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Minireview: Nutrient Sensing and the Regulation of Insulin Action and Energy Balance

Albert Einstein College of Medicine, Diabetes Research and Training Center, Bronx, New York 10461

Address all correspondence and requests for reprints to: Luciano Rossetti, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Belfer 701, Bronx, New York 10461. E-mail: lrossetti{at}aecom.yu.edu.

	Abstract

Top Abstract Introduction Cellular Sensor of Nutrient... HBP and Modulation of... HBP and Regulation of... Conclusions References

 
Obesity is the result of an imbalance between energy intake and energy expenditure. Under most circumstances, the increased availability of nutrients is tightly coupled with nutrient-sensing mechanisms that in turn activate appropriate behavioral and metabolic responses. The latter responses include decreases in food intake and the production of endogenous nutrients and increased expenditure of energy. The availability of nutrients can be sensed at central sites (mostly in the hypothalamus) or directly in peripheral tissues such as skeletal muscle and fat. The hypothalamus links the sensing of nutrients to the control of metabolism and feeding behavior. Here, we discuss how two central and peripheral nutrient-sensing mechanisms participate in this complex feedback system.

	Introduction

Top Abstract Introduction Cellular Sensor of Nutrient... HBP and Modulation of... HBP and Regulation of... Conclusions References

 
THE INCREASED PREVALENCE of obesity and type 2 diabetes in affluent societies is largely linked to excessive caloric intake and decreased physical activity (1, 2). Insulin resistance is regarded as a cardinal feature of the metabolic defects associated with weight gain, and it is postulated to develop as an adaptation to increased nutrients’ availability. Energy balance and metabolic homeostasis are maintained by complex regulatory systems. In this regard, changes in nutrient availability and body weight induce adaptive responses in feeding behavior and in metabolic processes that are designed to preserve each individual’s set point. Thus, increased food intake tends to promote weight gain and insulin resistance. However, the body normally senses changes in energy balance and activates appropriate responses, which include decreased food intake, increased energy expenditure, and regulation of substrate oxidation and intermediate metabolism. The latter biological responses are effective in maintaining a relatively stable body weight during the adult life of most individuals.

However, according to Neel’s (3) hypothesis of thrifty genotype, the ability to efficiently store energy during periods of sporadic feast represented a survival advantage in ancestral societies subjected to periods of starvation. This hypothesis postulates the existence of multiple cellular mechanisms that sense the increased availability of food and trigger biological responses designed to paradoxically increase the efficiency of energy storage. These hypothetical thrifty biochemical pathways may act in part via negative modulation of the adaptive responses to nutrient excess (4).

In this review, we will discuss the role of peripheral and central nutrient-sensing pathways in modulating insulin action and energy balance. The experimental evidence discussed below supports the model outlined in Fig. 1A, i.e. nutrient excess activates biochemical pathways that initiate cellular responses designed to limit the oxidation of excess energy (insulin resistance) and favor weight gain. Simultaneously, the activation of the same pathways either directly or indirectly (by increasing the expression and release of counterregulatory hormones such as leptin and insulin) induces hypothalamic efferent signals that attempt to limit further intake of energy and favor dissipation of excess energy via thermogenesis. We will focus on two nutrient-sensing pathways, the hexosamine biosynthesis pathway (HBP) and the malonyl coenzyme A (CoA)/long-chain fatty acid (LCFA)-CoA fuel sensing pathway, and on the apparently opposite effects they have in peripheral tissues and within the central nervous system.

View larger version (37K): [in this window] [in a new window]   FIG. 1. A, Proposed role of nutrient sensing in modulating insulin action and energy balance. A prolonged period of nutrient excess activates nutrient-sensing pathways that in turn lead to weight gain and insulin resistance. Simultaneously, nutrient-sensing pathways stimulate secretion and biosynthesis, respectively, of insulin and leptin, which in turn elicit biological counterregulatory responses to weight gain and insulin resistance. This negative feedback of insulin and leptin is mainly mediated by their hypothalamic receptors. Additionally, the hypothalamus can directly sense nutrient availability and trigger neuronal counterregulatory responses to weight gain and insulin resistance. B, Convergence of different nutrient fluxes into the HBP. In muscle cells, after transport into cells and phosphorylation to glucose-6-phosphate (Glc-6P), glucose is primarily used for glycogen synthesis and glycolysis. Only 1–3% of the intracellular Glc-6P enters the hexosamine pathways via conversion of Fru-6-P into GlcN-6-P, reaction catalyzed by the rate-limiting enzyme GFAT. GlcN can enter cells via the glucose transport system and be phosphorylated to GlcN-6-P. Uridine as well can increase the fluxes through HBP by increasing the intracellular UDP/UTP pool. Also, increased fatty acid oxidation can inhibit glycolysis at the level of the enzymes phosphofructokinase and pyruvate dehydrogenase and generate accumulation of Fru-6-P, which will ultimately overflow into HBP. The intracellular levels of UDP-GlcNAc, the major end-product of HBP, reflect the rates of cellular nutrient fluxes. UDP-GlcNAc moieties are used for glycosylation. C, Consequences of increased carbon fluxes into the nutrient-sensing HBP on insulin action and oxidative phosphorylation of skeletal muscle. Persistent glucose oxidation increases carbon fluxes through HBP and intracellular levels of O-GlcNAc. Intracellular glycosylation of specific targets of the insulin signal cascade will lead to down-regulation of glucose transport and glycogenolysis. Additionally, glycosylation of transcriptional factors may affect insulin action and fuel oxidation. In particular, O-GlcNAc modification of transcription factors involved in the regulation of OXPHOS genes, such as Sp1, PGC-1, and NRF1, may ultimately cause a decline in mitochondrial function and oxidative phosphorylation. Direct modulation of Sp1 function by O-GlcNAc modification has been reported (solid arrows), although the direct interaction of HBP with PGC-1 and NRF1 is still speculative (broken arrows). By contrast, HBP activates the expression of the leptin gene in adipose and other tissues. Leptin counteracts the suppressive effects of HBP on OXPHOS by inducing mitochondrial proliferation, increasing OXPHOS gene expression, and uncoupling proteins. Hyperglycemia-induced formation of mitochondrial reactive oxygen species (ROS) induces a partial block of glycolysis at the level of the enzyme glyceraldehyde-3-phosphate dehydroxygenase. This block will further activate HBP by substrate overflow and enhance the effects of HBP on oxidative phosphorylation.

	Cellular Sensor of Nutrient Abundance

Top Abstract Introduction Cellular Sensor of Nutrient... HBP and Modulation of... HBP and Regulation of... Conclusions References

 
All cells adapt their metabolism alike, according to changes in the availability of nutrients. To sense nutrient availability, cells must possess biochemical sensors that detect nutrient levels and initiate adaptive responses. McGarry et al. (5) first identified malonyl-CoA as a biochemical sensor implicated in the switch from fatty acid to glucose oxidation. Malonyl-CoA is a potent allosteric inhibitor of carnitine palmitoyltransferase (CPT)1 (6). This enzyme controls the entry of LCFA-CoA into the mitochondria and is the initial and rate-limiting step for the oxidation of fatty acids. Therefore, malonyl-CoA levels represent a fuel sensor that may switch substrate oxidation from fatty acids to glucose [for extensive review, see Ruderman et al. in this issue (Ref. 6A )]. In the presence of high concentrations of glucose and insulin, the accumulation of malonyl-CoA inhibits CPT1 and reduces lipid oxidation, favoring lipid storage into triglycerides.

Another biochemical mechanism of nutrient sensing is the HBP that becomes activated by increased glucose fluxes (Fig. 1B). After transport and phosphorylation of glucose to glucose-6-phosphate, the latter is primarily used in the synthesis of glycogen and in glycolysis. A small fraction of the incoming glucose (1–3%), after the conversion to fructose-6-phosphate (Fru-6-P), enters the HBP. The enzyme glutamine:Fru-6-P aminotransferase (GFAT) catalyzes the first committed step of HBP and regulates the flux through this pathway (7, 8, 9).

The final step in HBP is the formation of uridine diphosphate (UDP)-N-acetylglucosamine (GlcNAc), which not only is a main substrate for protein glycosylation, but whose intracellular levels are nutritionally regulated (10, 11, 12, 13). Many cytoplasmic and nuclear proteins are glycosylated on their serine and/or threonine residues by the addition of a single molecule of O-linked-ß-N-acetylglucosamine (O-GlcNAc) (14, 15). Enzymes responsible for the addition (O-GlcNAc transferase) and removal (O-GlcNAcase) of O-GlcNAc have been cloned and characterized (16, 17, 18). This posttranslational modification of enzymes, transporters, or transcriptional factors may modulate in a nutrient-dependent fashion the activity or stability of proteins (19, 20).

Although the major carbon source for the activation of HBP is glucose, other fuels have been implicated (21). Free fatty acids can inhibit the entry of Fru-6-P into the glycolytic pathway, thereby causing a shunt of Fru-6-P toward the formation of glucosamine (GlcN)-6-P (22). Short-term voluntary overfeeding induced with a high-fat diet is also associated with increased fluxes through HBP and elevated levels of skeletal muscle UDP-GlcNAc (13, 21). Conversely, calorie restriction results in decreased levels of UDP-GlcNAc (12). These observations suggest that HBP could not only sense high concentration of glucose-derived fuels but also function as a general sensor of nutrient availability.

	HBP and Modulation of Insulin Action

Top Abstract Introduction Cellular Sensor of Nutrient... HBP and Modulation of... HBP and Regulation of... Conclusions References

 
Early studies have shown that activation of HBP plays an important role in the modulation of insulin action in adipose tissue and skeletal muscle. Marshall et al. (7) first discovered that glucose induces desensitization of the insulin-dependent glucose uptake in adipose cells via the activation of HBP and suggested that this fuel-sensing mechanism is a signal of cellular satiety.

GlcN reproduces insulin resistance of hyperglycemia in both in vitro (7, 8) and in vivo (9) studies. Most important, glucose-induced insulin resistance is blunted by inhibition of GFAT activity and expression (23), suggesting that the deleterious effects of hyperglycemia are mediated by activation of HBP. The link between insulin resistance and HBP has been validated in transgenic models in which the overexpression of GFAT in muscle and fat leads to peripheral insulin resistance (24, 25). HBP induces insulin resistance by inhibiting multiple sites of insulin-signaling cascade. Several groups have shown that insulin-dependent glucose uptake, as well as glycogen synthesis, are down-regulated by HBP activation (Fig. 1C) (26, 27).

	HBP and Regulation of Energy Balance

Top Abstract Introduction Cellular Sensor of Nutrient... HBP and Modulation of... HBP and Regulation of... Conclusions References

 
A prominent role of HBP in the regulation of energy balance is suggested by its role in inducing leptin expression (21). Transgenic mice overexpressing GFAT in adipose and muscle tissues, have increased levels of plasma leptin (28). Activation of the HBP in rats via infusion of different carbon sources (glucose, uridine, fatty acid, or GlcN) increases the levels of circulating leptin (21). Interestingly, several nutrients including GlcN can also induce leptin expression in skeletal muscle (29) and in cultured myocytes (21). The significance of this local production of leptin after the stimulation of nutrient-sensing pathways is still unknown. HBP controls leptin expression mostly via the transcriptional activation of the leptin promoter (30).

Nutrient availability is a potent regulator of energy expenditure. Fasting and weight loss are associated with decreased energy expenditure (31). Conversely, nutrients have been implicated in the activation of facultative thermogenesis, also named diet-induced thermogenesis (32). Although the molecular mechanisms for diet-induced thermogenesis are not entirely understood, studies on cafeteria diets in several strains of rodents models, including ob/ob mice, have established that the activation of the leptin pathway is an essential component of the adaptive thermogenic response to nutrient excess (33). However, prolonged nutrient excess leads to weight gain, which is even more pronounced in a subgroup of individuals prone to obesity (34). Most obese individuals have high levels of circulating leptin and insulin (35). This discrepancy is attributed to the development of resistance to the biological effects of leptin, as well as insulin (13, 36). However, it is not yet clear how nutrient-induced leptin action fails to fully activate counterregulatory responses to nutrient excess in susceptible individuals.

In a recent report, we have unveiled a biochemical link between nutrient sensing and energy expenditure (37). Short-term infusion of GlcN decreased the expression of genes involved in oxidative phosphorylation (OXPHOS) and fatty acid oxidation in skeletal muscle. Simultaneously, the acute activation of HBP resulted in a moderate increase in circulating leptin and in the induction of uncoupling protein-1 and OXPHOS genes in brown adipose tissue (BAT). Thus, the down-regulation of OXPHOS genes in skeletal muscle could result in the shunting and dissipation of excess energy by thermogenesis in BAT, whose activation is largely under the control of leptin-dependent neuroendocrine pathways. However, despite early activation of leptin secretion and uncoupling protein-1 transcript in BAT, the acute HBP stimulation resulted in a marked decrease in whole-body energy expenditure, as measured in vivo by indirect calorimetry. Similar down-regulation of OXPHOS expression occurs in skeletal muscle of rats after 3 d of overfeeding, suggesting that this adaptation to nutrient abundance occurs under physiological conditions. Nutrient-induced down-regulation of OXPHOS genes in skeletal muscle may represent a thrifty response to nutrient excess, which attempts to limit the compensatory increase in energy expenditure normally designed to counteract the increase in energy intake.

The mechanisms by which nutrient-sensing pathways trigger adaptive responses to nutrient excess have not been completely elucidated (Fig. 1C). Several effects of HBP on insulin action have been ascribed to O-GlcNAc modification of key regulatory proteins in the insulin signal transduction cascade (26, 27). Additionally, many transcriptional factors have been reported as targets of O-GlcNAc modification (38, 39), including Sp1, which is a transcriptional regulator of OXPHOS promoters (40, 41). This posttranslational modification of transcriptional factors may result in down-regulation of OXPHOS gene expression and decreased mitochondrial function by impairing the activity and/or expression of known regulators of OXPHOS transcription [proliferator-activated receptor- coactivator 1 (PGC1) and nuclear respiratory factor (NRF)]. In fact, recent reports have shown decreased expression of PGC1 and NRF1 in skeletal muscle of diabetic individuals (32, 42). Conversely, the simultaneous transcriptional activation of the leptin gene by HBP (30) may counteract the inhibitory effect of O-GlcNAc modification on the transcription of OXPHOS genes. In fact, leptin is known to activate sympathetic outflow, which in turn induces mitochondrial biogenesis and thermogenesis (32, 43). Hyperglycemia-induced overproduction of mitochondrial superoxide (reactive oxygen species) activates HBP by partially blocking glycolytic fluxes and shunting substrates toward GFAT, suggesting that oxidative stress associated to nutrient excess causes mitochondrial dysfunction at least in part, via activation of HBP (44, 45).

Both insulin resistance and inhibition of OXPHOS may represent adaptive responses to acute bouts of nutrient excess, which are designed to limit oxidative damage. Conversely, insulin resistance and defects in oxidative phosphorylation are also associated with obesity (46), hyperglycemia (47, 48), and aging (49, 50), which are all chronic pathophysiological states characterized by increased or altered cellular fluxes of nutrients. Although the causal relationship between insulin resistance and mitochondrial dysfunction is still the object of intense debate, the role of biochemical sensors of fuel overflow in generating both insulin resistance and mitochondrial dysfunction may provide an important etiological link.

Nutrient sensing and the hypothalamus
According to the lipostatic model for the regulation of energy balance, peripheral signals proportional to the size of the energy stores communicate the energy status to brain centers involved in the regulation of food intake and fuel metabolism (51, 52). Leptin and insulin are ideal candidates for this lipostatic function because their circulating levels are proportional to adiposity and their central administration decreases food intake (51, 53, 54, 55). Circulating macronutrients also acutely increase leptin and insulin plasma levels, which in turn activate hypothalamic responses to nutrient abundance (52). In addition to their anorectic effects, central delivery of insulin or leptin can induce rapid shifts in the metabolic fluxes of peripheral tissues such as liver and skeletal muscle (56, 57, 58, 59). We have recently shown that the effect of circulating insulin on the suppression of glucose production is partly due to the activation of hypothalamic insulin receptors located in the arcuate nucleus (57, 58). The homeostatic model of negative feedback between circulating nutrients and hypothalamic responses is summarized in Fig. 2A.

View larger version (20K): [in this window] [in a new window]   FIG. 2. A, Model of nutrient homeostasis. The scheme illustrates the two main sources for circulating nutrients: intake and absorption of exogenous calories (Food), and hepatic glucose production of glucose and lipids (Liver). Circulating nutrients stimulate secretion and synthesis of insulin and leptin, which in turn activate central efferent pathways through their hypothalamic receptors and inhibit food intake and hepatic glucose production. Additionally, the hypothalamus may directly sense nutritional status via neural nutrient sensing pathways and activate neural responses of negative feedback on feeding behavior and glucose production. B, Hypothalamic lipid sensing. This scheme illustrates a proposed mechanism of hypothalamic nutrient sensing for the regulation of feeding behavior and endogenous glucose production. Inhibition of fatty acid synthase (FAS) leads to accumulation of malonyl-CoA, the product of the enzyme acetyl-CoA carboxylase (ACC). High levels of malonyl-CoA inhibit the CPT1-dependent oxidation of LCFA-CoA. The resulting increase in neuronal LCFA-CoA leads to inhibition of food intake and glucose production. Exogenous administration of LCFA results in similar suppression of feeding behavior and glucose production, most likely due to its accumulation as LCFA-CoA.

Lipid sensing in the hypothalamus
Several recent findings suggest that hypothalamic neurons can directly sense circulating nutrients (60, 61). Central administration of oleic acid inhibits food intake and glucose production (60). The central effect of oleic acid is not reproduced by fatty acids with medium chain, suggesting that LCFAs are a specific signal of nutrient abundance that is not simply mediated by increased fatty acid oxidation (Fig. 2B). Fatty acids are transported from the circulation to the brain (62), converted into LCFA-CoAs, and further metabolized in oxidative (by ß-oxidation in mitochondria) or biosynthetic pathways (incorporation in phospholipids) (63). Although the brain largely derives its ATP from the oxidation of glucose, lipid oxidation occurs as well. Studies performed with radiotracer techniques have shown that, although up to 50% of fatty acids delivered to the whole brain are oxidized to acetate, the bulk of palmitate and oleate incorporated into brain lipids is derived from circulating fatty acid and not from newly synthesized LCFA-CoA (63). The potent anorectic effects of inhibitors of fatty acid synthase have further focused attention on the role of the neuronal lipid metabolism. The effect of fatty acid synthase inhibitors on food intake requires the accumulation of malonyl-CoA, a potent inhibitor of CPT1. This enzyme is necessary for the transport of LCFA-CoA in mitochondria and is the rate-limiting step in the oxidative metabolism of LCFA-CoA. In peripheral tissues (liver and muscle), malonyl-CoA has been identified as a fuel sensor that regulates the rate of fatty acid oxidation and consequently determines the intracellular levels of LCFA-CoA. Recent evidence supports the notion that the accumulation of LCFA-CoA in hypothalamic neurons represents a signal of nutrient abundance (64). Inhibition of hypothalamic CPT1 with pharmacological tools or antisense technique increased neuronal levels of LCFA-CoA. This elevation was sufficient to suppress food intake and endogenous glucose production. In physiological conditions, the inhibition of CPT1 activity may occur when levels of malonyl-CoA increase due to an increased flux of glucose-derived carbons. Therefore, increased availability of LCFAs and carbohydrates may activate a central lipid-sensing signal of negative feedback designed to further restrain the entry of nutrients in the circulation.

	Conclusions

Top Abstract Introduction Cellular Sensor of Nutrient... HBP and Modulation of... HBP and Regulation of... Conclusions References

 
Multiple and complex biological circuitries participate in the regulation of energy balance and insulin action. Here, we focused on two nutrient-sensing mechanisms that, by virtue of their potent impact on both energy and metabolic pathways, are likely to play a pivotal role in the tight association between weight and glucose homeostasis. Signals of nutrient abundance are received in peripheral sites such as skeletal muscle and adipose tissue and in central sites, such as the arcuate nuclei of the hypothalamus. In peripheral tissues, an increased flux of lipids and carbohydrates enhances the activity of both the malonylCoA/LCFA-CoA fuel sensing and the HBP (Fig. 3A). The activation of each of these biochemical sensors has been shown to cause insulin resistance and to decrease fat oxidation. Furthermore, we have recently shown that HBP activation also decreases energy expenditure (muscle) and induces the expression of leptin (adipose tissue and muscle). The combined effects of these two nutrient-sensing pathways in peripheral sites are therefore consistent with a thrifty effect with decrease in energy expenditure and substrate oxidation and induction of insulin resistance. However, we are now also cognizant of the potent hypothalamic effects of the malonyl CoA/LCFA-CoA fuel sensing in the regulation of both feeding behavior and hepatic insulin action (Fig. 3B). These newly discovered (10, 11, 64, 65) central properties of lipid sensing combined with the well-established hypothalamic actions of leptin (induced by HBP) appear to provide a negative feedback system designed to limit the effects of nutrient excess on body weight and insulin action via regulation of food intake and metabolic fluxes. It is tempting to speculate that the balance between peripheral and central effects of nutrient sensing partly determines the impact of increased energy intake on fat mass and insulin action (Fig. 4A). In this regard, a rapid failure of the central responses to nutrients and leptin may leave the thrifty peripheral effects unopposed and favor diet-induced weight gain and insulin resistance in susceptible individuals (Fig. 4B).

View larger version (20K): [in this window] [in a new window]   FIG. 3. Biochemical signals of nutrient abundance: central vs. peripheral effects. A, In peripheral tissues (e.g. skeletal muscle), increased fluxes of lipids and carbohydrates activate both malonyl-CoA/LCFA-CoA fuel sensor and HBP. Both sensors cause insulin resistance and decreased fatty acid oxidation. The activation of HBP reduces energy expenditure in muscle and increases leptin biosynthesis. B, In the hypothalamus, increased levels of malonyl-CoA and/or LCFA-CoA trigger counterregulatory responses that decrease food intake and endogenous glucose production.

View larger version (12K): [in this window] [in a new window]   FIG. 4. Homeostatic model of the regulation of energy balance and insulin action. A, Nutrient-sensing signals have both peripheral and central effects. The peripheral effects trigger responses that favor insulin resistance and weight gain. On the other hand, nutrient-induced leptin and hypothalamic nutrient-sensing mechanisms provide a negative feedback that counteracts the peripheral effects. B, Pathogenesis of obesity. In susceptible individuals, nutrients may fail to activate hypothalamic counterregulatory responses, leaving the thrifty peripheral effects unopposed and consequently favoring diet-induced obesity and insulin resistance.

	Footnotes

 
Abbreviations: BAT, Brown adipose tissue; CoA, coenzyme A; CPT, carnitine palmitoyltransferase; Fru-6-P, fructose-6-phosphate; GFAT, glutamine:Fru-6-P aminotransferase; GlcN, glucosamine; GlcNAc, N-acetyl GlcN; HBP, hexosamine biosynthesis pathway; LCFA, long-chain fatty acid; NRF, nuclear respiratory factor; OXPHOS, oxidative phosphorylation; PGC1, proliferator-activated receptor- coactivator 1.

Received August 5, 2003.

Accepted for publication September 4, 2003.

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