9.1. Importance of Glucose Monitoring for Normal Brain Function
Glucose is the essential metabolic fuel for the brain. Acute and severe reduction of brain glucose leads quickly to impairment of cognitive and reflex function, autonomic failure, seizures, loss of consciousness, and permanent and irreversible brain damage and, if not rapidly corrected, can be lethal. Because of its importance to survival and brain function, maintenance of adequate blood glucose for brain metabolism is an urgent and continuous physiological priority. Survival depends on the fact that reduced brain glucose availability (glucoprivation) evokes highly coordinated glucoregulatory responses adapted to conserve and restore this essential fuel. These responses include increased food intake, mobilization of stored glucose, increased gastric motility, corticosterone secretion, suppression of reproductive responses, and others. Despite these protective responses to glucose deficit, diabetic patients on insulin therapy are faced with a constant threat of glucoprivic crisis due to inadvertent mismatch of prevailing glucose levels and insulin dose that results in a fall in blood glucose concentrations (iatrogenic hypoglycemia). In the aftermath of a severe hypoglycemic episode or after repeated hypoglycemic bouts, the responsiveness of central mechanisms to glucose deficit is reduced, resulting in a condition known as hypoglycemia associated autonomic failure (HAAF) and hypoglycemia unawareness (Cryer 2001, Dagogo-Jack, Craft, and Cryer 1993). In this condition, both the cognitive awareness of hypoglycemia and the normally elicited glucoregulatory responses (known as counterregulatory responses [CRRs]) are diminished or absent, greatly increasing the threat of death or injury resulting from a subsequent hypoglycemic episode. The prevalence of diabetes for all age groups worldwide was estimated to be 2.8% (171 million) in 2000 and is projected to rise to 4.4% (366 million) by 2030 (Wild et al. 2004). The number of diabetics worldwide threatened with iatrogenic hypoglycemia and HAAF will therefore rise during the coming years. Hypoglycemia is not limited to diabetics, however, but can be associated with stomach removal or gastric bypass surgery, diseases of liver or kidneys, heart attack, stroke, alcohol addiction, and other metabolic problems. These medical problems reveal the impact of glucose deficit on brain function and survival, providing a strong incentive to understand the physiology and mechanisms of the brain’s glucoregulatory circuitry.
Carbohydrates are the most abundant nutrient on the planet, but they are costly in terms of their required storage space, and glycogen storage within the brain itself is minimal. Rather than storing glycogen, the brain relies on delivery of glucose by the blood from peripheral sources. Even in the periphery, however, the amount of stored glucose is minimal. George Bray (1994) calculated that in a normal-weight adult human body, stored nutrients amount to approximately 140,000 kcal fat, 24,000 kcal protein, but only 800 kcal total as glucose, including both glycogen and circulating glucose. On a 2000 kcal/day diet of 40% carb, 40% fat, and 20% protein, daily intake of fat and protein amount to about 0.57% and 1.67% of body stores, respectively, whereas daily intake of carbohydrates would be comparable to total body carbohydrate stores. Add to this the fact that the brain is highly active, accounting for about 20% of ongoing whole body energy metabolism at rest, despite its small size (2% of body weight) (Clark and Sokoloff 1999). In addition, brain glucose levels are significantly lower than in peripheral blood under all conditions, as shown by results of microdialysis studies (Silver and Erecinska 1994). During euglycemic conditions (about 5 mM glucose peripherally), brain glucose concentrations range between 1 and 2.5 mM and may vary depending on local activity levels. During severe hypoglycemia (2–3 mM glucose peripherally), brain concentrations as low as 0.5 have been measured, and during hyperglycemia (up to 20 mM glucose peripherally), brain concentrations may rise to only about 5 mM. CRRs are elicited when blood glucose levels fall to 3.6–3.8 mM (Cryer 1997). From these considerations, it is clear not only that glucose availability must be effectively monitored by the brain, but also that glucose must be monitored separately from other nutrient sources (fat and protein) that cannot be utilized by the brain. Caloric monitoring of overall nutrient availability, although important for other reasons, is not appropriate or sufficient to protect brain function in the face of glucose deficit.
9.2. Glucose-Sensing Mechanisms
Although it is clear that the brain monitors glucose availability in order to ensure overall neurological function and survival, it also is likely that glucose monitoring mechanisms exist to provide for local regional and cellular energy requirements that vary across the brain depending on local activity levels. In addition, there may be glucose monitoring mechanisms that contribute to maintenance of overall energy homeostasis through control of daily food intake and energy expenditure. A significant body of research also suggests that the sensitivity of some central glucose-sensing mechanisms is gender related and modifiable by ambient hormonal conditions (Briski, Ibrahim, and Tamrakar 2014, Cersosimo et al. 2000, Cherian and Briski 2012, Tamrakar et al. 2015). Indeed, glucose sensitivity has been detected in numerous central and peripheral neurons, as well as in nonneuronal cell populations. Nonneural brain cells that appear to have glucose-sensing capability include ependymocytes (Maekawa et al. 2000, Moriyama et al. 2004) and astrocytes (Marty et al. 2005). For a review of astrocyte participation in glucose monitoring, see Rogers et al. in this volume (Chapter 10). Peripheral nonneural glucose-sensing cell types include, for example, pancreatic alpha and beta cells, glucagon-like 1-secreting enteroendocrine cells in the intestinal mucosa, and taste cells in the oral cavity. In addition to these, a glucose-sensing capability with impact on central control of CRRs has been convincingly demonstrated in the portal mesenteric vein (PMV) (Bohland et al. 2014, Donovan and Watts 2014, Jokiaho, Donovan, and Watts 2014, Saberi, Bohland, and Donovan 2008), although the cellular phenotype(s) of the PMV glucose sensors has not been identified.
Neurons with glucose-sensing capability have been categorized as being either glucose excited (gE) or glucose inhibited (gI) (Song et al. 2001). gE neurons are activated by high glucose and gI neurons are inhibited by high glucose. Both gE and gI neurons have been identified in brain sites of recognized importance for control of metabolism and food intake, including the ventromedial and lateral hypothalamus (Aou et al. 1984) and the caudal hindbrain (Adachi et al. 1984, Mizuno and Oomura 1984), as well as in structures less directly associated with feeding and metabolism, such as the amygdala (Nakano et al. 1986) and subfornical organ (Medeiros, Dai, and Ferguson 2012).
Mechanisms contributing to the glucose-sensing capabilities of gE and gI neurons include sensors directly linked to and dependent upon intracellular glucose metabolism. Many, but not all, gE neurons utilize adenosine triphosphate (ATP)-gated potassium channels (KATP channels). KATP channels are directly controlled by glucose metabolism. ATP generated by glucose metabolism closes these inhibitory K+ channels, leading to depolarization and thus linking fuel availability directly to membrane polarity. These channels were first described as the mechanism responsible for glucose sensing in the pancreatic beta cell. Subsequently, they have been investigated extensively in the ventromedial hypothalamus (Ashford, Boden, and Treherne 1990a, 1990b, Dunn-Meynell, Rawson, and Levin 1998, Kang et al. 2004, Levin et al. 2004), where inactivation of this channel reduces glucose-induced alteration of neuronal firing (Miki et al. 2001), as well as in the nucleus of the solitary tract (NTS) (Dallaporta, Perrin, and Orsini 2000). Although highly suited for glucose sensing, ATP-gated channels are also found ubiquitously in non-glucose-sensing cells in brain and periphery (Dunn-Meynell, Rawson, and Levin 1998).
The best characterized of the gI cell type are the neuropeptide Y (NPY)/agouti-related peptide (AGRP) neurons in the ventromedial hypothalamus and orexin neurons in the lateral hypothalamus (Burdakov and Gonzalez 2009, Oomura et al. 1969), but they have also been studied in the dorsal hindbrain (Adachi, Kobashi, and Funahashi 1995, Balfour, Hansen, and Trapp 2006). The mechanisms utilized for glucose sensing by gI neurons are still unclear, but glucose-stimulated K+ and Cl− channels have been implicated (Song et al. 2001).
5′ adenosine monophosphate-activated protein kinase (AMPK) is also considered to be a sensor of cellular energy status and is present in some gE neurons, for example, gonadotropin releasing hormone neurons (Roland and Moenter 2011). AMPK is activated (phosphorylated) by a decrease in the cellular ATP/AMP ratio (Kahn et al. 2005). Phosphorylation promotes cellular metabolism, resulting in generation of ATP. AMPK is not exclusively located in glucose-sensing neurons but is important in maintaining cellular energy levels in a variety of cell types.
In contrast to KATP channels and AMPK, gluco*kinase (GK), a hexokinase IV isoform, is thought to be present only in cells that are glucose sensing. Hexokinases mediate phosphorylation of glucose to glucose-6-phosphate (G6P), the first step in glycolysis (and glycogen synthesis). GK differs importantly from the hexokinase isoforms that initiate glycolysis in most cells in that it selectively phosphorylates only glucose, has a low affinity for glucose, and is not inhibited by its product, G6P (Dunn-Meynell et al. 2002, Iynedjian 2009). Peripherally, GK plays a major role in stimulating beta cell insulin secretion in response to elevation of blood glucose levels. Although GK is distributed sparsely in the brain, it has been detected in areas important for control of food intake (Dunn-Meynell et al. 2002, Kang et al. 2006, Lynch et al. 2000), including in hypothalamic gE and gI neurons and NTS (Balfour, Hansen, and Trapp 2006).
Glucose transporters (GLUTs) 1–4 are critical for glucose homeostasis, and some isoforms may contribute to glucose sensing (Mueckler and Thorens 2013, Thorens 1996, Thorens and Mueckler 2010). GLUT1 transports glucose into the brain across the capillary endothelium that forms the blood–brain barrier. It is also expressed in astrocytes and red blood cells. GLUT1 is upregulated by hypoglycemia but not altered by hyperglycemia. GLUT2 is strongly associated with glucose-sensing cells in the brain and periphery but is not found exclusively in such cells. Peripherally, GLUT2 is expressed in pancreatic beta cells, hepatic and intestinal endothelial cells, and the kidney. Centrally, GLUT2 is expressed in some neurons (including neurons in feeding-related areas of the hypothalamus and hindbrain), in astrocytes, and endothelial cells, including tanycytes in the ventricular lining. GLUT2 has a uniquely high Km for glucose (approximately 17 mM), providing for fast and efficient transport of glucose into brain cells under all physiological brain glucose concentrations (1–2.5 mM), except during extreme hypoglycemic conditions. Because of the strong association of GLUT2 with glucose sensitive cells in the brain and periphery, astrocytic cells expressing GLUT2 have been proposed to be glucoreceptors involved in elicitation of CRRs. The proposed roles of GLUT2 and astrocytes in central glucose monitoring have been discussed extensively in this volume (R.C. Rogers et al.) and will not be discussed further here. GLUT3 is the predominant GLUT in most, possibly all, neurons. GLUT4 is insulin regulated and primarily expressed by peripheral tissues, where insulin is required for glucose uptake. All of these transporters contribute in some way, directly or indirectly, to the availability and distribution of glucose within the brain, but their specific involvement in CRRs remains to be convincingly demonstrated and depends largely on whether the cells that express them actually communicate with neurons involved in executing glucoregulatory responses. The functions of GLUT5–14 largely remain to be determined.
The sodium-linked GLUT 1 and 2 (SGLT1 and 2) also are of interest as glucose sensors (Mueckler and Thorens 2013, Thorens 1996, Thorens and Mueckler 2010, Yu et al. 2010, 2013). These membrane proteins are capable of transporting glucose into cells against the glucose concentration gradient by coupling glucose transport to inward depolarizing sodium current that, in neurons, contributes to glucose-induced depolarization. They are found in both neural and nonneural cell types. Peripherally, SGLT1 and 2 are present in the proximal tubule of the kidney and in enterocytes of the small intestine. SGLTs have been identified centrally in the hippocampus, amygdala, hypothalamus, cerebral cortex, and striatum but appear to have little or no expression in the hindbrain (Yu et al. 2010, 2013). They are present in both gE and gI neurons (Burdakov and Gonzalez 2009, Gonzalez, Reimann, and Burdakov 2009, O’Malley et al. 2006). SGLT1 and 2 have been described as “nonmetabolic glucose sensors” in part because neurons that express SGLTs, glucose-induced excitation or inhibition (respectively), are mimicked, rather than blocked, by antimetabolic glucose analogues, alpha-methylglucopyranoside (alpha-MDG), and 2-deoxy-d-glucose (2DG) (Gonzalez, Reimann, and Burdakov 2009). These effects are dependent on SGLT (they are abolished by elimination of sodium and by SGLT inhibitors) and are independent of GK (they are not altered by glucosamine). It has been proposed that the nonmetabolic glucose sensing mediated by these receptors enables cells to monitor glucose availability in the extracellular space independently of cellular metabolism, possibly allowing such cells to serve a predictive function, sensing extracellular glucose decline prior to intracellular metabolic deficit. Hypothalamic orexin neurons are examples of gI neurons that respond to ambient glucose via SGLTs (Burdakov and Gonzalez 2009, Burdakov and Lesage 2010, Gonzalez, Reimann, and Burdakov 2009). SGLT3 is also suggested to be a glucose-sensing element but does not have a transport function (Diez-Sampedro et al. 2003). The possible contribution of SGLT3 to neuronal glucose monitoring requires further study.
9.3. Peripheral Responses to Glucose Deficit
Control of blood glucose concentration begins with the opposing actions of pancreatic hormones, glucagon, and insulin, secretion of which are directly responsive to blood glucose levels. Insulin is required for glucose uptake and utilization by most peripheral tissues. However, when glucose levels fall, pancreatic beta cells are inhibited and insulin secretion is reduced, thereby limiting glucose uptake by peripheral tissues and conserving circulating glucose to the benefit of the brain. Low glucose and insulin levels also activate glucagon secretion. Glucagon acts on the liver to stimulate glycogenolysis, gluconeogenesis, and entry of glucose into the blood. Glucagon secretion is also under strong autonomic (Havel et al. 1994) and central control by both hypothalamic and hindbrain sites (Andrew, Dinh, and Ritter 2007, Borg et al. 1995, Marty et al. 2005).
In addition to affecting blood glucose concentrations via direct effects on pancreatic alpha and beta cells, peripheral glucose deficit also alerts the central nervous system by activating receptors in the PMV (Saberi, Bohland, and Donovan 2008). These glucose sensors project to neurons in the dorsomedial hindbrain that transmit messages to more rostral brain sites (Fujita et al. 2007, Hevener, Bergman, and Donovan 2000, Matveyenko et al. 2007). These signals from the PMV appear to be transmitted to the brain via spinal afferents, as sectioning the celiac–superior mesenteric ganglion and T5 spinal transection, but not vagotomy (Fujita and Donovan 2005, Jackson et al. 2000, 1997), significantly reduces the sympathoadrenal response to hypoglycemia. Dennervation of the portal and superior mesenteric vein reduces the adrenal epinephrine (E) response to graded onset of hypoglycemic conditions by 91% (Saberi, Bohland, and Donovan 2008). Interestingly, the PMV glucose sensors are most responsive to gradual, rather than abrupt, declines in blood glucose, and portal-mesenteric denervation eliminates the response to slow-onset hypoglycemia (Saberi, Bohland, and Donovan 2008). Hence, these are not the receptors that respond to precipitous drops in blood glucose, as occurs with insulin overdose.
The PMV responsiveness to gradual-onset hypoglycemia may serve a preventative function, rather than a restorative function, since denervation of the PMV eliminates the response to gradual-onset hypoglycemia but does not eliminate the response to acute glucose deficit. A mechanism such as this may be important to the maintenance of glucose levels in the brain under normal conditions, such as during the intermeal interval or during brief periods of food deprivation, where adequate fuel reserves are available, but may require gradual mobilization. This mechanism, in addition to maintaining glucose levels, would also serve to avoid premature and excessive mobilization of metabolic fuels. As noted, the glucoreceptive mechanism in the PMV has not been systematically investigated. However, GLUT2 knockout mice do not detect glucose changes in the PMV (Burcelin and Thorens 2001), suggesting a critical contribution of this GLUT to the sensing mechanism.
Vagal afferents also appear to be glucose sensing. Elevated glucose activates K(ATP) channels in a subpopulation of gastric afferents, resulting in activation of the afferent neuron (Grabauskas et al. 2010, 2013). Other work has shown that glucose modulates the responsiveness of gastric vagal afferents to serotonin (Troy et al. 2016).
9.4. Central Responses to Glucose Deficit
Key responses to acute glucoprivic challenge are initiated by receptors within the brain. These include increased appetite, the sole mechanism for restoration of deficient glucose supplies (Miselis and Epstein 1975, Smith and Epstein 1969), and increased gastric motility, which facilitates absorption of ingested nutrients within the digestive tract (Cryer 1999, Hermann, Viard, and Rogers 2014). Glucoprivation also triggers secretion of corticosteroid releasing hormone (CRH), with a consequent increase in downstream corticotropin secretion that, among other actions, facilitates peripheral fatty acid metabolism, thereby conserving available glucose for brain utilization. Glucoprivation also stimulates adrenal medullary epinephrine (E) secretion (Cannon, McIver, and Bliss 1924), which complements the adrenal cortical response by stimulating lipolysis and mobilizing glycogen release from storage sites. Glucose deficit also suppresses estrous cycles (I’Anson, Starer, and Bonnema 2003, I’Anson et al. 2003, Nagatani et al. 1996), a response that conserves fuel over the long-term by preventing pregnancy.
9.5. Importance of Hindbrain Catecholamine Neurons in Systemic Glucoregulation
Because glucose monitoring likely contributes to a variety of physiological processes, and because biochemical mechanisms involved in glucose monitoring may differ depending on the specific functions served, determining the mechanisms and cellular populations in brain and periphery that detect, avert, and repair hypoglycemic conditions is a complex task. Nevertheless, current evidence has begun to define a system of catecholamine (CA) neurons in the hindbrain that responds immediately to acute and urgent glucose deficit by enlisting widespread behavioral, endocrine, and autonomic systems to restore brain glucose levels (Ritter et al. 2011). The remainder of this review will focus primarily on hindbrain CA neurons and their connections and functional interactions with forebrain and spinal sites involved in mediation of glucose restorative and glucose protective responses. Evidence implicating glucodetection mechanisms potentially capable of activating CA neurons during glucose deficit also will be discussed briefly.
9.5.1. Brief Overview of Hindbrain CA Neuroanatomy
Given the array of CRRs evoked by glucose deficit, it is apparent that glucoregulation involves circuitry and mechanisms that extend throughout the longitudinal axis of the central nervous system and into the periphery. Nevertheless, it is incontrovertible that all of the CRRs can be elicited by inducing glucoprivic conditions selectively at specific hindbrain sites (Andrew, Dinh, and Ritter 2007, Ritter, Dinh, and Zhang 2000). In addition, glucoprivically evoked feeding, corticosteroid secretion, adrenal medullary secretion, and suppression of reproductive responses all require intact hindbrain CA neurons (Ritter, Bugarith, and Dinh 2001, Ritter, Dinh, and Li 2006, Ritter et al. 2003). The diverse projections and high degree of collateralization of hindbrain CA neurons are ideally suited to triggering rapid and coordinated mobilization of physiologically diverse glucoregulatory responses. That said, it appears that not all CA neurons are involved in glucoregulatory function, but rather that subgroups of these neurons are functionally heterogeneous (Guyenet et al. 2013), with select subpopulations of CA neurons being specialized to mediate CRR, while other subpopulations are involved in non-CRR functions. An ongoing challenge, therefore, is to determine which specific CA neurons mediate glucoregulatory functions, thus enabling a productive analysis of the circuitry and glucose-sensing mechanisms that enable them to perform their critical glucoprotective functions.
As a prologue to further discussion of hindbrain CA neurons implicated in glucoregulatory function, a simplified diagram showing the distribution of E and norepinephrine (NE) subgroups, designated as C and A groups, respectively, is presented in Figure 9.1. For more detailed neuroanatomy of these cell groups, refer to Paxinos and Watson (1997). Both C and A groups synthesize NE and can be identified by the presence of the biosynthetic enzymes, tyrosine hydroxylase (TH) and dopamine-β-hydroxylase (DBH). E neurons can be distinguished from NE neurons by their unique expression of phenethanolamine-N-methyltransferase (PNMT), which converts NE to E. Together, these E and NE neurons are referred to as “‘hindbrain CA”’ neurons to distinguish them from the dopaminergic neurons in the midbrain and hypothalamus.
Figure 9.1
Diagramatic view showing anatomical relationship between hindbrain catecholamine cell groups. “A” groups are noradrenergic. “C” groups are adrenergic. The dorsal groups are situated in the dorsomedial medulla. Group A2 (more...)
9.5.2. Evidence for Hindbrain Participation inGlucose Counterregulation
The hindbrain was identified by very early studies as a site where stimulation produced mobilization of peripheral glucose stores. Subsequently, in the 1980s, experiments by Harvey Grill and his students definitively showed that two crucial glucoprivic responses—increased consummatory feeding and hyperglycemia—could be elicited by systemic glucoprivation in chronic decerebrate rats in which the brain was completely transected at the supracollicular level (DiRocco and Grill 1979, Flynn and Grill 1983). These results indicated that receptors and reflex circuitry capable of mediating these responses are present in the hindbrain. Robert Ritter (Ritter, Slusser, and Stone 1981) demonstrated that the anti-glycolytic agent, 5-thio-d-glucose (5TG), stimulated food intake and blood glucose responses when injected into either the lateral or fourth cerebroventricle (LV or 4V). However, if the cerebral aqueduct, connecting the forebrain ventricles with the fourth ventricle, was acutely occluded, feeding in response to LV 5TG was abolished and the adrenomedullary hyperglycemic response was severely impaired. In contrast, 4V 5TG continued to be effective in stimulating robust feeding and blood glucose responses in the aqueduct occluded rat.
The presence of hindbrain glucoreceptors controlling these and other glucoregulatory responses was confirmed by experiments revealing that nanoinjections of 5TG directly into specific hindbrain tissue sites evoked increased feeding, hyperglycemia, glucagon, and corticosterone secretion (Andrew, Dinh, and Ritter 2007, Ritter, Dinh, and Zhang 2000). Figure 9.2 shows hindbrain sites where unilateral nanoinjections of 5TG elicited food intake (Ritter, Dinh, and Zhang 2000). In contrast, none of these glucoregulatory responses were triggered when 5TG was injected into hypothalamic sites, even when higher doses were injected. Positive responses to hindbrain 5TG were just as robust as those evoked by systemic 2DG or insulin-induced hypoglycemia. A provocative outcome of the cannula mapping experiments discussed previously was that many of the sites positive for elicitation of glucoregulatory responses overlap CA subgroups that are preferentially activated by glucoprivation, as indicated by increased Fos-immunoreactivity (Ritter, Llewellyn-Smith, and Dinh 1998). These include the majority of neurons in A1 and C1, excepting the most rostral, retrofacial segment of C1 (or C1r). In comparison, a smaller proportion of the total CA population in A2 and C2 were activated by 2DG.
Figure 9.2
Cannula sites tested for feeding and blood glucose responses induced by unilateral injection of 5TG (24 μg in 200 nl). Positive sites (stars) and negative sites (circles) are shown. In (a) (caudal medulla) and (b) (rostral medulla), left and (more...)
9.5.3. Hindbrain CA Neurons Are Required for Eliciting Key Protective Responses to Brain Glucose Deficit
The availability of a highly selective retrogradely transported immunotoxin, anti-DBH-saporin (DSAP), made it possible to rigorously test the hypothesis that hindbrain E/NE neurons mediate and are required for responses to glucoprivation. Unlike 6-hydroxydopamine or electrolytic lesion of CA projections used previously, DSAP produced deficits that are highly selective for NE and E neurons anatomically, neurochemically, and behaviorally. It does not lesion dopamine neurons (Picklo et al. 1994, 1995, Wiley and Kline 2000, Wrenn et al. 1996). DSAP consists of a monoclonal antibody against the uniquely expressed NE/E biosynthetic enzyme, DBH, conjugated to the ribosomal toxin, saporin (SAP). As a ribosomal toxin, toxicity requires SAP internalization by cells. Due to the DBH antibody in the conjugate, DSAP selectively binds with and is internalized by DBH-containing synaptic vesicles and is retrogradely transported to the CA neuron cell body, where SAP disrupts protein synthesis, causing cell death. Although uptake of DSAP in CA terminal areas, with subsequent toxin transport to the cell bodies, is extraordinarily useful, DSAP internalization is not restricted to terminals of CA neurons but also occurs when injected into the vicinity of the CA cell bodies (Madden et al. 1999, Rinaman 2003, Schreihofer and Guyenet 2000).
Injection of DSAP into spinal and hypothalamic terminal sites produced different patterns of selective CA neuron degeneration and impaired distinct CRRs. Intraspinal DSAP injection retrogradely lesioned E/NE neurons known to innervate preganglionic sympathetic neurons and eliminated the adrenal medullary response to glucoprivation. Glucoprivic feeding was not impaired and rostrally projecting E/NE neurons in the hindbrain were not damaged. In contrast, injecting DSAP into the paraventricular nucleus of the hypothalamus (PVH) destroyed E/NE neurons with known projections to the hypothalamus and eliminated feeding (Ritter, Bugarith, and Dinh 2001), corticosterone secretion (Ritter et al. 2003), suppression of estrous cycles (I’Anson et al. 2003), and modulation of growth hormone secretion (Emanuel and Ritter 2010) in response to glucoprivation. In contrast to spinal DSAP, PVH DSAP injections did not impair the adrenal medullary hyperglycemic response.
Importantly, DSAP lesions did not appear to alter the ability of the feeding, neuroendocrine, and adrenal medullary systems to function normally under standard nonglucodeprived laboratory conditions, as shown in Figure 9.3. In animals with DSAP lesions, glucoprivic feeding was impaired without obvious impairment of feeding responses to nonglucoprivic stimuli such as the feeding responses to overnight food deprivation, mercaptoacetate (a fatty acid antagonist that stimulates feeding), the diurnal pattern of food intake, or the ability of rats to maintain their body weight (Ritter, Bugarith, and Dinh 2001). Although glucoprivation-induced corticosterone secretion was significantly impaired by PVH DSAP, DSAP did not damage CRH neurons themselves, nor did DSAP treatment disrupt the circadian pattern of corticosterone secretion or the corticosterone response to swim stress, both of which remained intact (Ritter et al. 2003). Rats in which DSAP was injected into the PVH did not exhibit suppression of estrous in response to glucoprivation, but the normal estrous cycles of the DSAP-treated rats were not impaired in the absence of glucoprivation (I’Anson et al. 2003). Neither PVH nor intraspinal DSAP impaired the ability of rats to maintain normal glucose levels during ad libitum access to food (Ritter, Bugarith, and Dinh 2001). This suggests that the glucoregulatory circuits mediating these responses to glucoprivation are distinct from circuits mediating the same responses to nonglucoprivic stimuli.
Figure 9.3
Food intake and blood glucose responses to systemic injection of saline (Control) or 2DG in rats previously injected with DSAP or SAP into the spinal cord (left panels) or into the PVN (right panels). Intraspinal injection of DSAP impaired the blood (more...)
9.5.4. Which CA Neurons Mediate Glucoregulatory Responses?
Despite their considerable functional heterogeneity (Guyenet et al. 2013) and complex neuroanatomical organization, progress has been made in determining the functional specificity of different CA subgroups. For example, groups C1 and C3 each contain at least two distinct populations of neurons—those that innervate the spinal cord and those that innervate the hypothalamus. Spinally projecting neurons in C1 are sympathetic and adrenal medullary premotor neurons, some of which are involved in control of blood pressure (C1r), and others, in adrenal medullary secretion (Morrison and Cao 2000, Morrison, Milner, and Reis 1988).
Several lines of evidence indicate that the glucoprivic feeding response is heavily dependent on a subgroup of CA neurons located primarily within C1m and A1/C1 and coexpressing NPY and DBH (Li and Ritter 2004, Li, Wang, and Ritter 2006). Expression of mRNA for both DBH and NPY is increased in A1/Ca following glucoprivation (Li and Ritter 2004, Li, Wang, and Ritter 2006). Moreover, localized silencing of Npy and Dbh simultaneously, but not separately, significantly and reversibly reduces glucoprivic feeding (by 61%), as shown in Figure 9.4, without altering feeding elicited by the fatty acid antagonist, β-mercaptoacetate, or by overnight food deprivation (Li et al. 2009). These results suggest that CAs and NPY as cotransmitters act conjointly to control glucoprivic feeding in response to glucoprivation.
Figure 9.4
Effects of combined Npy and Dbh siRNAs (“mixed”) injected into A1/C1 or dorsally to miss this area (“missed”) on food intake (a) and blood glucose (b) responses to 2DG and control treatments. (c) Cell counts for DBH- and (more...)
The importance of A1/C1 neurons for stimulation of feeding has been confirmed using designer receptors exclusively activated by designer drug (DREADD) technology to selectively activate these neurons. hM3D(Gq), a “designer” receptor for the “designer drug” clozapine-N-oxide (CNO), was selectively expressed in A1/C1 CA neurons by injection of AAV-DIO-hM3D(Gq)-mCherry into the A1/C1 area of Th-Cre+ rats (Li et al. 2015b). Using this procedure, over 85% of mCherry-labeled neurons were double labeled for DBH, 92% of mCherry-labeled neurons were also TH-positive, and 90% of TH/mCherry cells expressed c-Fos after CNO treatment, which selectively activates only neurons transfected to express hM3D(Gq). Selective activation of A1/C1 neurons by a peripheral injection of CNO increased food intake. Rats consumed approximately 4 g of chow in the 4-hour test after CNO, compared to just 0.8 g after control injections. The magnitude of this response to CNO activation was equivalent to responses induced by systemic 2DG. These same rats, tested in the absence of food, did not exhibit increased blood glucose responses to CNO injections, supporting the hypothesis that the latter control is mediated by neurons distinct from those controlling food intake.
9.5.5. Potential Involvement of the Dorsomedial Medulla in CRRs
In the NTS, expression of c-Fos in response to glucoprivation is present in A2, C2, and C3 (Ritter, Llewellyn-Smith, and Dinh 1998). However, very few A2 neurons in the medial and commissural subnuclei of the NTS express c-Fos in response to glucoprivation. Non-CA neurons throughout the NTS are also activated. Although it is tempting to conclude, based on work done to date, that the CA neurons in the dorsal vagal complex are less critical for CRR elicitation than those located in the ventrolateral medulla (VLM), it has been reported that electrolytic and aspiration lesions of the area postrema and underlying NTS (Bird, Cardone, and Contreras 1983, Contreras, Fox, and Drugovich 1982, Ritter and Taylor 1990) severely impair or abolish glucoprivic feeding, although not all studies have obtained this result (Hyde and Miselis 1983). Moreover, PVH DSAP lesions that eliminate glucoprivic feeding and corticosterone secretion not only eliminate most CA neurons in A1, A1/C1, and C1m but also destroy a significant percentage of the CA neurons in the dorsal vagal complex (Ritter, Bugarith, and Dinh 2001, Ritter et al. 2003), indicating that the contribution of the dorsal medulla to glucoregulation cannot be ruled out.
A plausible hypothesis is that the role of the dorsomedial medulla in glucose CRR may differ from that of the ventromedial medulla, as suggested by its anatomical connections. It is known that A2 neurons are heavily influenced by input from the vagus nerve. Electrophysiological experiments in hindbrain slices have shown that approximately half of the A2 neurons are activated by the gastrointestinal satiety peptide, cholecystokinin, via activation of presynaptic vagal afferent fibers (Appleyard et al. 2007). Data such as these suggest that A2 neurons are involved in integration of inputs that influence normal appetite and daily food intake (Contreras, Kosten, and Bird 1984), but perhaps not in glucoprivic feeding. Alternatively, the CA neurons involved may be inhibited during glucoprivation, and if so, their role may be to suppress competing effects of satiety or malaise on stimulation of feeding in response to glucoprivation.
9.6. Interaction of CA Neurons withForebrain Neurons
9.6.1. NPY/AgRP Neurons as Downstream Comediators of Glucose CRR Circuitry
In contrast to the finding that localized A1/C1 silencing of both Npy and Dbh was required for impairment of glucoprivic feeding, Sindelar et al. (2004) have reported that global NPY knockout mice, with apparently intact CA neurons, have deficient feeding responses to glucoprivation but have normal neuroendocrine responses. This result further confirms the importance of NPY neurons for glucoprivic feeding and suggests that NPY neurons in the hypothalamic arcuate nucleus, which are downstream of those in A1/C1, in addition to those in A1/C1 itself, are critical for the feeding response. Alternatively, the effectiveness of the global knockout may be due to the more complete loss of Npy in the hindbrain CA neurons than could be achieved using localized gene silencing, overriding the necessity for a contribution from CA neurons.
In this regard, another SAP conjugate, NPY-SAP, has been useful in evaluating the importance of arcuate NPY/AGRP neurons in glucoprivic feeding (Bugarith et al. 2005). This conjugate binds to NPY receptors and presumably enters the cell by agonist-driven receptor internalization. Unlike DSAP, but like most other peptide-SAP conjugates, NPY-SAP is not retrogradely transported and therefore lesions only NPY receptive neurons at the injection site. When injected into the basomedial hypothalamus, NPY-SAP, but not blank-SAP (B-SAP) control, destroyed NPY-receptor-expressing neurons in the ARC, including NPY/AGRP and proopiomelanocortin (POMC)/ cocaine- and amphetamine-regulated transcript (CART) neurons. There was a virtually complete loss of NPY, AGRP, and CART mRNA expression in the NPY-SAP rats. In addition, NPY-Y1 receptor immunoreactivity in the ARC was profoundly reduced in the NPY-SAP-injected rats. Dopamine β-hydroxylase and NPY terminals (presumably from the hindbrain) remained abundant in the NPY-SAP injected area, despite the loss of hypothalamic NPY cell bodies. Hindbrain NPY/CA neurons with terminals at the injection site were not destroyed by NPY-SAP, confirming that this conjugate is not retrogradely transported to cell bodies of these neurons. Hypothalamic injection of NPY-SAP eliminated both weight loss and suppression of food intake induced by central leptin injection, as well as eliminated the stimulation of feeding by central ghrelin injection (Bugarith et al. 2005). Leptin and ghrelin are thought to produce their primary effects on feeding by actions on POMC/CART and NPY/AGRP neurons within the arcuate nucleus (Cone et al. 2001, Cowley et al. 2001, Elias et al. 1999, Elias et al. 1998a, 1998b, Elmquist 1998). Both deficits are therefore consistent with loss of arcuate NPY/AGRP and POMC/CART neurons. However, NPY-SAP did not impair the glucoprivic feeding and hyperglycemic or corticosterone responses. In short, DSAP injections that destroy hindbrain CA/NPY neurons impair glucoprivic feeding, despite the fact that arcuate NPY neurons remain intact. Arcuate NPY-SAP injections that destroy NPY/AGRP neurons, leaving the hindbrain CA/NPY neurons intact, do not impair glucoprivic feeding. A reasonable conclusion from these findings is that hindbrain, not arcuate, NPY neurons are required for glucoprivic feeding but that both populations are important contributors. This conclusion is consistent with the fact that supracollicular decerebration does not abolish glucoprivation-induced increase in food intake (Flynn and Grill 1983).
Although hypothalamic NPY/AgRP neurons are not required for glucoprivic feeding, they may be recruited by hindbrain CA neurons to facilitate glucoprivic responses, as suggested by Fraley et al. (Fraley, Dinh, and Ritter 2002, Fraley and Ritter 2003), who showed that hypothalamic Npy and Agrp expressions are increased in response to systemic glucoprivation and that PVH DSAP eliminates this increase. Another interesting aspect of this work is that the basal expression levels of these same genes are increased in DSAP rats, perhaps as a compensatory response to loss of hindbrain NPY/CA input.
9.6.2. Orexin and CA Neurons as Comediators of Glucose CRRs
Recent evidence suggests that orexinergic neurons contribute importantly to glucoregulation. Orexin is known to stimulate food intake when injected into the brain. Injections of orexin-A into the hypothalamus (Sakurai 2007, Yamanaka et al. 1999), lateral and fourth ventricles (Li et al. 2015a, 2015b, Yamanaka et al. 1999, Zhao et al. 2015, Zheng, Patterson, and Berthoud 2005), and the A1/C1 region of the ventrolateral medulla are all effective in stimulating feeding. Moreover, in vitro electrophysiological studies have determined that some orexin neurons are glucosensing and respond directly to extracellular glucose concentrations; that is, for some orexin neurons, glucose itself acts as a signaling agent, distinct from its role as a metabolic substrate, since some orexin neurons are inhibited by high glucose, as well as by elevated levels of nonmetabolic glucose analogues, such as 2DG (Burdakov and Gonzalez 2009, Burdakov and Lesage 2010, Gonzalez, Reimann, and Burdakov 2009). However, in vivo systemic 2DG also activates a large number of orexin neurons, presumably in response to glucoprivation. A role for orexin neurons as participants in control of glucose homeostasis would complement their role in coordinating states of arousal and activity and is an area of current research interest.
Of special interest for the present review is the interaction of orexin and CA neurons. Sites of orexin innervation in the brain and spinal cord are similar to those of the hindbrain CA neurons (Date et al. 1999, Nambu et al. 1999, Peyron et al. 1998). In addition, the C1 cell group contains E neurons that project to orexinergic areas of the hypothalamus (Bochorishvili et al. 2014, Card et al. 2006, Guyenet et al. 2013). Hypothalamically projecting C1 neurons identified by expression of the E biosynthetic enzyme, PNMT, forms synaptic connections with orexin cell bodies and dendrites, as shown by neuron-selective viral tracing, immunohistochemistry, and electron microscopy (Bochorishvili et al. 2014). In fact, the same study showed that a majority of PNMT-ir terminals in the hypothalamic area in which orexin neurons are concentrated originate from the C1 cell group and the majority form asymmetric (excitatory) synapses on orexin neurons. Thus, CA neurons are anatomically situated to communicate directly with orexin neurons and, based on studies of c-Fos expression, appear able to activate them.
Similarly, orexin neurons innervate sites containing CA neurons. Indeed, pivotal glucoregulatory CA cell populations and orexin neurons may be reciprocally innervated. Orexin fibers and receptors are expressed in close proximity to CA neurons in both the VLM and the NTS. In addition, injection of orexin into either the LV or 4V increases Fos expression in CA neurons.
Given the broad range of physiological functions associated with both orexin and CA neurons, two pertinent questions are (1) which of the sites they innervate control food intake and (2) are the responses elicited at these sites related to glucose counterregulation? CA terminals are particularly dense within the perifornical lateral hypothalamus (PeFLH), and this area is an exceptionally sensitive site for stimulation of feeding by NPY (Stanley et al. 1993, Stanley and Thomas 1993), which is coexpressed by nearly all C1 neurons with projections to the hypothalamus (Everitt et al. 1984, Sawchenko et al. 1985). Therefore, it is likely that some of the orexin neurons innervated by CA/NPY coexpressing neurons are involved in control of food intake.
As noted, LV and 4V injections of orexin A stimulate feeding. However, Zheng, Patterson, and Berthoud (2005), using a number of feeding paradigms, reported that injection of orexin-A into the NTS itself, an area concentrating rostrally projecting CA neurons and expressing orexin terminals and orexin receptors (AandB), did not increase food intake, although ventricular injections were effective. This puzzling dissociation of NTS and 4V effects requires further investigation. Nevertheless, orexin terminals are present in the A1/C1 area, and injection of orexin into that site stimulates feeding. Furthermore, injection of DSAP into the hypothalamus to lesion A1/C1 neurons eliminated the feeding response to both LV and 4V orexin administration (Figure 9.5), reduced 2DG-induced Fos expression in orexin neurons, and eliminated feeding induced by systemic 2DG, indicating that CA neurons are required for orexin-induced feeding. Perifornical lateral hypothalamic DSAP injections produced results that were similar to those reported previously after PVH DSAP injections, and not surprisingly, results of retrograde tracing experiments indicate that many CA neurons appear to project collaterally to innervate both PVH and PeFLH. An important role for CA neuron projections to orexin neurons has been supported by results of DREADD experiments in which hM3D(Gq) was selectively expressed in A1/C1 neurons of Th-Cre+ rats (Li et al. 2015b). The results showed that systemic CNO injections increased food intake and c-Fos expression in PVH neurons and in orexin neurons in the PeFLH, indicating that input from A1/C1 neurons mediates this activation. Neither LV, 4V, or A1/C1 injections of orexin in control rats nor A1/C1 injection of CNO altered blood glucose concentrations.
Figure 9.5
Food intake in response to 4V orexin and saline control in PVH DSAP- and SAP-injected rats in a 4-h test following 4V (a) or LV (b) injection of orexin-A (0.5 nmol in 3μl) or saline control. (From Li, A.J., Wang, W., Davis, H., Wang, (more...)
Taken together, these results suggest that CA-induced activation of orexin neurons may contribute to glucoprivic feeding. Due to their known roles in controlling arousal (Ohno and Sakurai 2008, Sakurai 2007), it is reasonable to speculate that they might contribute to glucoprivic feeding by increasing behavioral activation necessary for appetitive responses to glucose deficit. It also is conceivable that orexin neurons, which are reported as having unique glucoreceptive properties (Burdakov and Gonzalez 2009, Gonzalez, Reimann, and Burdakov 2009), provide input to engage CA neurons in glucoregulatory activity in the absence of glucoprivic crisis, for example, in anticipation of increased physical activity. In any case, there currently is not sufficient evidence to conclude whether or not orexin neurons are required for appetitive responses to glucose deficit.
9.6.3. Feeding Elicited by Various Glucose-Sensing Mechanisms Requires CA Neurons
A number of cellular glucose-sensing mechanisms capable of stimulating food intake have been identified in brain tissue. 2DG and 5TG are glucose analogues that inhibit glucose utilization in all cells. In addition to insulin-induced hypoglycemia, these are the most extensively used experimental tools for elicitation of CRRs, and their effects have been discussed extensively in this review. 2DG is an antimetabolic glucose analogue that inhibits glycolysis via its phosphorylated product, 2DG-6-phosphate, which competitively inhibits phosphohexose isomerase (Brown 1962, Parniak and Kalant 1985). 5TG most potently inhibits phosphoglucomutase and G6P dehydrogenase, but it also inhibits hexokinases, including GK (Chen and Whistler 1975). Although the mechanisms responsible for blockade of glucose utilization by 2DG and 5TG have been delineated by biochemical studies, the specific mechanisms through which these agents trigger CRRs are not fully understood.
Many studies examining glucose-sensing mechanisms in the brain have now shown that AMPK, which is phosphorylated (activated) in response to increased ADP/ATP ratio, is a cellular fuel sensor that also contributes to control of food intake, suggesting that it may also contribute to control of CRRs. For example, in brain sites involved in control of food intake, AMPK phosphorylation is increased by food deprivation and decreased by feeding (Hayes et al. 2009). Intraparenchymal NTS injections of Compound C, an AMPK inhibitor, reduce food intake and body weight (Hayes et al. 2009). Results have also been reported showing that intracerebroventricular administration of the AMPK inhibitor, Compound C, reduced feeding, glucagon, and corticosterone responses to systemic hypoglycemia and, in addition, that hypoglycemia induced AMPK activity in medial hypothalamic nuclei (Han et al. 2005).
AMPK phosphorylation is also increased by systemic glucoprivation in tissue sampled from the A1/C1 area, but not in an adjacent non-CA site in the ventromedial medulla and not significantly in A2 (Li, Wang, and Ritter 2011). Furthermore, phosphorylation of AMPK is not increased by glucoprivation in the A1/C1 area in rats in which the CA neurons had been eliminated by PVH injection of DSAP, suggesting localization of the AMPK to the CA neurons. Fourth ventricular injection of the AMPK activator, AICAR, increased food intake during the first 60 min of a 4-h test. Fourth ventricle injection of Compound C, which boosts cellular metabolism, attenuated 2DG-induced feeding during the first 2 hours of a 4-hour test (Li, Wang, and Ritter 2011). Therefore, AMPK may participate in glucose sensing that activates CA neurons and elicits CRRs. However, it is interesting that neither stimulation nor inhibition of AMPK altered blood glucose concentrations in these experiments, again suggesting that the blood glucose response and the feeding response are mediated by distinctly different biochemical mechanisms.
In additional experiments, antagonists of two proposed glucose-sensing mechanisms were injected into the LV and 4V (Li et al. 2014). Glucosamine was used to inhibit GK (Iynedjian 2009), phloridzin was used to inhibit SGLT (Ehrenkranz et al. 2005), and 5TG was used to inhibit glucose metabolism by inhibition of glycolysis (Chen and Whistler 1975). The ability of these agents to stimulate feeding and blood glucose in DSAP-treated and unconjugated SAP control rats was examined. As shown previously by other investigators, glucosamine (Zhou et al. 2011), phloridzin (Flynn and Grill 1985, Glick and Mayer 1968, Tsujii and Bray 1990) and 5TG (Ritter, Slusser, and Stone 1981) all evoked increased feeding when injected into either LV or 4V of controls. However, these responses were absent in rats that had received PVH DSAP injections (Figure 9.6), indicating that feeding induced by glucosamine and phloridzin requires hindbrain CA neurons (Li et al. 2014).
Figure 9.6
Food intake in response to 4V or LV injection of 0.6 mg glucosamine (a), 112.5μg phloridzin (b), and saline control in PVH DSAP- and SAP-injected rats. Both drugs were administered in a 3 μl volume. Food intake was measured in (more...)
Of the agents tested in the experiments discussed previously (AMPK, glucosamine, phloridzin, and 5TG), only 5TG elicited a blood glucose response (Li et al. 2014). GK and phloridzin were ineffective, even though they were injected into the same rats and into same sites at which 5TG was effective in robustly elevating blood glucose. The blood glucose response to 5TG was not impaired by PVH DSAP, even though the feeding response was abolished. As described previously, injections of DSAP at this hypothalamic site do not retrogradely lesion spinally projecting CA neurons that are critical for the adrenal medullary hyperglycemic response (Ritter, Bugarith, and Dinh 2001, Ritter et al. 2003). Together, these results suggest that AMPK, GK, and SGLT do not contribute to the activation of hindbrain CA neurons that mediate the hyperglycemic response to glucose deficit but may contribute to glucoprivic feeding. Whether they are expressed by CA neurons or are present in cells converging on them remains to be determined.
9.7. Challenges for Future Research
From this brief overview of glucose counterregulation, it is clear that significant progress is being made in this area but that major questions remain unanswered. Significant progress has been made in identifying potential mechanisms for cellular glucose-sensing, in characterizing the nature of stimuli that activate these mechanisms, and in defining the neuroanatomical localization of cell types that express them. The manner in which these sensing mechanisms interact at the cellular level also appears to be a rich area for future investigation. We can look forward to progress in determining the specific roles that these mechanisms play, locally and regionally, in maintaining glucose homeostasis.
Progress has also been made in identifying a pivotal central neural system comprised of hindbrain CA neurons and their projections that are required for elicitation of glucoregulatory responses to acute and profound glucose deficit. Progress has also been made in identifying a variety of glucose-sensing mechanisms that may contribute to the activation of this system and is beginning to identify functional interactions with forebrain NPY/AGRP and orexin neurons that refine and possibly expand their role in averting hypoglycemic conditions during predicted or ongoing changes in glucose requirements. Additional progress is anticipated in determining the mechanisms by which CA neurons are activated, specifically in determining whether these neurons are capable of responding directly to glucose, whether they depend upon converging inputs from other neurons, astrocytes, or tanycytes. A key requirement for progress in these areas is determination of which specific neurons, among the functionally diverse population of CA neurons, mediate CRRs.
Finally, progress has been made in the development of technical procedures that allow assessment of brain function under different pathological conditions in human and animal populations. Further research that will translate fundamental discoveries regarding brain glucose sensing to clinically beneficial treatments for complications of diabetes, obesity, and other conditions associated with impairment of glucose homeostasis, such as stroke, heart attack, and head injuries, is needed. However, our current appreciation of the variety of glucose-sensing mechanisms and the diversity of neural and nonneural systems involved in CRR caution that translational discoveries will be achieved only when we more fully appreciate the specific cellular mechanisms and brain circuits involved in the glucoregulatory responses extant during specific conditions.
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