dogrukol-Ak D, Tore F, Tuncel N (2004) Passage of VIP/PACAP/secretin family across the blood-brain barrier: therapeutic effects. Curr Pharm Des 10:1325–1340

    Article  PubMed  CAS  Google Scholar 

  • Eigler N, Saccà L, Sherwin RS (1979) 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

    Article  PubMed  CAS  PubMed Central  Google Scholar 

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

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Filippi BM, Yang CS, Tang C, Lam TKT (2012) Insulin activates Erk1/2 signaling in the dorsal vagal complex to inhibit glucose production. Cell Metab 16:500–510

    Article  PubMed  CAS  Google Scholar 

  • Gelling RW, Du XQ, Dichmann DS, Romer J, Huang H, Cui L, Obici S, Tang B, Holst JJ, Fledelius C, Johansen PB, Rossetti L, Jelicks LA, Serup P, Nishimura E, Charron MJ (2003) Lower blood glucose, hyperglucagonemia, and pancreatic alpha cell hyperplasia in glucagon receptor knockout mice. Proc Natl Acad Sci USA 100:1438–1443

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Gerich JE (1981) Physiology of glucagon. Int Rev Physiol 24:243–275

    PubMed  CAS  Google Scholar 

  • Hamilton JA, Brunaldi K (2007) A model for fatty acid transport into the brain. J Mol Neurosci 33:12–17

    Article  PubMed  CAS  Google Scholar 

  • Hoehn KL, Turner N, Swarbrick MM, Wilks D, Preston E, Phua Y, Joshi H, Furler SM, Larance M, Hegarty BD, Leslie SJ, Pickford R, Hoy AJ, Kraegen EW, James DE, Cooney GJ (2010) Acute or chronic upregulation of mitochondrial fatty acid oxidation has no net effect on whole-body energy expenditure or adiposity. Cell Metab 11:70–76

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Honda K, Kamisoyama H, Saito N, Kurose Y, Sugahara K, Hasegawa S (2007) Central administration of glucagon suppresses food intake in chicks. Neurosci Lett 416:198–201

    Article  PubMed  CAS  Google Scholar 

  • Honda K, Kamisoyama H, Uemura T, Yanagi T, Saito N, Kurose Y, Sugahara K, Katoh K, Hasegawa S (2012) The mechanism underlying the central glucagon-induced hyperglycemia and anorexia in chicks. Comp Biochem Physiol A: Mol Integr Physiol 163:260–264

    Article  CAS  Google Scholar 

  • Hoosein NM, Gurd RS (1984) Identification of glucagon receptors in rat brain. Proc Natl Acad Sci USA 81:4368–4372

    Article  PubMed  CAS  PubMed Central  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  • Jiang G, Zhang BB (2003) Glucagon and regulation of glucose metabolism. Am J Physiol Endocrinol Metab 284:E671–E678

    CAS  Google Scholar 

  • Johnson DG, Goebel CU, Hruby VJ, Bregman MD, Trivedi D (1982) Hyperglycemia of diabetic rats decreased by a glucagon receptor antagonist. Science 215:1115–1116

    Article  PubMed  CAS  Google Scholar 

  • Kahn BB, Alquier T, Carling D, Hardie DG (2005) AMP-activated protein kinase: ancient energy gauge provides clues to modern understanding of metabolism. Cell Metab 1:15–25

    Article  PubMed  CAS  Google Scholar 

  • Kishore P, Boucai L, Zhang K, Li W, Koppaka S, Kehlenbrink S, Schiwek A, Esterson YB, Mehta D, Bursheh S, Su Y, Gutierrez-Juarez R, Muzumdar R, Schwartz GJ, Hawkins M (2011) Activation of K(ATP) channels suppresses glucose production in humans. J Clin Invest 121:4916–4920

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Kong D, Vong L, Parton LE, Ye C, Tong Q, Hu X, Choi B, Brüning JC, Lowell BB (2010) Glucose stimulation of hypothalamic MCH neurons involves K(ATP) channels, is modulated by UCP2, and regulates peripheral glucose homeostasis. Cell Metab 12:545–552

    Article  PubMed  CAS  Google Scholar 

  • Könner AC, Janoschek R, Plum L, Jordan SD, Rother E, Ma X, Xu C, Enriori P, Hampel B, Barsh GS, Kahn CR, Cowley Ma, Ashcroft FM, Brüning JC (2007) Insulin action in AgRP-expressing neurons is required for suppression of hepatic glucose production. Cell Metab 5:438–449

    Article  PubMed  Google Scholar 

  • Kurose Y, Kamisoyama H, Honda K, Azuma Y, Sugahara K, Hasegawa S, Kobayashi S (2009) Effects of central administration of glucagon on feed intake and endocrine responses in sheep. Anim Sci J 80:686–690

    Article  PubMed  CAS  Google Scholar 

  • Lam TK (2010) Neuronal regulation of homeostasis by nutrient sensing. Nat Med 16:392–395

    Article  PubMed  CAS  Google Scholar 

  • Lam TK, Pocai A, Gutierrez-Juarez R, Obici S, Bryan J, Aguilar-Bryan L, Schwartz GJ, Rossetti L (2005) Hypothalamic sensing of circulating fatty acids is required for glucose homeostasis. Nat Med 11:320–327

    Article  PubMed  CAS  Google Scholar 

  • Le Foll C, Irani BG, Magnan C, Dunn-Meynell AA, Levin BE (2009) Characteristics and mechanisms of hypothalamic neuronal fatty acid sensing. Am J Physiol Regul Integr Comp Physiol 297:R655–R664

    Article  PubMed  PubMed Central  Google Scholar 

  • Le Foll C, Dunn-Meynell AA, Musatov S, Magnan C, Levin BE (2013) FAT/CD36: a major regulator of neuronal fatty acid sensing and energy homeostasis in rats and mice. Diabetes 62:2709–2716

    Article  PubMed  PubMed Central  Google Scholar 

  • Light PE, Bladen C, Winkfein RJ, Walsh MP, French RJ (2000) Molecular basis of protein kinase C-induced activation of ATP-sensitive potassium channels. Proc Natl Acad Sci USA 97:9058–9063

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • López M, Varela L, Vazquez MJ, Rodriguez-Cuenca S, Gonzalez CR, Velagapudi VR, Morgan DA, Schoenmakers E, Agassandian K, Lage R, Martinez de Morentin PB, Tovar S, Nogueiras R, Carling D, Lelliott C, Gallego R, Oresic M, Chatterjee K, Saha AK, Rahmouni K, Dieguez C, Vidal-Puig A (2010) Hypothalamic AMPK and fatty acid metabolism mediate thyroid regulation of energy balance. Nat Med 16:1001–1008

    Article  PubMed  PubMed Central  Google Scholar 

  • Marubashi S, Tominaga M, Katagiri T, Yamatani K, Yawata Y, Hara M, Sasaki H (1985) Hyperglycaemic effect of glucagon administered intracerebroventricularly in the rat. Acta Endocrinol (Copenh) 108:6–10

    CAS  Google Scholar 

  • McGarry JD (1992) What if Minkowski had been ageusic? An alternative angle on diabetes. Science 258:766–770

    Article  PubMed  CAS  Google Scholar 

  • Mighiu PI, Yue JT, Filippi BM, Abraham MA, Chari M, Lam CK, Yang CS, Christian NR, Charron MJ, Lam TK (2013) Hypothalamic glucagon signaling inhibits hepatic glucose production. Nat Med 19:766–772

    Article  PubMed  CAS  Google Scholar 

  • Minokoshi Y, Alquier T, Furukawa N, Kim Y-B, Lee A, Xue B, Mu J, Foufelle F, Ferré P, Birnbaum MJ, Stuck BJ, Kahn BB (2004) AMP-kinase regulates food intake by responding to hormonal and nutrient signals in the hypothalamus. Nature 428:569–574

    Article  PubMed  CAS  Google Scholar 

  • Mitchell RW, Edmundson CL, Miller DW, Hatch GM (2009) On the mechanism of oleate transport across human brain microvessel endothelial cells. J Neurochem 110:1049–1057

    Article  PubMed  CAS  Google Scholar 

  • Morgan K, Obici S, Rossetti L (2004) Hypothalamic responses to long-chain fatty acids are nutritionally regulated. J Biol Chem 279:31139–31148

    Article  PubMed  CAS  Google Scholar 

  • Moritz W, Leech CA, Ferrer J, Habener JF (2001) Regulated expression of adenosine triphosphate-sensitive potassium channel subunits in pancreatic beta-cells. Endocrinology 142:129–138

    PubMed  CAS  Google Scholar 

  • Morton GJ, Schwartz MW (2011) Leptin and the central nervous system control of glucose metabolism. Physiol Rev 91:389–411

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Morton GJ, Gelling RW, Niswender KD, Morrison CD, Rhodes CJ, Schwartz MW (2005) Leptin regulates insulin sensitivity via phosphatidylinositol-3-OH kinase signaling in mediobasal hypothalamic neurons. Cell Metab 2:411–420

    Article  PubMed  CAS  Google Scholar 

  • Müller WA, Faloona GR, Aguilar-Parada E, Unger RH (1970) Abnormal alpha-cell function in diabetes. Response to carbohydrate and protein ingestion. N Engl J Med 283:109–115

    Article  PubMed  Google Scholar 

  • Obici S, Feng Z, Morgan K, Stein D, Karkanias G, Rossetti L (2002a) Central administration of oleic acid inhibits glucose production and food intake. Diabetes 51:271–275

    Article  PubMed  CAS  Google Scholar 

  • Obici S, Zhang BB, Karkanias G, Rossetti L (2002b) Hypothalamic insulin signaling is required for inhibition of glucose production. Nat Med 8:1376–1382

    Article  PubMed  CAS  Google Scholar 

  • Obici S, Feng Z, Arduini A, Conti R, Rossetti L (2003) Inhibition of hypothalamic carnitine palmitoyltransferase-1 decreases food intake and glucose production. Nat Med 9:756–761

    Article  PubMed  CAS  Google Scholar 

  • Pocai A, Lam TK, Gutierrez-Juarez R, Obici S, Schwartz GJ, Bryan J, Aguilar-Bryan L, Rossetti L (2005) Hypothalamic K(ATP) channels control hepatic glucose production. Nature 434:1026–1031

    Article  PubMed  CAS  Google Scholar 

  • Pocai A, Lam TK, Obici S, Gutierrez-Juarez R, Muse ED, Arduini A, Rossetti L (2006) Restoration of hypothalamic lipid sensing normalizes energy and glucose homeostasis in overfed rats. J Clin Invest 116:1081–1091

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Posey KA, Clegg DJ, Printz RL, Byun J, Morton GJ, Vivekanandan-Giri A, Pennathur S, Baskin DG, Heinecke JW, Woods SC, Schwartz MW, Niswender KD (2009) Hypothalamic proinflammatory lipid accumulation, inflammation, and insulin resistance in rats fed a high-fat diet. Am J Physiol Endocrinol Metab 296:E1003–E1012

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Rapoport SI (1996) In vivo labeling of brain phospholipids by long-chain fatty acids: relation to turnover and function. Lipids 31(Suppl):S97–S101

    Article  PubMed  CAS  Google Scholar 

  • Rapoport SI, Chang MC, Spector AA (2001) Delivery and turnover of plasma-derived essential PUFAs in mammalian brain. J Lipid Res 42:678–685

    PubMed  CAS  Google Scholar 

  • Reaven GM, Chen YD, Golay A, Swislocki AL, Jaspan JB (1987) Documentation of hyperglucagonemia throughout the day in nonobese and obese patients with noninsulin-dependent diabetes mellitus. J Clin Endocrinol Metab 64:106–110

    Article  PubMed  CAS  Google Scholar 

  • Ross R, Wang PY, Chari M, Lam CK, Caspi L, Ono H, Muse ED, Li X, Gutierrez-Juarez R, Light PE, Schwartz GJ, Rossetti L, Lam TK (2008) Hypothalamic protein kinase C regulates glucose production. Diabetes 57:2061–2065

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Sandoval DA, Bagnol D, Woods SC, D’Alessio DA, Seeley RJ (2008) Arcuate glucagon-like peptide 1 receptors regulate glucose homeostasis but not food intake. Diabetes 57:2046–2054

    Article  CAS  PubMed Central  Google Scholar 

  • Schwartz MW, Seeley RJ, Tschöp MH, Woods SC, Morton GJ, Myers MG, D’Alessio D (2013) Cooperation between brain and islet in glucose homeostasis and diabetes. Nature 503:59–66

    Article  PubMed  CAS  Google Scholar 

  • Su Y, Lam TK, He W, Pocai A, Bryan J, Aguilar-Bryan L, Gutierrez-Juarez R (2012) Hypothalamic leucine metabolism regulates liver glucose production. Diabetes 61:85–93

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Taylor SI (1999) Deconstructing type 2 diabetes. Cell 97:9–12

    Article  PubMed  CAS  Google Scholar 

  • Unson CG, Gurzenda EM, Merrifield RB (1989) Biological activities of des-His1[Glu9]glucagon amide, a glucagon antagonist. Peptides 10:1171–1177

    Article  PubMed  CAS  Google Scholar 

  • Vranic M, Kawamori R, Wrenshall GA (1975) The role of insulin and glucagon in regulating glucose turnover in dogs during exercise. Med Sci Sports 7:27–33

    PubMed  CAS  Google Scholar 

  • Wang R, Cruciani-Guglielmacci C, Migrenne S, Magnan C, Cotero VE, Routh VH (2006) Effects of oleic acid on distinct populations of neurons in the hypothalamic arcuate nucleus are dependent on extracellular glucose levels. J Neurophysiol 95:1491–1498

    Article  PubMed  CAS  Google Scholar 

  • Wetsel WC, Eraly SA, Whyte DB, Mellon PL (1993) Regulation of gonadotropin-releasing hormone by protein kinase-A and -C in immortalized hypothalamic neurons. Endocrinology 132:2360–2370

    PubMed  CAS  Google Scholar 

  • Yang CS, Lam CK, Chari M, Cheung GWC, Kokorovic A, Gao S, Leclerc I, Rutter GA, Lam TK (2010) Hypothalamic AMP-activated protein kinase regulates glucose production. Diabetes 59:2435–2443

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Yue JT, Lam TK (2012) Lipid Sensing and insulin resistance in the brain. Cell Metab 15:646–655

    Article  CAS  Google Scholar 

Download references

Acknowledgments

The work discussed in this review produced by the Lam laboratory was supported by research grants from the Canadian Diabetes Association (OG-3–13-4156-TL) and the Canadian Institute of Health Research (MOP-86554). Mary P. LaPierre is supported by an Ontario Graduate Scholarship and a UHN Unilever Graduate Fellowship in Neuroscience. Mona A. Abraham is supported by a Banting and Best Diabetes Center graduate scholarship. Jessica T. Y. Yue is supported by post-doctoral fellowships from the Canadian Institutes of Health Research and Canadian Diabetes Association. Tony K. T. Lam holds the J. K. 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.

Author information

Authors and Affiliations

  1. Toronto General Research Institute & Department of Medicine, University Health Network, Toronto, M5G 1L7, Canada

    Mary P. LaPierre, Mona A. Abraham, Beatrice M. Filippi, Jessica T. Y. Yue & Tony K. T. Lam

  2. Departments of Physiology, University of Toronto, Toronto, M5S 1A8, Canada

    Mary P. LaPierre, Mona A. Abraham & Tony K. T. Lam

  3. Departments of Medicine, University of Toronto, Toronto, M5S 1A8, Canada

    Tony K. T. Lam

  4. Banting and Best Diabetes Centre, University of Toronto, Toronto, M5G 2C4, Canada

    Tony K. T. Lam

  5. MaRS Centre, 101 College Street, Toronto Medical Discovery Tower, 10th floor, Room 705, Toronto, ON, M5G 1L7, Canada

    Tony K. T. Lam

Authors
  1. Mary P. LaPierre
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Mona A. Abraham
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Beatrice M. Filippi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jessica T. Y. Yue
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Tony K. T. Lam
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Tony K. T. Lam.

Additional information

Mary P. LaPierre and Mona A. Abraham have contributed equally to this invited perspective.

Rights and permissions

Reprints and permissions

About this article

Cite this article

LaPierre, M.P., Abraham, M.A., Filippi, B.M. et al. Glucagon and lipid signaling in the hypothalamus. Mamm Genome 25, 434–441 (2014). https://doi.org/10.1007/s00335-014-9510-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00335-014-9510-6

Keywords

Search

Navigation