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Exp Physiol 99.9 (2014) pp 1104–1109
Themed Issue (Obesity) Review
Insulin action in the hypothalamus and dorsal vagal complex Mona A. Abraham1,2 , Beatrice M. Filippi1 , Gil Myoung Kang3 , Min-Seon Kim3 and Tony K. T. Lam1,2,3,4,5 1
Toronto General Research Institute and Department of Medicine, University Health Network, Toronto, Ontario, Canada Department of Physiology, University of Toronto, Toronto, Ontario, Canada 3 Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea 4 Department of Medicine, University of Toronto, Toronto, Ontario, Canada 5 Banting and Best Diabetes Centre, University of Toronto, Toronto, Ontario, Canada
Experimental Physiology
2
New Findings r What is the topic of this review? This review documents a metabolic role of insulin action in brain. r What advances does it highlight? This review highlights the role of insulin signalling in the hypothalamus and dorsal vagal complex in the regulation of hepatic glucose production and food intake.
Insulin resistance is a hallmark feature of type 2 diabetes and obesity. In addition to the classical view that insulin resistance in the liver, muscle and fat disrupts glucose homeostasis, studies in the past decade have illustrated that insulin resistance in the hypothalamus dysregulates hepatic glucose production and food intake, leading to type 2 diabetes and obesity. This invited review argues that in addition to the hypothalamus, insulin signalling in the dorsal vagal complex regulates hepatic glucose production and food intake. A thorough understanding of the physiological and pathophysiological mechanisms of insulin action in the hypothalamus and dorsal vagal complex is necessary in order to identify therapeutic targets for obesity and type 2 diabetes. (Received 6 April 2014; accepted after revision 16 June 2014; first published online 27 June 2014) Corresponding author T. K. T. Lam: MaRS Centre, 101 College Street, Toronto Medical Discovery Tower, 10th floor, Room 705, Toronto, Ontario, Canada M5G 1L7. Email: [email protected]
Obesity and type 2 diabetes are now the most challenging public health concerns of the 21st century. According to the International Diabetes Federation, an estimated 381.8 million people were diagnosed with diabetes in 2013, which is predicted to increase by 55% to 591.9 million by 2035 (Beagley, 2014). The incidence of obesity is also dramatically increasing and has nearly doubled from 6.4% in 1980 to 12.0% in 2008 (Stevens et al. 2012). These chronic diseases predispose individuals to cardiovascular diseases, mucoskeletal disorders and cancer (Stratton et al. 2000; Field et al. 2001), thereby reducing life expectancy, as well as costing heavily in healthcare expenses. Therapeutic
interventions aimed at proper regulation of glucose and energy balance to combat this ‘diabesity’ burden are needed today, more than ever. Insulin resistance, or the inability of insulin to carry out its metabolic effects, is a pathophysiological feature of obesity and type 2 diabetes (Reaven, 1988; Kahn et al. 2006). Reversing insulin resistance, by enhancing the ability of insulin to inhibit hepatic glucose production (GP) and to increase glucose uptake in muscle and fat, is an important therapeutic strategy in type 2 diabetes and obesity (Reaven, 1988; Kahn et al. 2006). Interestingly, studies in the past decade have illustrated that insulin signalling in the hypothalamus also modulates glucose homeostasis. For example, insulin activates insulin
DOI: 10.1113/expphysiol.2014.079962
C 2014 The Authors. Experimental Physiology C 2014 The Physiological Society
Introduction
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Exp Physiol 99.9 (2014) pp 1104–1109
Insulin action in the hypothalamus and dorsal vagal complex
receptor–phosphoinositide 3-kinase (PI3K) signalling and ATP-dependent potassium (KATP ) channels expressed in the Agouti- related peptide (AgRP) neurons of the mediobasal hypothalamus (MBH) to lower GP in normal rodents via hepatic vagal innervation (Obici et al. 2002b; Pocai et al. 2005; K¨onner et al. 2007), while insulin fails to activate MBH signalling pathways to inhibit GP in obesity (Ono et al. 2008). Hypothalamic insulin signalling also promotes negative energy balance by suppressing food intake and lowering body weight (Benoit et al. 2002; Clegg et al. 2003; Brown et al. 2006). Importantly, hypothalamic insulin infusion fails to lower food intake in obesity-prone rodents (Clegg et al. 2005, 2011), while selective knock-down of the hypothalamic insulin receptor increases hyperphagia and obesity (Obici et al. 2002a). These findings indicate that hypothalamic insulin resistance dysregulates glucose and energy balance. However, is hypothalamic insulin action clinically relevant? In humans, intranasal insulin delivery increases the insulin concentration in the CSF and, importantly, lowers food intake and plasma glucose levels (Hallschmid et al. 2012). Moreover, a recent study suggests that oral diazoxide activates brain KATP channels (downstream signalling effector of hypothalamic insulin signalling as discussed above) and lowers GP in normal humans (Kishore et al. 2011). These findings, however, do not directly indicate that hypothalamic insulin signalling lowers GP and feeding in humans, because intranasal insulin delivery or oral treatment with diazoxide does not limit the site of action to the hypothalamus. However, these observations provide the possibility that insulin triggers signalling pathways in extrahypothalamic regions within the brain to lower GP and appetite. This invited article argues for such a possibility. Specifically, we propose that the dorsal vagal complex (DVC) is a critical extrahypothalamic region within the brain that senses insulin to regulate glucose homeostasis and energy balance (Fig. 1).
Insulin signalling in the DVC regulates glucose homeostasis
The DVC contains the nucleus of the tractus solitarii (NTS), the dorsal motor nucleus of the vagus and the area postrema. N-Methyl-D-aspartate (NMDA) receptor-mediated neurotransmission in the DVC (or more specifically the NTS) relays signals generated by intestinal nutrient and hormonal signalling mechanisms to the liver to lower GP (Wang et al. 2008; Cheung et al. 2009; Lam, 2010; Breen et al. 2012; Rasmussen et al. 2014). Furthermore, direct activation of the NMDA receptors in the DVC is sufficient (Lam et al. 2010) and necessary for hypothalamic nutrient sensing (Lam et al. 2011) to
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lower GP. In light of these studies, and the fact that glucagon-like peptide-1 (GLP-1; Hayes et al. 2011) and leptin (Hayes et al. 2010) signal in the DVC to regulate feeding, a recent study tested the possibility that the DVC is a glucoregulatory site for brain insulin action (Filippi et al. 2012). Consistent with other reports (McKernan & Calaresu, 1996; Ruggeri et al. 2001; Yuan & Yang, 2002; Blake & Smith, 2012), the study by Filippi et al. (2012) first demonstrated that the DVC is insulin responsive, because direct insulin infusion into the DVC (targeting the NTS) activates insulin receptor-mediated signalling events in a dose-dependent manner. Indeed, DVC insulin signalling corresponds to an inhibition of GP in rodents, while inhibition of DVC insulin receptors negates the GP-lowering effect independent of changes in food intake and body weight. Secondly, this study addressed which of the DVC insulin receptor-mediated signalling pathways regulate GP. When insulin is infused into the DVC at the same dose as that which activates PI3K when administered into the MBH (Obici et al. 2002b; Ono et al. 2008), insulin fails to activate DVC PI3K. Instead, DVC insulin activates Erk1/2 (Filippi et al. 2012). Inhibition of DVC Erk1/2 signalling by a chemical approach, as well as a molecular approach (via administration of an adenovirus expressing the inactive form of MEK1, the upstream target of Erk1/2, into the DVC), abolishes the ability of insulin to lower GP (Filippi et al. 2012). In direct contrast, inhibition of DVC PI3K signalling does not alter the ability of insulin to control glucose. Furthermore, directly activating DVC Erk1/2 (via administration of an adenovirus expressing the constitutively active form of MEK1) lowers GP, strengthening the glucoregulatory role of DVC Erk1/2 signalling. Thus, insulin activates an Erk1/2-dependent signalling pathway in the DVC to lower GP, as opposed to the MBH, where insulin lowers GP via PI3K signalling (Obici et al. 2002b; Fig. 1). Given that insulin- and Erk1/2-dependent signalling activates KATP channels in hippocampal neurons (O’Malley et al. 2003) and that Erk1/2 phosphorylates the Kir6.2 subunit of the KATP channels (Lin & Chai, 2008) that are expressed in the DVC (Thomzig et al. 2005), KATP channels seem a likely downstream mediator. Indeed, KATP channels in the DVC are necessary for insulin–Erk1/2 signalling and sufficient to inhibit GP (Filippi et al. 2012; Fig. 1). As in the DVC, activation of KATP channels in the MBH is also required for insulin signalling and sufficient to lower GP (Pocai et al. 2005; K¨onner et al. 2007; Fig. 1). Given that activation of KATP channels in both the DVC and MBH plays a role in lowering GP, the issue arises of whether KATP channels expressed in the MBH and/or the DVC are responsible for mediating the effects of oral diazoxide in suppressing GP in humans (Kishore et al. 2011).
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The MBH and DVC are located within the third and fourth ventricles, respectively, which are characterized by a leaky blood–brain barrier and extensive vasculature. Thus, the GP-lowering effect of insulin signalling in the brain may be physiologically relevant. In fact, a physiological rise in plasma insulin levels activates Erk1/2–KATP channel signalling in the DVC to inhibit GP (Filippi et al. 2012). Likewise, MBH PI3K–KATP channel signalling also contributes to the GP-lowering effect of a rise in circulating insulin levels (Obici et al. 2002b). Given that hyperinsulinaemia would activate signalling cascades in both the MBH and the DVC, future studies are required to address the relative contribution of MBH versus DVC insulin signalling in the overall GP-lowering effect of hyperinsulinemia in healthy conditions. High-fat feeding disrupts the action of insulin in the DVC and dysregulates GP in association with the inability of insulin to activate Erk1/2 in the DVC (Filippi
Exp Physiol 99.9 (2014) pp 1104–1109
et al. 2012). Conversely, high-fat feeding disrupts the ability of insulin to suppress GP by inhibiting MBH PI3K–Akt signalling (Ono et al. 2008). An enhancement of endoplasmic reticulum stress (Purkayastha et al. 2011) and inflammation (Milanski et al. 2012), as well as the activation of p70 S6 kinase (Ono et al. 2008), have been implicated in the induction of hypothalamic insulin resistance and dysregulation of GP. Whether these possibilities lead to the defective DVC insulin signalling during a diseased state remains to be tested. Nonetheless, if insulin signalling in the DVC, as in the MBH, regulates glucose homeostasis, can it also regulate energy balance?
Insulin signalling in the DVC regulates energy balance
Indeed, direct administration of insulin into the DVC lowers food intake as early as 90 min compared with
Glucose production KATP channel
Insulin
KATP channel
IR
IR
IRS1/2 IRS1/2
MEK1/2
PI3K
Mediobasal hypothalamus
ERK1/2
Dorsal vagal complex
Akt
Feeding
Figure 1. Insulin acting in the mediobasal hypothalamus (MBH) and dorsal vagal complex (DVC) lowers hepatic glucose production and food intake Schematic representation that showing insulin triggers differential signalling pathways in the DVC (Erk1/2 dependent) and MBH (PI3K–Akt dependent) to regulate glucose and energy homeostasis. Of note, KATP channels in the DVC and MBH have not been demonstrated to mediate the anorectic effect of insulin. Abbreviations: IR, insulin receptor; IRS1/2, insulin receptor substrate 1/2; MEK1/2, MAP/ERK Kinase 1/2; ERK1/2, Extracellular signal-regulated protein kinase 1/2; PI3K, Phosphoinositide 3-kinase; Akt, Protein kinase B. C 2014 The Authors. Experimental Physiology C 2014 The Physiological Society
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Exp Physiol 99.9 (2014) pp 1104–1109
Insulin action in the hypothalamus and dorsal vagal complex
DVC saline infusions (Filippi et al. 2014). The mechanism underlying DVC insulin-induced satiety involves the activation of DVC Erk1/2, because molecular and chemical inhibition of Erk1/2 signalling negates the ability of DVC insulin infusion to reduce feedet al.ing. In contrast, inhibition of the PI3K–Akt pathway does not affect the action of insulin in the DVC, thereby suggesting that DVC insulin activates an Erk1/2-dependent and a PI3–Akt-independent pathway to regulate feeding (Fig. 1). Furthermore, direct inhibition of DVC Erk1/2 per se induces obesity (Filippi et al. 2014), while DVC leucine sensing activates Erk1/2 to lower feeding (Blouet & Schwartz, 2012). In contrast, insulin activates PI3K in hypothalamic AgRP and pro-opiomelanocortin neurons (Xu et al. 2005), as well as in the hypothalamic tissue (Niswender et al. 2003). The activation of hypothalamic PI3K is necessary for insulin to lower food intake (Niswender et al. 2003; Fig. 1). Interestingly, activation of Erk is also implicated in the insulin-mediated repression of AgRP and neuropeptide Y expression (Mayer & Belsham, 2009), but the in vivo relevance remains unknown. In addition, despite the established role of the KATP channels in the GP-lowering effect of both MBH and DVC insulin signalling, as discussed above, no evidence to date has established the role of the brain KATP channels in regulation of feeding (Fig. 1). Nonetheless, rats fed with a high-fat diet fail to lower food intake following a DVC insulin infusion (Filippi et al. 2014), while hypothalamic insulin infusion fails to suppress appetite in diet-induced obese rodents (Clegg et al. 2005), in association with impaired Akt activation and dysregulated pro-opiomelanocortin (Clegg et al. 2011) and neuropeptide Y expression (Schwartz et al. 1991). Future studies are warranted to characterize the underlying mechanisms as well as the relative contribution of insulin resistance in the MBH and the DVC that concurrently dysregulate feeding and GP.
Conclusion
In response to a rise in nutrients, pancreatic insulin is secreted into the circulation to maintain metabolic homeostasis. In normal conditions, the rise in circulating insulin activates not only an MBH PI3K-depedendent pathway but also a DVC Erk1/2-dependent pathway to lower GP and food intake. Importantly, high-fat feeding induces insulin resistance in both the MBH and the DVC, leading to increased hepatic glucose production and hyperphagia. Reversing insulin resistance in the MBH and DVC represents a potential therapeutic strategy to combat obesity and type 2 diabetes.
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Call for comments
Readers are invited to give their opinion on this article. To submit a comment, go to: http://ep.physoc.org/letters/ submit/expphysiol;99/9/1104 References Beagley J, Guariguata L, Weil C & Motala AA (2014). Global estimates of undiagnosed diabetes in adults. Diabetes Res Clin Pract 103, 150–160. Benoit SC, Air EL, Coolen LM, Strauss R, Jackman A, Clegg DJ, Seeley RJ & Woods SC (2002). The catabolic action of insulin in the brain is mediated by melanocortins. J Neurosci 22, 9048–9052. Blake CB & Smith BN (2012). Insulin reduces excitation in gastric-related neurons of the dorsal motor nucleus of the vagus. Am J Physiol Regul Integr Comp Physiol 303, R807–R814. Blouet C & Schwartz GJ (2012). Brainstem nutrient sensing in the nucleus of the solitary tract inhibits feeding. Cell Metab 16, 579–587. Breen DM, Rasmussen BA, Kokorovic A, Wang R, Cheung GW & Lam TK (2012). Jejunal nutrient sensing is required for duodenal-jejunal bypass surgery to rapidly lower glucose concentrations in uncontrolled diabetes. Nat Med 18, 950–955. Brown LM, Clegg DJ, Benoit SC & Woods SC (2006). Intraventricular insulin and leptin reduce food intake and body weight in C57BL/6J mice. Physiol Behav 89, 687–691. Cheung GW, Kokorovic A, Lam CK, Chari M & Lam TK (2009). Intestinal cholecystokinin controls glucose production through a neuronal network. Cell Metab 10, 99–109. Clegg DJ, Benoit SC, Reed JA, Woods SC, Dunn-Meynell A & Levin BE (2005). Reduced anorexic effects of insulin in obesity-prone rats fed a moderate-fat diet. Am J Physiol Regul Integr Comp Physiol 288, R981–R986. Clegg DJ, Gotoh K, Kemp C, Wortman MD, Benoit SC, Brown LM, D’Alessio D, Tso P, Seeley RJ & Woods SC (2011). Consumption of a high-fat diet induces central insulin resistance independent of adiposity. Physiol Behav 103, 10–16. Clegg DJ, Riedy CA, Smith KA, Benoit SC & Woods SC (2003). Differential sensitivity to central leptin and insulin in male and female rats. Diabetes 52, 682–687. Field AE, Coakley EH, Must A, Spadano JL, Laird N, Dietz WH, Rimm E & Colditz GA (2001). Impact of overweight on the risk of developing common chronic diseases during a 10-year period. Arch Intern Med 161, 1581–1586. Filippi BM, Bassiri A, Abraham MA, Duca FA, Yue JT & Lam TK (2014). Insulin signals through the dorsal vagal complex to regulate energy balance. Diabetes 63, 892–899. Filippi BM, Yang CS, Tang C & Lam TK (2012). Insulin activates Erk1/2 signaling in the dorsal vagal complex to inhibit glucose production. Cell Metab 16, 500–510.
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Hallschmid M, Higgs S, Thienel M, Ott V & Lehnert H (2012). Postprandial administration of intranasal insulin intensifies satiety and reduces intake of palatable snacks in women. Diabetes 61, 782–789. Hayes MR, Leichner TM, Zhao S, Lee GS, Chowansky A, Zimmer D, De Jonghe BC, Kanoski SE, Grill HJ & Bence KK (2011). Intracellular signals mediating the food intake-suppressive effects of hindbrain glucagon-like peptide-1 receptor activation. Cell Metab 13, 320–330. Hayes MR, Skibicka KP, Leichner TM, Guarnieri DJ, DiLeone RJ, Bence KK & Grill HJ (2010). Endogenous leptin signaling in the caudal nucleus tractus solitarius and area postrema is required for energy balance regulation. Cell Metab 11, 77–83. Kahn SE, Hull RL & Utzschneider KM (2006). Mechanisms linking obesity to insulin resistance and type 2 diabetes. Nature 444, 840–846. 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 KATP channels suppresses glucose production in humans. J Clin Invest 121, 4916–4920. K¨onner 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 & Br¨uning JC (2007). Insulin action in AgRP-expressing neurons is required for suppression of hepatic glucose production. Cell Metab 5, 438–449. Lam CK, Chari M, Rutter GA & Lam TK (2011). Hypothalamic nutrient sensing activates a forebrain-hindbrain neuronal circuit to regulate glucose production in vivo. Diabetes 60, 107–113. Lam CK, Chari M, Su BB, Cheung GW, Kokorovic A, Yang CS, Wang PY, Lai TY & Lam TK (2010). Activation of N-methyl-D-aspartate (NMDA) receptors in the dorsal vagal complex lowers glucose production. J Biol Chem 285, 21913–21921. Lam TK (2010). Neuronal regulation of homeostasis by nutrient sensing. Nat Med 16, 392–395. Lin YF & Chai Y (2008). Functional modulation of the ATP-sensitive potassium channel by extracellular signal-regulated kinase-mediated phosphorylation. Neuroscience 152, 371–380. McKernan AM & Calaresu FR (1996). Insulin microinjection into the nucleus tractus solitarii of the rat attenuates the baroreceptor reflex. J Auton Nerv Syst 61, 128–138. Mayer CM & Belsham DD (2009). Insulin directly regulates NPY and AgRP gene expression via the MAPK MEK/ERK signal transduction pathway in mHypoE-46 hypothalamic neurons. Mol Cell Endocrinol 307, 99–108. Milanski M, Arruda AP, Coope A, Ignacio-Souza LM, Nunez CE, Roman EA, Romanatto T, Pascoal LB, Caricilli AM, Torsoni MA, Prada PO, Saad MJ & Velloso LA (2012). Inhibition of hypothalamic inflammation reverses diet-induced insulin resistance in the liver. Diabetes 61, 1455–1462. Niswender KD, Morrison CD, Clegg DJ, Olson R, Baskin DG, Myers MG, Seeley RJ & Schwartz MW (2003). Insulin activation of phosphatidylinositol 3-kinase in the hypothalamic arcuate nucleus: a key mediator of insulin-induced anorexia. Diabetes 52, 227–231.
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Obici S, Feng Z, Karkanias G, Baskin DG & Rossetti L (2002a). Decreasing hypothalamic insulin receptors causes hyperphagia and insulin resistance in rats. Nat Neurosci 5, 566–572. Obici S, Zhang BB, Karkanias G & Rossetti L (2002b). Hypothalamic insulin signaling is required for inhibition of glucose production. Nat Med 8, 1376–1382. O’Malley D, Shanley LJ & Harvey J (2003). Insulin inhibits rat hippocampal neurones via activation of ATP-sensitive K+ and large conductance Ca2+ -activated K+ channels. Neuropharmacology 44, 855–863. Ono H, Pocai A, Wang Y, Sakoda H, Asano T, Backer JM, Schwartz GJ & Rossetti L (2008). Activation of hypothalamic S6 kinase mediates diet-induced hepatic insulin resistance in rats. J Clin Invest 118, 2959–2968. Pocai A, Lam TK, Gutierrez-Juarez R, Obici S, Schwartz GJ, Bryan J, Aguilar-Bryan L & Rossetti L (2005). Hypothalamic KATP channels control hepatic glucose production. Nature 434, 1026–1031. Purkayastha S, Zhang H, Zhang G, Ahmed Z, Wang Y & Cai D (2011). Neural dysregulation of peripheral insulin action and blood pressure by brain endoplasmic reticulum stress. Proc Natl Acad Sci U S A 108, 2939–2944. Rasmussen BA, Breen DM, Duca FA, Cote CD, Zadeh-Tahmasebi M, Filippi M & Lam TK (2014). Jejunal leptin-PI3K signaling lowers glucose production. Cell Metab 19, 155–161. Reaven GM (1988). Banting lecture 1988. Role of insulin resistance in human disease. Diabetes 37, 1595–1607. Ruggeri P, Olinari C, Brunori A, Cogo CE, Mary DASG, Picchio V & Vacca G (2001). The direct effect of insulin on barosensitive neurons in the nucleus tractus solitarii of rats. Neuroreport 12, 3719–3722. Schwartz MW, Marks JL, Sipols AJ, Baskin DG, Woods SC, Kahn SE & Porte D Jr (1991). Central insulin administration reduces neuropeptide Y mRNA expression in the arcuate nucleus of food-deprived lean (Fa/Fa) but not obese (fa/fa) Zucker rats. Endocrinology 128, 2645–2647. Stevens GA, Singh GM, Lu Y, Danaei G, Lin JK, Finucane MM, Bahalim AN, McIntire RK, Gutierrez HR, Cowan M, Paciorek CJ, Farzadfar F, Riley L & Ezzati M; Global Burden of Metabolic Risk Factors of Chronic Diseases Collaborating Group (Body Mass Index) (2012). National, regional, and global trends in adult overweight and obesity prevalences. Popul Health Metr 10, 22. Stratton IM, Adler AI, Neil HA, Matthews DR, Manley SE, Cull CA, Hadden D, Turner RC & Holman RR (2000). Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study. BMJ 321, 405–412. Thomzig A, Laube G, Pr¨uss H & Veh RW (2005). Pore-forming subunits of K-ATP channels, Kir6.1 and Kir6.2, display prominent differences in regional and cellular distribution in the rat brain. J Comp Neurol 484, 313–330. Wang PY, Caspi L, Lam CK, Chari M, Li X, Light PE, Gutierrez-Juarez R, Ang M, Schwartz GJ & Lam TK (2008). Upper intestinal lipids trigger a gut–brain–liver axis to regulate glucose production. Nature 452, 1012–1016. C 2014 The Authors. Experimental Physiology C 2014 The Physiological Society
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Additional Information Competing interests None declared.
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Funding The work discussed in this review produced by the Lam laboratory was supported by a research grant from the Canadian Diabetes Association (OG-3-13-4156-TL). M.A.A. is supported by a Canadian Institutes of Health Research Doctoral Award. T.K.T.L. holds the Canada Research Chair in Obesity and the John Kitson McIvor (1915–1942) Endowed Chair in Diabetes Research at the Toronto General Research Institute and the University of Toronto. Acknowledgements The authors would like to thank Frank Duca of the Toronto General Research Institute, UHN for reviewing the manuscript.
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Exp Physiol 99.9 (2014) pp 1104–1109
Themed Issue (Obesity) Review
Insulin action in the hypothalamus and dorsal vagal complex Mona A. Abraham1,2 , Beatrice M. Filippi1 , Gil Myoung Kang3 , Min-Seon Kim3 and Tony K. T. Lam1,2,3,4,5 1
Toronto General Research Institute and Department of Medicine, University Health Network, Toronto, Ontario, Canada Department of Physiology, University of Toronto, Toronto, Ontario, Canada 3 Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea 4 Department of Medicine, University of Toronto, Toronto, Ontario, Canada 5 Banting and Best Diabetes Centre, University of Toronto, Toronto, Ontario, Canada
Experimental Physiology
2
New Findings r What is the topic of this review? This review documents a metabolic role of insulin action in brain. r What advances does it highlight? This review highlights the role of insulin signalling in the hypothalamus and dorsal vagal complex in the regulation of hepatic glucose production and food intake.
Insulin resistance is a hallmark feature of type 2 diabetes and obesity. In addition to the classical view that insulin resistance in the liver, muscle and fat disrupts glucose homeostasis, studies in the past decade have illustrated that insulin resistance in the hypothalamus dysregulates hepatic glucose production and food intake, leading to type 2 diabetes and obesity. This invited review argues that in addition to the hypothalamus, insulin signalling in the dorsal vagal complex regulates hepatic glucose production and food intake. A thorough understanding of the physiological and pathophysiological mechanisms of insulin action in the hypothalamus and dorsal vagal complex is necessary in order to identify therapeutic targets for obesity and type 2 diabetes. (Received 6 April 2014; accepted after revision 16 June 2014; first published online 27 June 2014) Corresponding author T. K. T. Lam: MaRS Centre, 101 College Street, Toronto Medical Discovery Tower, 10th floor, Room 705, Toronto, Ontario, Canada M5G 1L7. Email: [email protected]
Obesity and type 2 diabetes are now the most challenging public health concerns of the 21st century. According to the International Diabetes Federation, an estimated 381.8 million people were diagnosed with diabetes in 2013, which is predicted to increase by 55% to 591.9 million by 2035 (Beagley, 2014). The incidence of obesity is also dramatically increasing and has nearly doubled from 6.4% in 1980 to 12.0% in 2008 (Stevens et al. 2012). These chronic diseases predispose individuals to cardiovascular diseases, mucoskeletal disorders and cancer (Stratton et al. 2000; Field et al. 2001), thereby reducing life expectancy, as well as costing heavily in healthcare expenses. Therapeutic
interventions aimed at proper regulation of glucose and energy balance to combat this ‘diabesity’ burden are needed today, more than ever. Insulin resistance, or the inability of insulin to carry out its metabolic effects, is a pathophysiological feature of obesity and type 2 diabetes (Reaven, 1988; Kahn et al. 2006). Reversing insulin resistance, by enhancing the ability of insulin to inhibit hepatic glucose production (GP) and to increase glucose uptake in muscle and fat, is an important therapeutic strategy in type 2 diabetes and obesity (Reaven, 1988; Kahn et al. 2006). Interestingly, studies in the past decade have illustrated that insulin signalling in the hypothalamus also modulates glucose homeostasis. For example, insulin activates insulin
DOI: 10.1113/expphysiol.2014.079962
C 2014 The Authors. Experimental Physiology C 2014 The Physiological Society
Introduction
Downloaded from Exp Physiol (ep.physoc.org) at UNIV OF PRINCE EDWARD ISLAND on November 1, 2014
Exp Physiol 99.9 (2014) pp 1104–1109
Insulin action in the hypothalamus and dorsal vagal complex
receptor–phosphoinositide 3-kinase (PI3K) signalling and ATP-dependent potassium (KATP ) channels expressed in the Agouti- related peptide (AgRP) neurons of the mediobasal hypothalamus (MBH) to lower GP in normal rodents via hepatic vagal innervation (Obici et al. 2002b; Pocai et al. 2005; K¨onner et al. 2007), while insulin fails to activate MBH signalling pathways to inhibit GP in obesity (Ono et al. 2008). Hypothalamic insulin signalling also promotes negative energy balance by suppressing food intake and lowering body weight (Benoit et al. 2002; Clegg et al. 2003; Brown et al. 2006). Importantly, hypothalamic insulin infusion fails to lower food intake in obesity-prone rodents (Clegg et al. 2005, 2011), while selective knock-down of the hypothalamic insulin receptor increases hyperphagia and obesity (Obici et al. 2002a). These findings indicate that hypothalamic insulin resistance dysregulates glucose and energy balance. However, is hypothalamic insulin action clinically relevant? In humans, intranasal insulin delivery increases the insulin concentration in the CSF and, importantly, lowers food intake and plasma glucose levels (Hallschmid et al. 2012). Moreover, a recent study suggests that oral diazoxide activates brain KATP channels (downstream signalling effector of hypothalamic insulin signalling as discussed above) and lowers GP in normal humans (Kishore et al. 2011). These findings, however, do not directly indicate that hypothalamic insulin signalling lowers GP and feeding in humans, because intranasal insulin delivery or oral treatment with diazoxide does not limit the site of action to the hypothalamus. However, these observations provide the possibility that insulin triggers signalling pathways in extrahypothalamic regions within the brain to lower GP and appetite. This invited article argues for such a possibility. Specifically, we propose that the dorsal vagal complex (DVC) is a critical extrahypothalamic region within the brain that senses insulin to regulate glucose homeostasis and energy balance (Fig. 1).
Insulin signalling in the DVC regulates glucose homeostasis
The DVC contains the nucleus of the tractus solitarii (NTS), the dorsal motor nucleus of the vagus and the area postrema. N-Methyl-D-aspartate (NMDA) receptor-mediated neurotransmission in the DVC (or more specifically the NTS) relays signals generated by intestinal nutrient and hormonal signalling mechanisms to the liver to lower GP (Wang et al. 2008; Cheung et al. 2009; Lam, 2010; Breen et al. 2012; Rasmussen et al. 2014). Furthermore, direct activation of the NMDA receptors in the DVC is sufficient (Lam et al. 2010) and necessary for hypothalamic nutrient sensing (Lam et al. 2011) to
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lower GP. In light of these studies, and the fact that glucagon-like peptide-1 (GLP-1; Hayes et al. 2011) and leptin (Hayes et al. 2010) signal in the DVC to regulate feeding, a recent study tested the possibility that the DVC is a glucoregulatory site for brain insulin action (Filippi et al. 2012). Consistent with other reports (McKernan & Calaresu, 1996; Ruggeri et al. 2001; Yuan & Yang, 2002; Blake & Smith, 2012), the study by Filippi et al. (2012) first demonstrated that the DVC is insulin responsive, because direct insulin infusion into the DVC (targeting the NTS) activates insulin receptor-mediated signalling events in a dose-dependent manner. Indeed, DVC insulin signalling corresponds to an inhibition of GP in rodents, while inhibition of DVC insulin receptors negates the GP-lowering effect independent of changes in food intake and body weight. Secondly, this study addressed which of the DVC insulin receptor-mediated signalling pathways regulate GP. When insulin is infused into the DVC at the same dose as that which activates PI3K when administered into the MBH (Obici et al. 2002b; Ono et al. 2008), insulin fails to activate DVC PI3K. Instead, DVC insulin activates Erk1/2 (Filippi et al. 2012). Inhibition of DVC Erk1/2 signalling by a chemical approach, as well as a molecular approach (via administration of an adenovirus expressing the inactive form of MEK1, the upstream target of Erk1/2, into the DVC), abolishes the ability of insulin to lower GP (Filippi et al. 2012). In direct contrast, inhibition of DVC PI3K signalling does not alter the ability of insulin to control glucose. Furthermore, directly activating DVC Erk1/2 (via administration of an adenovirus expressing the constitutively active form of MEK1) lowers GP, strengthening the glucoregulatory role of DVC Erk1/2 signalling. Thus, insulin activates an Erk1/2-dependent signalling pathway in the DVC to lower GP, as opposed to the MBH, where insulin lowers GP via PI3K signalling (Obici et al. 2002b; Fig. 1). Given that insulin- and Erk1/2-dependent signalling activates KATP channels in hippocampal neurons (O’Malley et al. 2003) and that Erk1/2 phosphorylates the Kir6.2 subunit of the KATP channels (Lin & Chai, 2008) that are expressed in the DVC (Thomzig et al. 2005), KATP channels seem a likely downstream mediator. Indeed, KATP channels in the DVC are necessary for insulin–Erk1/2 signalling and sufficient to inhibit GP (Filippi et al. 2012; Fig. 1). As in the DVC, activation of KATP channels in the MBH is also required for insulin signalling and sufficient to lower GP (Pocai et al. 2005; K¨onner et al. 2007; Fig. 1). Given that activation of KATP channels in both the DVC and MBH plays a role in lowering GP, the issue arises of whether KATP channels expressed in the MBH and/or the DVC are responsible for mediating the effects of oral diazoxide in suppressing GP in humans (Kishore et al. 2011).
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The MBH and DVC are located within the third and fourth ventricles, respectively, which are characterized by a leaky blood–brain barrier and extensive vasculature. Thus, the GP-lowering effect of insulin signalling in the brain may be physiologically relevant. In fact, a physiological rise in plasma insulin levels activates Erk1/2–KATP channel signalling in the DVC to inhibit GP (Filippi et al. 2012). Likewise, MBH PI3K–KATP channel signalling also contributes to the GP-lowering effect of a rise in circulating insulin levels (Obici et al. 2002b). Given that hyperinsulinaemia would activate signalling cascades in both the MBH and the DVC, future studies are required to address the relative contribution of MBH versus DVC insulin signalling in the overall GP-lowering effect of hyperinsulinemia in healthy conditions. High-fat feeding disrupts the action of insulin in the DVC and dysregulates GP in association with the inability of insulin to activate Erk1/2 in the DVC (Filippi
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et al. 2012). Conversely, high-fat feeding disrupts the ability of insulin to suppress GP by inhibiting MBH PI3K–Akt signalling (Ono et al. 2008). An enhancement of endoplasmic reticulum stress (Purkayastha et al. 2011) and inflammation (Milanski et al. 2012), as well as the activation of p70 S6 kinase (Ono et al. 2008), have been implicated in the induction of hypothalamic insulin resistance and dysregulation of GP. Whether these possibilities lead to the defective DVC insulin signalling during a diseased state remains to be tested. Nonetheless, if insulin signalling in the DVC, as in the MBH, regulates glucose homeostasis, can it also regulate energy balance?
Insulin signalling in the DVC regulates energy balance
Indeed, direct administration of insulin into the DVC lowers food intake as early as 90 min compared with
Glucose production KATP channel
Insulin
KATP channel
IR
IR
IRS1/2 IRS1/2
MEK1/2
PI3K
Mediobasal hypothalamus
ERK1/2
Dorsal vagal complex
Akt
Feeding
Figure 1. Insulin acting in the mediobasal hypothalamus (MBH) and dorsal vagal complex (DVC) lowers hepatic glucose production and food intake Schematic representation that showing insulin triggers differential signalling pathways in the DVC (Erk1/2 dependent) and MBH (PI3K–Akt dependent) to regulate glucose and energy homeostasis. Of note, KATP channels in the DVC and MBH have not been demonstrated to mediate the anorectic effect of insulin. Abbreviations: IR, insulin receptor; IRS1/2, insulin receptor substrate 1/2; MEK1/2, MAP/ERK Kinase 1/2; ERK1/2, Extracellular signal-regulated protein kinase 1/2; PI3K, Phosphoinositide 3-kinase; Akt, Protein kinase B. C 2014 The Authors. Experimental Physiology C 2014 The Physiological Society
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DVC saline infusions (Filippi et al. 2014). The mechanism underlying DVC insulin-induced satiety involves the activation of DVC Erk1/2, because molecular and chemical inhibition of Erk1/2 signalling negates the ability of DVC insulin infusion to reduce feedet al.ing. In contrast, inhibition of the PI3K–Akt pathway does not affect the action of insulin in the DVC, thereby suggesting that DVC insulin activates an Erk1/2-dependent and a PI3–Akt-independent pathway to regulate feeding (Fig. 1). Furthermore, direct inhibition of DVC Erk1/2 per se induces obesity (Filippi et al. 2014), while DVC leucine sensing activates Erk1/2 to lower feeding (Blouet & Schwartz, 2012). In contrast, insulin activates PI3K in hypothalamic AgRP and pro-opiomelanocortin neurons (Xu et al. 2005), as well as in the hypothalamic tissue (Niswender et al. 2003). The activation of hypothalamic PI3K is necessary for insulin to lower food intake (Niswender et al. 2003; Fig. 1). Interestingly, activation of Erk is also implicated in the insulin-mediated repression of AgRP and neuropeptide Y expression (Mayer & Belsham, 2009), but the in vivo relevance remains unknown. In addition, despite the established role of the KATP channels in the GP-lowering effect of both MBH and DVC insulin signalling, as discussed above, no evidence to date has established the role of the brain KATP channels in regulation of feeding (Fig. 1). Nonetheless, rats fed with a high-fat diet fail to lower food intake following a DVC insulin infusion (Filippi et al. 2014), while hypothalamic insulin infusion fails to suppress appetite in diet-induced obese rodents (Clegg et al. 2005), in association with impaired Akt activation and dysregulated pro-opiomelanocortin (Clegg et al. 2011) and neuropeptide Y expression (Schwartz et al. 1991). Future studies are warranted to characterize the underlying mechanisms as well as the relative contribution of insulin resistance in the MBH and the DVC that concurrently dysregulate feeding and GP.
Conclusion
In response to a rise in nutrients, pancreatic insulin is secreted into the circulation to maintain metabolic homeostasis. In normal conditions, the rise in circulating insulin activates not only an MBH PI3K-depedendent pathway but also a DVC Erk1/2-dependent pathway to lower GP and food intake. Importantly, high-fat feeding induces insulin resistance in both the MBH and the DVC, leading to increased hepatic glucose production and hyperphagia. Reversing insulin resistance in the MBH and DVC represents a potential therapeutic strategy to combat obesity and type 2 diabetes.
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Call for comments
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Additional Information Competing interests None declared.
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Funding The work discussed in this review produced by the Lam laboratory was supported by a research grant from the Canadian Diabetes Association (OG-3-13-4156-TL). M.A.A. is supported by a Canadian Institutes of Health Research Doctoral Award. T.K.T.L. holds the Canada Research Chair in Obesity and the John Kitson McIvor (1915–1942) Endowed Chair in Diabetes Research at the Toronto General Research Institute and the University of Toronto. Acknowledgements The authors would like to thank Frank Duca of the Toronto General Research Institute, UHN for reviewing the manuscript.
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