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Endocrinology Vol. 147, No. 6 2664-2669
Copyright © 2006 by The Endocrine Society

Minireview: The Brain as a Molecular Target for Diabetic Therapy

Elena Prodi and Silvana Obici

Department of Psychiatry, Obesity Research Center, University of Cincinnati, College of Medicine, Cincinnati, Ohio 45237

Address all correspondence and requests for reprints to: Silvana Obici, M.D., University of Cincinnati, Genome Research Institute, ML0506, 2180 East Galbraith Road, Cincinnati, Ohio 45237. E-mail: silvana.obici{at}uc.edu.


   Abstract
Top
 Abstract
Introduction
 Hypothalamic Insulin Action and...
 Central Effects of Leptin...
 Hypothalamic Nutrient Sensing...
 Targeting the Brain for...
 Conclusions
 References
 
Recent evidence highlights the important role of the brain in the control of glucose homeostasis. Hypothalamic centers sense the availability of peripheral nutrients via redundant and overlapping nutrient-induced peripheral signals such as leptin and insulin and via direct metabolic signaling. Responding to nutrient availability, these hypothalamic regions in turn exert a negative feedback not only on food intake but also on endogenous glucose production. Disruptions in the mechanisms of central nervous system nutrient sensing alter these homeostatic responses and contribute to the pathophysiology of obesity and type 2 diabetes. In this review, we discuss the neural and molecular pathways so far identified as possible targets for therapeutic intervention.


   Introduction
Top
 Abstract
 Introduction
Hypothalamic Insulin Action and...
 Central Effects of Leptin...
 Hypothalamic Nutrient Sensing...
 Targeting the Brain for...
 Conclusions
 References
 
TYPE 2 DIABETES MELLITUS is a complex disease mainly characterized by impaired insulin action and insulin secretion (1, 2). Hyperglycemia is the results of multiple defects in insulin action and glucose sensing. The ability of insulin to stimulate glucose uptake in muscle and fat, suppress glucose production in liver and lipolysis in adipose tissue is impaired, whereas glucose fails to stimulate insulin secretion and suppress its own production in liver and uptake in muscle. Patients with type 2 diabetes (DM2) have fasting hyperglycemia, which is greatly determined by the magnitude of the increase in hepatic glucose production (3). This increase is largely accounted for by a marked enhancement in the rate of gluconeogenesis despite elevated insulin levels (4, 5, 6).

Insulin resistance is the common feature of both obesity and DM2 (7, 8). Indeed, epidemiological and experimental evidence suggests a close link in the pathogenesis of obesity and DM2 (8, 9). This association underscores the importance of identifying the basic mechanisms that couple energy balance with glucose homeostasis. In this regard, new evidence suggests that hypothalamic centers control both energy balance and glucose homeostasis (10). In this review, we will discuss recent experimental evidence that identifies neural pathways directly involved in the modulation of glucose homeostasis and partly overlap with neural pathways involved in the regulation of feeding behavior and energy balance.


   Hypothalamic Insulin Action and Glucose Homeostasis
Top
 Abstract
 Introduction
 Hypothalamic Insulin Action and...
Central Effects of Leptin...
 Hypothalamic Nutrient Sensing...
 Targeting the Brain for...
 Conclusions
 References
 
Insulin, after its nutrient-induced release from pancreatic ß-cells, rapidly lowers blood glucose by promoting glucose use and suppressing endogenous glucose production (EGP). The latter effect of insulin is mediated by both direct action on hepatocytes (11, 12) and via the activation of insulin signaling in extrahepatic tissues that in turn inhibit glucose production via neural and/or humoral mediators (13, 14, 15). The activation of the insulin receptors in the brain, in particular the arcuate nucleus (ARC) of the hypothalamus, plays an important role in the regulation of glucose homeostasis. The activation of insulin signaling in ARC, in the absence of elevated systemic insulin levels, is sufficient to decrease blood glucose levels via a substantial inhibition of EGP (15). Conversely, blockade of insulin action in the ARC by insulin antibodies, decreasing ARC insulin receptors by antisense oligonucleotides, or inhibiting insulin-dependent activation of phosphatidylinositol 3OH kinase (PI3K), leads to decreased ability of circulating insulin to suppress EGP (Fig. 1Go). Thus, the hypothalamic action of insulin is required for the full inhibitory effect of systemic insulin on EGP and requires an intact insulin signaling cascade involving the activation of the insulin receptor, insulin receptor substrate (IRS), and PI3K (15, 16). By contrast, insulin-dependent activation of hypothalamic MAPK does not have any effect on glucose homeostasis.


Figure 1
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  		FIG. 1. Insulin action in the hypothalamus leads to suppression of glucose output. Circulating insulin acutely suppresses glucose production via direct action on liver and, after its transport across the blood-brain barrier (BBB) via activation of neural circuits in the hypothalamic arcuate nucleus. Insulin-mediated activation of IRS and PI3K and KATP channels are required steps for the transmission of an efferent neural input to the liver. The hypothalaimc insulin signal is conveyed via a synaptic relay to the motor nucleus of the vagus in the brainstem (DMX) and reaches the liver via vagal efferent fibers.

 
How does the insulin modulate neural activity in ARC? And how is the signal relayed to the liver? In ARC, insulin can alter the release and biosynthesis of neuropeptides such as {alpha}-MSH, agouti-related peptide (AGRP), and neuropeptide Y (NPY) (17, 18). Additionally, insulin action in ARC activates ATP-sensitive potassium channels (KATP) channels (19). The activation of KATP channels in ARC is per se sufficient to lower blood glucose via inhibition of hepatic glucose output and gluconeogenesis (16). Delivery in ARC of glybenclamide, a KATP channel blocker, abolishes the central effects of insulin on EGP, and prevents in part the suppression of EGP by circulating insulin (15, 16). The sulfonylurea receptor subunit (SUR1) of the KATP channels is expressed in the mediobasal hypothalamus and is required for the assembly of the associated pore-forming subunits (Kir6x) (66). Interestingly, in SUR1 null mice insulin’s ability to suppress hepatic gluconeogenesis and EGP is impaired (16). Overall, these data support the notion that the central effects of insulin on the suppression of EGP are mediated by the activation of KATP channels in ARC. This input is relayed to the motor nucleus of the vagus nerve in the brainstem and leads to the activation of efferent vagal fibers innervating the liver (Fig. 1Go). Hepatic branch vagotomy leads to a loss of about 50% of the inhibitory effect on glucose production of circulating insulin. However, this effect is not blocked by selective vagal deafferentation, suggesting that only the efferent vagal fibers are required for the neural and insulin-mediated inhibition of glucose production (16).


   Central Effects of Leptin on Glucose Homeostasis
Top
 Abstract
 Introduction
 Hypothalamic Insulin Action and...
 Central Effects of Leptin...
Hypothalamic Nutrient Sensing...
 Targeting the Brain for...
 Conclusions
 References
 
Leptin action in ARC regulates food intake and energy expenditure (20, 21). Because obesity is tightly linked to insulin resistance, the marked improvement in insulin sensitivity after central administration of leptin could be ascribed to the adipostatic effects of leptin (22). However, numerous lines of evidence suggest that central leptin action, as well as insulin, regulates energy balance and glucose homeostasis via neural pathways that are only partially overlapping. The binding of leptin to its receptor (LepR) in ARC leads to the activation of the signaling cascade involving Janus kinase and signal transducer and activator of transcription 3 (Jak-STAT3) (23, 24). Also, recent findings suggest that leptin, like insulin, activates the IRS-PI3K pathway (25, 26). Adenoviral delivery of a functional LepR in ARC of LepR-deficient rats improves peripheral insulin sensitivity via a mechanism requiring activation of PI3K (27). Additionally, experiments disrupting selectively the LepR interaction with STAT3 suggest that leptin may improve glucose homeostasis via signaling pathways independent of STAT3 activation (28, 29). Because leptin action in ARC (Fig. 2Go) inhibits neurons coproducing the orectic peptides NPY/Agrp neurons, and activates neurons producing anorectic (melanocortins) peptides arising from the posttranslational processing of proopiomelanocortin neurons, it is likely that its effects on peripheral glucose metabolism could be mediated by these downstream neural pathways. Indeed, central administration of NPY decreases (30), and intraventricular administration of melanocortin agonists improves (31) peripheral insulin sensitivity independently of their effect on food intake. Interestingly, acute activation of hypothalamic melanocortin receptors, in the absence of changes in body composition, does not lead to improved peripheral insulin sensitivity but results in increased rate of hepatic gluconeogenesis and increased expression of the rate limiting gluconeogenic enzyme phosphoenolpyruvate carboxykinase (PEPCK) and glucose 6-phosphatase (Glc6Pase) (32). By contrast, acute intraventricular administration of leptin increases the rate of hepatic gluconeogenesis and the expression of PEPCK and Glc6Pase, without changing glucose production, due to a simultaneous and compensatory inhibition of hepatic glycogenolysis (32, 33). Intraventricular coadministration of leptin and a melanocortin antagonist, which prevents leptin-induced activation of melanocortin receptors, abolishes the leptin-induced increase in gluconeogenic fluxes, without affecting leptin’s ability to suppress glycogenolysis, and results in decreased hepatic glucose production. Thus, the acute effects of central leptin on glucose homeostasis are quite complex and involve both melanocortin-dependent and melanocortin-independent mechanisms (Fig. 2Go) (32). Although the neural circuits mediating leptin action on hepatic glucose fluxes are still unknown, the melanocortin-independent effects of central leptin closely resemble the effects of central insulin on hepatic glucose flux (16). Leptin and insulin both activate PI3K in hypothalamus, and this signaling pathway has been implicated in the regulation of both feeding behavior and glucose homeostasis (15, 26). Therefore, we could speculate that the potent effect of central leptin on the suppression of glucose production is mediated by the stimulation of melanocortin-independent pathways involving insulin-like pathways such as PI3K signaling cascade (Fig. 2Go).


Figure 2
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  		FIG. 2. Hypothalamic leptin action on hepatic glucose fluxes. Leptin, upon binding its receptor in the arcuate nucleus, activates two distinct signaling pathways: Jak/STAT and IRS/ PI3K. The activation of leptin in the arcuate nucleus leads to stimulation of proopiomelanocortin (POMC)-positive neurons and inhibition of NPY/Agrp-positive neurons. The acute central effects of leptin on hepatic glucose fluxes can be divided into those mediated by the activation of the melanocortin pathway, which causes increasing of hepatic gluconeogenesis, and those that are melanocortin independent that lead to a reduction of glycogenolysis. The neural and molecular pathways conveying hypothalamic leptin signaling to the liver are still under investigation. BBB, Blood-brain barrier.

 

   Hypothalamic Nutrient Sensing and Glucose Homeostasis
Top
 Abstract
 Introduction
 Hypothalamic Insulin Action and...
 Central Effects of Leptin...
 Hypothalamic Nutrient Sensing...
Targeting the Brain for...
 Conclusions
 References
 
Hypothalamic centers, in particular the ARC, sense the availability of peripheral nutrients indirectly via nutrient-induced peripheral signals, such as insulin and leptin, and/or directly via the activation of biochemical sensors of nutrient fluxes. As in all other cells, fuel-sensing mechanisms in neurons operate to control cellular energy needs. These neuronal biochemical sensors also play a special role in sensing the nutritional status of the body (34, 35). For example, the enzyme AMP-activated protein kinase (AMPK) is activated by increased levels of AMP, which result from the consumption of ATP. In arcuate, AMPK is inhibited by glucose, leptin, and insulin, and the anorectic effects of leptin require the inhibition of AMPK (36, 37). Although the role of hypothalamic AMPK activity in modulating glucose metabolism is not yet delineated, recent evidence supports the notion that specific neural circuits in ARC respond to increased availability of circulating nutrients by activating efferent pathways that lead to suppression of endogenous glucose production (38, 39, 40).

For example, central administration of macronutrients such as glucose or oleic acid decreases blood glucose and insulin levels (38, 39, 41). Moreover, elevations of plasma levels of both free fatty acids (FFAs) and glucose trigger neural activation in hypothalamic centers that activate efferent neural circuits that in turn suppress endogenous glucose production (Fig. 3Go). Like central insulin action, the central effect of circulating macronutrients on glucose production are mediated by the activation of KATP channels in arcuate (38, 40). Several lines of evidence indicate that lipid metabolism in neurons plays a pivotal role in mediating the hypothalamic responses to fuel availability. First of all, intraventricular administration of inhibitors of fatty acid synthase reduces food intake, NPY expression and decreases blood glucose (42). Second, hypothalamic inhibition of CPT-1, the mitochondrial enzyme that transfers long-chain fatty acyl-coenzyme A (LCFA-CoAs) into the mitochondria and controls the rate of fatty acid ß-oxidation, decreases food intake and suppresses endogenous glucose production (43). Inhibition of fatty acid oxidation in arcuate suppresses EGP via a neural pathway that requires the activation of KATP channels localized in the arcuate nucleus and efferent vagal fibers innervating the liver (39, 44). In cells, as well as neurons, cellular oxidation of long-chain fatty acyl-CoAs is regulated by the cellular levels of malonyl-CoA, a potent inhibitor of CPT-1 activity (45). Because this metabolite accumulates in greater extent when increased glucose fluxes accelerate the glycolytic rate, cellular levels of malonyl-CoA can act as a gauge of both lipids and carbohydrates availability (Fig. 3Go) (46). The acetyl-CoA generated from glycolysis is used for production of malonyl-CoA by the enzyme acetyl-CoA carboxylase (ACC), whose activity is inhibited by AMPK-dependent phosphorylation. Hence, the variation of the intracellular pool of LCFA-CoAs is under the control of several biochemical events including FFA and glucose flux and key metabolic enzymes such as ACC and AMPK (Fig. 3Go). Indeed, recent evidence underscores the pivotal role played by malonyl-CoA in the arcuate as major modulator of intracellular LCFA-CoAs levels (47, 48). Overexpression in arcuate of malonyl-CoA decarboxylase, an enzyme that converts malonyl-CoA to acetyl-CoA, leads to reduced accumulation of LCFA-CoAs, increased food intake, and increased EGP (48). These results support the notion that neuronal levels of malonyl-CoA act as neural sensor of fuel availability and regulators of energy balance and glucose homeostasis.


Figure 3
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  		FIG. 3. Model of neuronal integration of metabolic and endocrine signals involved in regulation of glucose production. The hypothalamic sensing of macronutrients integrates multiple hormonal and metabolic homeostatic signals. Both glucose and FFAs can influence the intracellular levels of LCFA-CoAs. Cellular oxidation of LCFA-CoAs is regulated by the levels of malonyl-CoA, a potent inhibitor of CPT-1 activity. Glucose increases the levels of malonyl-CoA through glycolysis, and increases LCFA-CoAs by inhibiting their transport into the mitochondria by CPT1. Circulating FFAs are converted to LCFA-CoAs by the enzyme acyl-CoA synthase (ACS). Leptin and insulin may also affect the levels of LCFA-CoAs via modulation of ACC and AMPK activity. The enzyme malonyl-CoA decarboxylase lowers the levels of malonyl-CoA and prevents the accumulation of LCFA-CoAs by derepressing CPT1 activity and increasing LCFA-CoAs oxidation.

 

   Targeting the Brain for Diabetic Therapy
Top
 Abstract
 Introduction
 Hypothalamic Insulin Action and...
 Central Effects of Leptin...
 Hypothalamic Nutrient Sensing...
 Targeting the Brain for...
Conclusions
 References
 
Overall, the evidence described above supports the notion that the brain restrains glucose output via the activation of selective neural pathways, in response to peripheral signals of nutrient availability such as lipid, carbohydrates, leptin, and insulin. It is also emerging that the ability of the brain to sense peripheral inputs and to reset metabolic homeostasis in the face of increased calorie intake is impaired. It follows that the disruption of the complex neural control over energy balance and glucose homeostasis could lead to glucose intolerance and hyperglycemia (Fig. 4Go). Indeed, obesity induced by increased calorie intake rapidly leads to impaired hypothalamic action of nutrients and hormonal signals (49, 50).


Figure 4
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  		FIG. 4. Model of neural control of glucose homeostasis. The brain senses circulating nutrients (glucose, fatty acids), hormones (insulin, leptin), and other signals from a variety of peripheral organs (adipose tissue, pancreas, gut) and controls glucose homeostasis by promoting glucose use and suppressing glucose production. In obesity and DM2, the brain fails to correctly perceive and respond to the peripheral signals of nutrient availability.

 
The corollary to these observations is that new therapeutic interventions could be devised to recover the brain sensitivity and response to nutrient-derived inputs. Indeed, many lines of evidence suggest that restoration of hypothalamic insulin or leptin action in the hypothalamus of obese and diabetic rats improves peripheral insulin sensitivity and blood glucose levels (29, 51, 52, 53, 54). Potential hypothalamic targets for the treatment of type 2 diabetes are negative or positive regulators of insulin and leptin action. Mice lacking protein tyrosine phosphatase 1B, a negative regulator of both insulin and leptin receptors (55), are hypersensitive to insulin and leptin and resistant to obesity (56, 57). Additionally, the activity c-Jun N-terminal kinase, a serine kinase involved in the phosphorylation and inactivation of IRS, is elevated in hypothalami of rats with diet-induced insulin resistance (58). Conversely, Src homology 2-B, a JAK2-interacting protein, has been implicated as natural enhancer of leptin action (59). Although these modulators of insulin/leptin action have not yet been directly implicated in hypothalamic control of glucose homeostatis, they are very logical central nervous system targets of diabetes therapy. For example, protein tyrosine phosphatase 1B inhibition in the whole body has proven to be effective in improving glucose homeostasis.

In addition to the neuroendocrine circuits discussed above, new hypothalamic pathways are emerging as modulators of peripheral glucose metabolism. Glucagon-like peptide-1 (GLP-1), secreted both in the gut and brain, and its receptor are an effective molecular target for the treatment of diabetes (60, 61). Recent evidence also links the brain GLP-1 receptor to the modulation of peripheral glucose homeostasis (62, 63). Thus, targeting GLP-1 action in the hypothalamus, could represent a novel therapeutic strategy for type 2 diabetes.


   Conclusions
Top
 Abstract
 Introduction
 Hypothalamic Insulin Action and...
 Central Effects of Leptin...
 Hypothalamic Nutrient Sensing...
 Targeting the Brain for...
 Conclusions
References
 
Targeting the brain for diabetic therapy is a particularly challenging problem because of the difficulty to deliver drugs within the brain and maintain therapeutic local levels. The presence of the central nervous system blood-brain barrier blocks the penetration of many compounds administered systemically. Additionally, some drugs (such as Diazoxide and CPT-1 inhibitors), that could be beneficial for the treatment of insulin resistance in the brain (16, 43), have adverse or deleterious effects due to their action on peripheral target tissues. Nonetheless, new therapeutic strategies are under active investigation to improve central delivery of drugs (64, 65).

Although much progress has been made in the understanding of the neural control of energy balance and glucose homeostasis, many questions remain unanswered. To improve our therapeutic tools for diabetes and insulin resistance, we need to better understand the intricate pattern of neuronal network involved in the regulation of glucose homeostasis.


   Footnotes
 
This work was supported by a grant from the National Institutes of Health (DK066058).

Apologies are extended to all those whose findings or opinions pertinent to this subject were not referenced or discussed due to limitations of space or inadvertent omission.

First Published Online March 23, 2006

Abbreviations: ACC, Acetyl-CoA carboxylase; Agrp, agouti-related peptide; AMPK, AMP-activated protein kinase; ARC, arcuate nucleus; DM2, type 2 diabetes; EGP, suppressing endogenous glucose production; FFA, free fatty acid; GLP-1, glucagon-like peptide-1; IRS, insulin receptor substrate; JAK, Janus kinase; KATP, ATP-sensitive potassium; LCFA-CoAs, long-chain fatty acyl-coenzyme A; LepR, leptin receptor; NPY, neuropeptide Y; PI3K, phosphatidylinositol 3OH kinase; STAT3, signal transducer and activator of transcription 3.

Received February 6, 2006.

Accepted for publication March 7, 2006.


   References
Top
 Abstract
 Introduction
 Hypothalamic Insulin Action and...
 Central Effects of Leptin...
 Hypothalamic Nutrient Sensing...
 Targeting the Brain for...
 Conclusions
 References
 

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