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Am J Physiol Endocrinol Metab 294: E810-E816, 2008. First published February 19, 2008; doi:10.1152/ajpendo.00685.2007
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Neurocircuits integrating hormone and nutrient signaling in control of glucose metabolism

Eva Rother, A. Christine Könner, and Jens C. Brüning

Institute for Genetics, Department of Mouse Genetics and Metabolism, Center of Molecular Medicine, Cologne (CMMC), and Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany

Submitted 25 October 2007 ; accepted in final form 7 February 2008

ABSTRACT

As obesity, diabetes, and associated comorbidities are on a constant rise, large efforts have been put into better understanding the cellular and molecular mechanisms by which nutrients and metabolic signals influence central and peripheral energy regulation. For decades, peripheral organs as a source and a target of such cues have been the focus of study. Their ability to integrate metabolic signals is essential for balanced energy and glucose metabolism. Only recently has the pivotal role of the central nervous system in the control of fuel partitioning been recognized. The rapidly expanding knowledge on the elucidation of molecular mechanisms and neuronal circuits involved is the focus of this review.

central nervous system; insulin; glucose metabolism

Peripheral and Central Control of Hepatic Glucose Production

THE REGULATION OF PLASMA GLUCOSE CONCENTRATION by the liver plays a decisive role in maintaining glucose homeostasis. In times of starvation, glycogenolysis and hepatic de novo synthesis of glucose from precursors such as lactate, gluconeogenic amino acids, and glycerol provide the organism with glucose. On the other hand, when food and, consequently, glucose are available, hepatic glucose production (HGP) needs to be suppressed. Hormones and nutrients directly regulate these processes.

The pancreatic hormone insulin controls HGP through regulation of both glycogen metabolism and gluconeogenesis. By binding to its receptor on the hepatocyte plasma membrane, insulin activates the phosphatidylinositol 3-kinase (PI3K) pathway, which mediates insulin-induced suppression of gluconeogenic gene expression (53, 58) (Fig. 1). For decades, the search for insulin-regulated transcription factors occupied the field. Only recently, the critical role of forkhead transcription factor-1 (FOXO-1) and transcriptional coactivator PPAR-{gamma} coactivator-1{alpha} (PGC-1{alpha}) have been identified as insulin's main mediators in gene expression regulation controlling gluconeogenesis. Phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G-6-Pase) are the limiting enzymes in this process, and their promoters contain FOXO-1 binding sites (29, 72). Activation of Akt, a key protein kinase downstream of the insulin-PI3K pathway, negatively regulates FOXO-1 by promoting its export from the nucleus upon phosphorylation, thus reducing PEPCK and G-6-Pase expression (9) (Fig. 1). Moreover, PGC-1{alpha} has been identified as an important coactivator of FOXO-1 (69). Its expression is induced upon fasting and other states of insulin deficiency (89). Contrariwise, upon insulin stimulation, Akt-mediated phosphorylation abrogates PGC-1{alpha}'s association with FOXO-1, and gluconeogenic gene expression is reduced (69) (Fig. 1). Only recently, signal transducer and activator of transcription-3 (STAT3) was identified as another important regulator of hepatic gluconeogenic gene expression. Mice lacking STAT3 specifically in the liver display insulin resistance associated with an increase in glucose production and the expression of gluconeogenic genes in the liver (35) (Fig. 1), which complements the picture of transcriptional regulation of HGP, although the upstream regulatory signals controlling hepatic STAT3 activation remain largely unclear.


Figure 1
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  		Fig. 1. Model of central regulation of hepatic glucose production. Insulin-mediated activation of the phosphatidylinositol 3-kinase (PI3K) pathway in hypothalamic agouti-related peptide (AgRP) neurons leads to hyperpolarization and reduced firing in these neurons. The resulting modulation in neuropeptide release regulates innervation of liver, leading to increased hepatic IL-6 expression, which consequently suppresses gluconeogenic gene expression in the liver, thereby potentiating insulin's direct suppressing effect on hepatic gluconeogenic gene expression via activation of PI3K signaling and subsequent export of forkhead transcription factor-1 (FOXO-1) from the nucleus.

 
Expanding the model of insulin's direct hepatic effects, Prager et al. (68) demonstrated that suppression of HGP in obese, nondiabetic humans could also occur after peripheral insulin infusion, even when portal vein insulin concentrations remained unchanged. This finding suggested that insulin is also able to suppress HGP through indirect extrahepatic actions, a notion that was further supported by subsequent work in dogs (3, 77, 78). In 2002, Obici et al. (62) defined the hypothalamus as one important extrahepatic site of insulin action to regulate HGP. They demonstrated that hypothalamic insulin signaling is required for insulin's ability to suppress HGP in euglycemic hyperinsulinemic clamps of rats, a finding that was also described in mice (34, 61). Furthermore, suppression of HGP and regulation of peripheral insulin sensitivity were demonstrated to depend on insulin-stimulated activation of hypothalamic IRS-PI3K-Akt signaling (25, 62, 64) (Fig. 1).

In addition to insulin, the adipocyte-derived hormone leptin has been strongly implicated in the central regulation of glucose metabolism. Morton et al. (59) revealed that rats lacking a functional leptin receptor presented with improved peripheral insulin sensitivity and glucose response following both 1) reconstituted expression of the leptin receptor and 2) introduction of a constitutively active mutant of Akt in the arcuate nucleus (ARC) by adenoviral gene therapy. Interestingly, this effect was not dependent on food intake and body weight (59).

In conclusion, these results narrow down the mediobasal hypothalamus as a critical region for regulation of peripheral glucose metabolism targeted by both insulin and leptin and controlled by the PI3K signaling pathway. However, extrahypothalamic hormone- and nutrient-sensing neurons have also been under investigation lately, yet their contribution to metabolic regulation remains to be defined (2, 4).

Identification of Neuronal Circuits in Control of HGP

Besides analyzing molecular targets and pathways, another key question is the nature of the neurocircuitry in control of peripheral metabolism. Among the potential candidates for mediating insulin's central effects on peripheral glucose metabolism are the well-investigated agouti-related peptide (AgRP)/neuropeptide Y (NPY)- and proopiomelanocortin (POMC)-expressing neurons of the mediobasal hypothalamus. Both cell types express insulin and leptin receptors and are targeted by the respective hormones (10, 74, 86). Toxin-mediated ablation of these cells has recently demonstrated that they play a pivotal role in the acute regulation of feeding in adult mammals (27, 49), and the significant contribution of their integratory functions to the control of energy homeostasis has been demonstrated by multiple complementary approaches (16, 23, 36, 45, 66, 80, 81). Moreover, lack of leptin receptor signaling or inactivation of STAT3 specifically in POMC neurons has been shown to result in obesity and other elements of the metabolic syndrome in rodents (6, 88).

Leptin and insulin have been shown to activate PI3K in both cell types, yet there is evidence that leptin differentially regulates PI3K activity in POMC and AgRP/NPY neurons (87). However, both hormones act in parallel to increase POMC mRNA levels and decrease NPY and AgRP mRNA levels, respectively (40, 75, 79). This downregulation of hypothalamic NPY by insulin was subsequently shown to be a prerequisite for suppression of HGP, as continous intracerebroventricular infusion of NPY impaired insulin's ability to suppress HGP in euglycemic hyperinsulinemic clamps in mice (84). Along this line, Könner et al. (42) revealed the pivotal role of insulin's action on AgRP neurons by selective inactivation of the insulin receptor (IR) in AgRP-expressing neurons in mice (42). In these animals, insulin failed to efficiently suppress HGP in euglycemic hyperinsulinemic clamps. Inoue et al. (34) had demonstrated that hepatic IL-6-STAT3 signaling is essential for insulin's central action suppressing HGP by STAT3-mediated reduced expression of gluconeogenic genes in the liver (35). Interestingly, animals with AgRP neuron-specific IR knockout exhibited reduced insulin-stimulated hepatic IL-6 expression and increased hepatic expression of G-6-Pase, defining a key role for AgRP neurons in the neurocircuit regulating hepatic IL-6 action (42) (Fig. 1). Further work clearly has to define the exact nature of other components of the neurocircuitry controlling hepatic metabolism.

Modulation of Neuronal Electrical Properties Mediate the Integration of Metabolic Signals

The classical effector mechanisms, such as regulation of gene transcription or protein synthesis, elicited by nutrient and hormonal signals in ARC neurons have often been discussed and reviewed. Over the past few years, however, the assumption that modulation of the electrical properties of hypothalamic AgRP/NPY and POMC neurons results in significant regulatory output on energy metabolism has gained rising attention. There are a growing number of studies addressing the modulatory effect of various metabolic signals on membrane characteristics, ion channel activity, and firing pattern of (identified) hypothalamic neurons.

Leptin was among the first hormonal signals shown to influence electrical properties of ARC neurons (18). Various independent groups demonstrated that bath application of leptin to living brain slices of mice depolarizes and increases the firing rate of identified POMC neurons and, at the same time, inhibits the tone of NPY/AgRP neurons (14, 17, 18). In contrast, insulin has lately been shown to cause hyperpolarization and a reduction in firing rate in both POMC- and NPY/AgRP-expressing neurons (14, 42, 65). Thus, leptin and insulin act in parallel to regulate transcription and electrical activity in AgRP/NPY neurons. However, in POMC neurons, they seem to have opposing effects on transcriptional and electrical regulation of the cell (Fig. 2).


Figure 2
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  		Fig. 2. Modulation of electrical properties of hypothalamic proopiomelanocortin (POMC) neurons in control of glucose and energy homeostasis. Various hormonal and nutrient-related signals regulate the electrical properties of hypothalamic POMC cells. Insulin-mediated activation of PI3K results in generation of phosphatidylinositol 3,4,5-trisphosphate (PIP3). PIP3 activates ATP-sensitive potassium (KATP) channels, leading to hyperpolarization and reduced firing. Contrariwise, KATP channels are inhibited by increased ATP levels following a rise in intracellular glucose concentration. AMP-activated protein kinase (AMPK) and uncoupling protein-2 (UCP2) contribute to the regulation of KATP channel activity in POMC neurons by altering intracellular ATP levels. Furthermore, leptin causes depolarization and increased firing in POMC neurons, most likely via the modulation of nonspecific cation channels.

 
In 2004, Roseberry et al. (71) showed that NPY inhibits action potential firing in ARC POMC-expressing cells. This dose-dependent suppression of firing frequency was reproduced by Ghamari-Langroudi et al. (26). The same study addressed the role of gut hormone PYY3-36 in the regulation of the electrical activity of POMC neurons. The authors demonstrated that PYY3-36 significantly and reversibly caused hyperpolarization and decreased spontaneous firing frequency of identified POMC neurons (26). Subsequent work by other groups supported this finding, whereas initially increased action potential firing of POMC neurons after bath application of PYY3-36 was reported (7).

Last but not least, the orexigenic signalers ghrelin and orexin have been demonstrated to induce burst firing by modulation of transient outwardly rectifying potassium conductance in AgRP/NPY neurons of rats (85). Orexin-containing nerve terminals are found on and around ARC POMC neurons (28, 60), which have recently been shown to reduce their electrical activity upon orexin application (50). The release of orexin is highest during active, awake periods (41). In addition to their anabolic effects, orexins are critical for sustaining normal wakefulness in mammals (13). Thus, electrical inhibition of POMC neurons by orexin helps to ensure that food seeking coincides with periods when the animal is most alert and active. Conversely, during periods of rest and sleep, the reduced release of orexin (41) may enhance the firing of POMC neurons, suppressing hunger to facilitate the induction and maintenance of sleep.

In conclusion, the modulation of electrical properties of ARC-feeding neurons by hormonal signals resembles the overall picture arising from the analysis of their transcriptional regulation and the functional consequences. Nevertheless, there are some concerns that arise when one addresses comparability of electrophysiological cell characteristics. In the majority of the above-mentioned studies, hormonal neuromodulation has been analyzed using whole cell recordings with varying, partly unphysiological, concentrations of ions and glucose. Moreover, comparability between studies is complicated by further differences in, e.g., feeding status of the euthanized animal, manner of brain slice preparation, temperature of the applied substances, etc. Thus, standardized and well-defined experimental conditions will be essential to improve direct comparability of these important studies.

KATP Channels as Integrators of Hormonal and Nutrient Signals

Besides the regulation of ARC neurons by hormones such as insulin and leptin, direct nutrient sensing of AgRP/NPY and POMC neurons appears to play an important role in control of energy and glucose homeostasis. Among the nutrient signals that can be sensed by ARC neurons, glucose has gained considerable notice. Specialized neurons, including POMC neurons, respond to elevated exposure to glucose by altering their firing rate (38, 46–48). These "glucose-responsive" (GR) neurons increase their firing rate as extracellular glucose levels rise (20, 46, 48). The presence of ATP-sensitive potassium (KATP) channels is at the core of the capacity of these neurons to alter their membrane potential in response to changes in glucose (46, 48).

KATP channels are heterooctameric proteins composed of inwardly rectifying K+ channel subunits (KIR6.1 or KIR6.2) and regulatory sulfonylurea receptor (SUR) subunits (32, 33). They are present in various tissues, including pancreatic β-cells, heart, skeletal muscle, and brain (5). KATP channel function depends on the expressing cell type: in pancreatic β-cells, increased ATP concentration as a consequence of increased glucose metabolism closes the KATP channels, depolarizing the plasma membrane, leading to opening of voltage-dependent calcium channels, which allows calcium influx. The rise in intracellular calcium concentration, in turn, triggers exocytosis of insulin-containing granules. KATP channel-closing sulfonylureas such as glibenclamide pharmacologically stimulate insulin release and are therefore widely used in the treatment of type 2 diabetes (5). In the cardiovascular system, KATP channels participate in ischemic preconditioning (IPC) (82) and the regulation of the vascular tonus (55), whereas in skeletal muscle KATP channel function is essential for the regulation of glucose uptake (56).

In the brain, KATP channels with different properties are found in various cell types: glial cells (90) and dorsal vagal (83), hippocampal (24), and hypothalamic neurons, including POMC and NPY/AgRP neurons of the ARC (19, 31). Interestingly, hyperglycemia per se has been shown to alter expression of KATP channels and thereby induces changes in the excitability of certain ARC neurons (1).

Modulation of KATP channel activity is achieved by different intracellular mechanisms. Channels containing KIR6.2, as present in the ARC, are closed by ATP binding to KIR6.2 and opened by MgADP binding to SUR (Fig. 2). In parallel to the well-described β-cell mechanism, rise of neuronal intracellular glucose levels increases the ATP/ADP ratio, resulting in closure of KATP channels. Consecutive depolarization supposedly leads to liberation of the respective neurotransmitters that can now exert their effects on second-order neurons.

A second mechanism regulating intracellular ATP levels and, hence, KATP channel activity has recently been discussed. Hypothalamic AMP-activated protein kinase (AMPK) activates catabolic pathways that generate ATP and switch off ATP-consuming processes through acute phosphorylation of metabolic enzymes and long-term alterations in gene expression (37) (Fig. 2). Contrariwise, AMPK is allosterically activated by intracellular AMP levels, which increase under conditions of cellular stress or energy deficiency, such as hypoxia, ischemia, and glucose deprivation (30, 37). Therefore, AMPK has been suggested as an important glucose sensor. It was shown in cell lines and ex vivo hypothalamic tissue that AMPK activity is stimulated by low glucose levels and that direct AMPK activation upregulates orexigenic AgRP expression (44). That study also demonstrated that small changes in hypothalamic glucose levels in the physiological range of 1–5 mM altered cellular ATP levels sufficiently to induce AMPK activation and gene expression. Another study suggested a potential role for ventromedial hypothalamic AMPK in the counterregulatory response to insulin-induced hypoglycaemia in vivo by stimulation of HGP via a nonhormonal signaling mechanism (52). Together, these studies raise the possibility that hypothalamic GR neurons, which have been shown to respond to small alterations in glucose levels and change their firing rate, may utilize the AMPK system in this signaling pathway; however, the precise neuronal populations and cellular mechanisms involved are largely unclear. Moreover, the effects of long-term manipulation of hypothalamic AMPK on energy balance were also unknown. To directly address these issues, Claret et al. (15) very recently generated mice lacking AMPK{alpha}2 in POMC (POMC{alpha}2KO) and AgRP/NPY cells (AgRP{alpha}2KO). POMC{alpha}2KO mice developed obesity due to reduced energy expenditure and dysregulated food intake but remained sensitive to leptin. In contrast, AgRP{alpha}2KO mice developed an age-dependent lean phenotype with increased sensitivity to a melanocortin agonist. Electrophysiological studies in AMPK{alpha}2-deficient POMC or AgRP neurons revealed normal leptin or insulin action but absent responses to withdrawal of extracellular glucose (15). This result was interpreted as evidence for differential mechanisms for glucose-sensing and leptin/insulin-stimulated pathways in hypothalamic neurons (15). Taken together, the authors suggest that, although AMPK plays a key role in hypothalamic function, it does not act as a general sensor and integrator of energy homeostasis in the mediobasal hypothalamus (15). This assumption is further supported by another study showing that adiponectin stimulates AMPK in the hypothalamus, leading to increased food intake and reduced energy expenditure (15). However, functional analysis of the exact mechanisms by which AMPK exerts its effects on energy metabolism and whether regulation of KATP channels might be involved is still required.

Moreover, a recent study addressed the mechanism for obesity-induced loss of glucose sensing in POMC neurons by examining the role of hypothalamic uncoupling protein-2 (UCP2) (63). UCP2 mediates proton leak across the inner mitochondrial membrane, decreasing the yield of ATP from glucose metabolism (21, 43, 91) (Fig. 2). Thus, UCP2 is hypothesized to be another potential regulator of ATP and, thus, KATP channel regulation in GR neurons. Parton et al. (63) showed that depletion of UCP2 prevented obesity-induced loss of POMC glucose sensing, whereas pharmacological activation of UCP2 in POMC neurons promoted high-fat diet-induced loss of glucose sensing in POMC neurons. These results suggest a pathogenic role for UCP2 action in POMC neurons in the development of type 2 diabetes, potentially involving KATP channel dysregulation.

KATP channel modulators, which have been extensively studied, range from synthetic compounds, such as the channel-blocking sulfonylureas used in the therapy of diabetes and the KATP channel openers (e.g., diazoxide), which act by binding SUR to membrane phospholipids, such as phosphatidylinositol 4,5-bisphosphate (PIP2), phosphatidylinositol 3,4,5-trisphosphate (PIP3), and long-chain acyl-CoA-esters, such as oleoyl-CoA, that are also known to bind to KIR6.2 and alter ATP sensitivity of the channels (73, 76). Since activation of the PI3K signaling pathway in hypothalamic neurons provides a potential point of convergence for multiple hormones regulating energy homeostasis including leptin, insulin (39), NPY, and PYY (11), the role of PIP3 in the modulation of KATP channel activity is of special interest. PIP3 modulates KATP channel activity via different mechanisms: 1) PIP3 increases the probability that KATP channels are open, which indirectly lowers the ability of ATP to inhibit the channels; 2) PIP3 directly decreases ATP binding to the channel (8, 51, 76); and 3) PIP3 can modulate KATP channel activity by degradation of local actin filaments around KATP channels (57) (Fig. 2). The proteins that control and induce actin cytoskeletal degradation after PIP3 accumulation have not yet been identified, although Rho or Rac GTPases are likely candidates (70).

Recent studies have addressed PIP3-mediated KATP channel modulation in hypothalamic neurons with regard to energy and glucose metabolism. Constitutive activation of PIP3 formation in POMC cells by conditional ablation of the phospholipid phosphatase and tensin homolog (PTEN) resulted in augmented PIP3-dependent KATP channel activation and consecutive electrical silencing of POMC neurons, leading to hyperphagia, diet-sensitive obesity, and leptin resistance in mice (65). Additionally, Parton et al. (63) recently showed that mimicking part of this KATP channel phenotype by introducing constitutively open KATP channels selectively in POMC neurons resulted in impaired whole body response to a systemic glucose load albeit with no obvious effect on body weight. Moreover, KATP channels were shown to be required for the central regulation of neuroglycopenia-induced glucagon secretion (22, 54), a mechanism that seems to involve the regulation of GABA release in the ventromedial hypothalamus (12).

Furthermore, central administration of KATP channel-inhibiting sulfonylurea abolishes insulin's central effect on HGP (62). Pocai et al. (67) detected decreased G-6-Pase and PEPCK expression levels in the liver as a result of insulin's action on hypothalamic KATP channels, also suggesting a possible mechanism for hypothalamic, KATP channel-mediated control of HGP. This was further substantiated by the finding that insulin signaling in KATP channel-expressing AgRP neurons is essential for effective suppression of HGP (42). Thus, modulation of KATP channel activity plays a pivotal role in the regulation of energy and glucose homeostasis by hypothalamic neurons.

Broadening our knowledge of such integrative homeostatic functions of the brain is pivotal for a better understanding of the pathomechanisms responsible for the growing obesity epidemic. The use of refined techniques to characterize the complex interactions of neuronal circuits and the further characterization of integrative signaling components such as KATP channels in the regulation of energy and glucose metabolism may ultimately allow for the development of novel therapeutic approaches for the treatment of type 2 diabetes mellitus and obesity.

GRANTS

This work was supported by grants from the Köln Fortune Program (94/2005 to A. C. Könner), the Bundesministerium für Bildung und Forschung (ZMMK, TV-2 to J. C. Brüning), the European Union (LSHM-CT-2003-503041 to J. C. Brüning), the Thyssen-Stiftung (10.04.1.153 to J. C. Brüning), and the Deutsche Forschungsgemeinschaft (BR1492-7 to J. C. Brüning).

ACKNOWLEDGMENTS

We thank Gisela Schmall for excellent secretarial assistance.

FOOTNOTES


Address for reprint requests and other correspondence: J. C. Brüning, Institute for Genetics, Dept. of Mouse Genetics and Metabolism, and Center of Molecular Medicine Cologne (CMMC), Zülpicher Straße 47, 50674 Cologne, Germany (e-mail: jens.bruening{at}uni-koeln.de)

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

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