Role of Insulin, Adipocyte Hormones, and Nutrient-Sensing Pathways in Regulating Fuel Metabolism and Energy Homeostasis: A Nutritional Perspective of Diabetes, Obesity, and Cancer

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Science's STKE  01 Aug 2006:
Vol. 2006, Issue 346, pp. re7
DOI: 10.1126/stke.3462006re7


Traditionally, nutrients such as glucose and amino acids have been viewed as substrates for the generation of high-energy molecules and as precursors for the biosynthesis of macromolecules. However, it is now apparent that nutrients also function as signaling molecules in functionally diverse signal transduction pathways. Glucose and amino acids trigger signaling cascades that regulate various aspects of fuel and energy metabolism and control the growth, proliferation, and survival of cells. Here, we provide a functional and regulatory overview of three well-established nutrient signaling pathways—the hexosamine signaling pathway, the mTOR (mammalian target of rapamycin) signaling pathway, and the adenosine monophosphate–activated protein kinase (AMPK) signaling pathway. Nutrient signaling pathways are interconnected, coupled to insulin signaling, and linked to the release of metabolic hormones from adipose tissue. Thus, nutrient signaling pathways do not function in isolation. Rather, they appear to serve as components of a larger "metabolic regulatory network" that controls fuel and energy metabolism (at the cell, tissue, and whole-body levels) and links nutrient availability with cell growth and proliferation. Understanding the diverse roles of nutrients and delineating nutrient signaling pathways should facilitate drug discovery research and the search for novel therapeutic compounds to prevent and treat various human diseases such as diabetes, obesity, and cancer.


Nutrients, such as glucose, amino acids, and fatty acids, have traditionally been viewed as metabolic fuels used to generate high-energy molecules such as adenosine triphosphate (ATP) and the reduced forms of nicotinamide adenine dinucleotide phosphate and nicotinamide adenine dinucleotide (NADPH and NADH). However, this perspective is rapidly changing with the realization that glucose and amino acids can serve as important signaling molecules in complex, nutrient-sensing transductional pathways collectively known as nutrient signaling pathways. Nutrient signaling pathways trigger signaling cascades that regulate various aspects of fuel and energy metabolism and influence cell growth, proliferation, and survival. Such pathways contain two components: (i) a sensor that detects changes in nutrient availability or low ATP levels, and (ii) a transductional element (typically an enzyme) that covalently modifies regulatory proteins through either protein phosphorylation or O-linked glycosylation.

Three functionally distinct nutrient signaling pathways have now been identified, and substantial progress has been made in delineating the complex network of upstream events that regulate them and in identifying their downstream targets and functions. Here, we provide a functional and regulatory overview of the hexosamine signaling pathway, the mTOR (mammalian target of rapamycin) signaling pathway, and the adenosine monophosphate (AMP)–activated protein kinase (AMPK) signaling pathway. We also illustrate how these pathways are interconnected at multiple levels and tightly linked to insulin signaling and action. An important concept emerging from our understanding of nutrient signaling pathways is that such pathways do not function in isolation. Rather, they serve as components of a larger "metabolic regulatory network" that coordinates fuel metabolism and regulates energy homeostasis at the cellular and whole-body levels. This perspective provides a unifying framework for understanding how nutrients control intermediary metabolism and for conceptualizing how nutrient excess, hormone signaling defects, or both, can play a role in the pathogenesis of various diseases such as diabetes, obesity, and cancer.

The Hexosamine Signaling Pathway

Discovery of the hexosamine signaling pathway

Hyperglycemia is the hallmark of type 2 diabetes mellitus and contributes to disease pathogenesis by impairing both insulin action and insulin secretion (1, 2). Thus, hyperglycemia is not only a consequence of diabetes, it is a pathophysiological factor that can perpetuate and sustain the diabetic state. The detrimental effects of hyperglycemia are generally referred to as "glucose toxicity" (26), and for many years the question of how hyperglycemia mediates desensitization to insulin at the cellular level remained unanswered.

The hexosamine biosynthesis pathway was elucidated in the 1950s and 1960s. The first product of this pathway is generated through the conversion of fructose-6-phosphate to glucosamine-6-phosphate, and through a series of additional enzymatic reactions, various substrates are rapidly produced. These include the formation of uridine diphosphate (UDP)–N-acetylglucosamine (UDP-GlcNAc), which served as crucial precursors for the formation of complex glycoproteins in the endoplasmic reticulum and Golgi apparatus (7, 8).

In 1991, new insights into the functional role of the hexosamine pathway were obtained when it was shown that incubation of isolated adipocytes under hyperglycemic conditions enhanced the flux of glucose through the hexosamine pathway and culminated in a state of cellular insulin resistance (9). Under these conditions, the ability of adipocytes to respond to insulin was reduced, leading to desensitization of the insulin-responsive glucose transport system (9). Although the mechanistic details were unknown, it was postulated that the hexosamine biosynthesis pathway served as a glucose sensor coupled to a biological transduction system that desensitizes the glucose transport system as the rate of glucose uptake exceeds the capacity of the major glucose-using pathways.

As new information about the hexosamine-linked insulin desensitization pathway accumulated, it became apparent that the hexosamine biosynthesis pathway not only mediates the synthesis of complex glycoproteins (that are either secreted from the cell or inserted into the plasma membrane), it also contains a novel intracellular signaling arm in which UDP-GlcNAc is used to modify various regulatory proteins in the cytosol and nucleus through O-linked glycosylation. With the realization that the hexosamine biosynthesis pathway contains multiple arms, it was proposed that the metabolic signaling arm of the hexosamine biosynthesis pathway be renamed the "hexosamine signaling pathway" (10). Thus, in retrospect, it can be said that a new signaling pathway was discovered in 1991 that used many of the early steps within the hexosamine biosynthesis pathway. The point at which the signaling pathway diverges from the common hexosamine biosynthesis pathway is at the level of UDP-GlcNAc. In future studies, it will be of interest to determine how cells balance the regulation of complex glycoprotein formation with cytosolic O-linked glycosylation, because both processes use the same precursor, UDP-GlcNAc. Since 1991, numerous studies have confirmed the role of the hexosamine signaling pathway in glucose-induced desensitization and have extended the scope of this regulatory system to muscle tissue and other cell types (1113).

Components and functions of the hexosamine signaling pathway

As shown in Fig. 1, the first and rate-limiting enzyme of the hexosamine signaling pathway is glutamine:fructose-6-phosphate amidotransferase (GFAT). This soluble enzyme uses glutamine as an amino donor to convert fructose-6-phosphate to glucosamine-6-phosphate (GlcN-6-P). Under hyperglycemic conditions, GlcN-6-P is formed and rapidly converted to UDP-GlcNAc, a high-energy substrate used to covalently modify various proteins through the addition of a single monosaccharide (GlcNAc) onto serine or threonine residues.

Fig. 1.

Model of nutrient- and hormone-signaling pathways. The AMPK pathway (blue) senses diminished ATP levels and restores ATP concentration by phosphorylating downstream targets that stimulate catabolic pathways generating ATP and inhibit anabolic pathways that consume ATP. The mTOR-GβL-raptor (mTORC1) pathway (green) senses amino acid availability and functions to regulate cell proliferation and the growth of cells, tissues, and organs. The mTORC1 pathway enhances the rate of protein synthesis, inhibits autophagy, and stimulates ribosomal biogenesis. The mTOR-GβL-rictor (mTORC2) pathway regulates actin organization and activates Akt. The hexosamine pathway (orange) functions as a glucose sensor coupled to a transductional cascade that directly regulates intracellular fuel metabolism, controls glucose metabolism by modulating insulin signaling, and facilitates the release of metabolic hormones (such as leptin and adiponectin) from adipose tissue. In the central nervous system (CNS), leptin acts to influence appetite and modulate neuroendocrine secretion, thereby altering nutrient utilization in various peripheral tissues. In muscle and liver, leptin and adiponectin influence fuel metabolism. The insulin pathway (yellow) regulates glucose and lipid metabolism, facilitates cell growth and proliferation, promotes cell survival through inhibition of apoptosis, and protects cells from oxidative stress and DNA damage. The insulin pathway also modulates the actions of various nutrient-signaling pathways. Interpathway reactions are shown by dotted lines and illustrate that these four pathways comprise a metabolic regulatory network.

The enzyme catalyzing O-linked glycosylation is UDP–N-acetylglucosaminyl transferase (OGT). This enzyme was first identified and partially characterized in 1990 (14), purified in 1992 (15), cloned in 1997 (16, 17), overexpressed in a stable, tetracycline-inducible HeLa cell line in 2003 (18), and extensively studied (1922). Numerous cytosolic and nuclear proteins have now been identified as substrates for O-linked glycosylation, and the growing list includes most transcription factors, several oncogenes, various nuclear proteins, metabolic enzymes, signal transduction proteins, and numerous cytoskeletal and structural proteins (23, 24). On the basis of the identity and function of these targets, it appears that O-linked glycosylation plays a role in controlling gene expression, fuel metabolism, cell growth, cell differentiation, and cytoskeleton organization. In regard to fuel metabolism, convincing evidence indicates that increased flux through the hexosamine signaling pathway rapidly elevates UDP-GlcNAc levels (25) and enhances glycosylation of transcription factors that regulate the expression of genes encoding proteins that are involved in controlling the insulin-responsive glucose transport system. Specifically, studies have established a link between O-linked glycosylation and the induction of insulin resistance (2628) and have shown that transcriptional inhibitors can completely block glucose-induced desensitization (29).

In addition to controlling glucose metabolism, enhanced flux through the hexosamine signaling pathway increases triglyceride synthesis through a mechanism involving up-regulation of mRNA encoding various lipogenic enzymes, such as acetyl-CoA carboxylase (ACC), fatty acid synthase (FAS), and glycerol-3-phosphate dehydrogenase (30, 31). Thus, regulation of lipid metabolism appears to constitute another downstream action of the hexosamine signaling pathway. A third action of enhanced hexosamine flux involves an increase in the rate of glycogen biosynthesis, but in this case, hexosamine action is mediated by the intracellular accumulation of GlcN-6-P and allosteric activation of glycogen synthase (32). From these studies, it can be concluded that enhanced flux through the hexosamine signaling pathway leads to increased O-linked glycosylation of various regulatory proteins and orchestrates both short-term (allosteric) and long-term (transcriptional) regulatory actions in response to glucose and glutamine availability. This coordinated regulatory response under hyperglycemic conditions makes sense, in that overall glucose uptake would be reduced (by development of insulin resistance) and excess incoming glucose would be stored as triglycerides (through enhancement of lipogenesis) and glycogen.

Role of the hexosamine signaling pathway in controlling fuel metabolism at the whole-body level through release of adipocyte-specific hormones

Adipose tissue is now recognized as an endocrine organ that synthesizes and secretes various hormones and other regulatory proteins, including leptin, adiponectin, plasminogen activator inhibitor–1, and several cytokines (3337). The hexosamine signaling pathway regulates the secretion of both leptin and adiponectin (3840). The metabolic hormone leptin is the product of the obesity gene (ob) and plays a key role in controlling body weight by acting on food satiety centers in the hypothalamus (41). Glucosamine infusion into rats results in a marked increase in leptin mRNA abundance (in fat and muscle) and increased concentrations of circulating leptin (hyperleptinemia) (42), revealing a connection between the regulatory actions of the hexosamine signaling pathway and endocrine control of body weight. Leptin gene expression is also increased in vitro when glucosamine is used to treat 3T3-L1 preadipocytes (35), human adipocytes (43), pancreatic islets (44), or differentiated 3T3-L1 adipocytes (45). Transgenic mice that overexpress GFAT, the first and rate-limiting enzyme of the hexosamine signaling pathway, display increased abundance of both UDP-GlcNAc and leptin mRNA in fat tissue plus elevated levels of plasma leptin (46). Collectively, these findings indicate that glucose uptake and enhanced hexosamine flux in adipose tissue play a major role in regulating whole-body fuel and energy metabolism through effects on the central nervous system (CNS).

Peripheral tissues such as liver and muscle are also affected by hexosamine-mediated release of adipocyte hormones. For example, the combined actions of leptin and adiponectin increase fatty acid oxidation and insulin sensitivity while decreasing hepatic glucose output, triglyceride synthesis, and gluconeogenesis (4750). Moreover, by affecting other cells and tissues, these hormones appear to influence inflammation, angiogenesis, immune function, cell growth, and atherogenesis (36, 37, 5155). Although the cellular mechanisms underlying leptin and adiponectin action remain to be elucidated, it has been established that these hormones play a key role in regulating energy metabolism by triggering a signaling cascade that culminates in the phosphorylation of AMPK and activation of the AMPK signaling pathway. Thus, a functional link exists between the hexosamine signaling pathway in adipocytes and the regulation of fuel and energy metabolism in liver and muscle.

On the basis of the above studies, it appears that the hexosamine signaling pathway plays a global role in regulating metabolism by functioning as an integral component of a larger "metabolic regulatory network." This network comprises various organs that interact in a coordinated manner to control metabolism at the whole-body level. For example, when blood glucose levels rise after consumption of a carbohydrate-rich meal, the pancreas detects this change and responds through release of insulin. Circulating insulin then binds to cell surface receptors on adipose tissue and triggers a signal transduction cascade that induces translocation of glucose transporters from the cell interior to the cell surface. The resulting increase in the rate of glucose uptake is detected by the hexosamine signaling pathway, which responds by altering intracellular glucose and lipid metabolism in an adaptive effort to restore intracellular glucose homeostasis. Another action of the hexosamine signaling pathway in adipose tissue entails the release of various hormones that convey metabolic information to the brain and other key tissues such as liver and muscle. The pancreas–adipose tissue–brain axis is particularly important, because leptin influences whole-body metabolism by altering neuroendocrine secretion, thus elevating thermogenesis and whole-body energy expenditure. Leptin also exerts well-established effects such as diminished appetite, reduced food intake, and long-term control of body weight.

New insights into the metabolic functioning of adipose tissue are changing our perceptions of how this tissue functions in intermediary metabolism. Traditionally, adipose tissue has been viewed as a passive tissue that is hormonally regulated and functions simply as a fat depot and energy reservoir. It is now apparent that adipose tissue also serves as an integral component of two interorgan regulatory networks: the pancreas–adipose tissue–brain axis and the pancreas–peripheral tissue axis. From a nutritional perspective, adipose tissue can sense blood glucose levels (through insulin binding and signaling) and can assess the rate of glucose delivery and intracellular availability (through the hexosamine signaling pathway). This information is then integrated into a multihormonal response that conveys nutritional information to the CNS and peripheral target tissues. Under hyperglycemic conditions, the end result is reduced nutrient intake (by decreased appetite at the CNS level) and increased whole-body fuel use and storage (at the peripheral target tissue level). When viewed in this manner, it appears that adipose tissue functions as a critical component of an integrated negative-feedback network that regulates fuel metabolism and energy homeostasis at the whole-body level.

The mTOR Signaling Pathway

Evolutionary role of the mTOR signaling pathway in controlling cell growth, proliferation, and survival

All cells require a constant supply of nutrients to provide the substrates and metabolic energy necessary for cell growth, proliferation, and repair. In single-cell organisms, nutrients are derived directly from the environment. In contrast, mammalian cells derive nutrients from the circulatory system after food is consumed and digested within the gastrointestinal tract. Because nutrient availability is indirect and intermittent (between meals), a complex metabolic regulatory system has evolved that allows mammalian cells to monitor both intracellular nutrient levels and the abundance of nutrients and hormones within the circulatory system (the extracellular environment). This nutritional information is then linked to the control of fuel metabolism and energy homeostasis and to various aspects of cell growth, proliferation, repair, and survival. Such a system is necessary to ensure that vital organs and tissues of the body receive sufficient fuel (and energy) to meet basic metabolic needs and that various tissues receive a relatively constant supply of nutrients to perform specialized functions essential for the survival and benefit of the organism.

A particularly important regulatory system in regard to cell growth is the mTOR-raptor (regulatory-associated protein of mTOR) signaling pathway, which monitors intracellular amino acid availability and cellular energy status and links this information with external signals originating from cell surface receptors (such as insulin signaling). This sensory input is then biochemically integrated and tightly coupled to a coordinated response that controls cell growth and proliferation as well as other aspects of cellular function (Table 1). The biological importance of this nutrient-sensing transductional pathway is highlighted by the fact that the function and components of the TOR signaling pathway have been evolutionarily conserved from yeast to mammals. Thus, many of the discoveries and insights into TOR signaling and function have been derived from the convergence of genetic studies in yeast, worms, and Drosophila; biochemical studies in mammalian cells; and pharmacological studies using rapamycin as a specific inhibitor of TOR and mTOR (5661).

Table 1.

Nutrient-sensing and hormone signaling pathways as components of a larger "metabolic regulatory network." Nutrient signaling pathways do not function in isolation. Rather, they are part of a larger "metabolic regulatory network" that functions to coordinate fuel metabolism and energy homeostasis at the cell, tissue, and whole-body levels through integrated organismal and cellular responses. This regulatory network comprises elements of the classical endocrine system, newly discovered hormones released from adipose tissue, and intracellular signaling pathways that monitor and respond to nutrient availability. Understanding the functions and mechanisms that underlie the "metabolic regulatory network" can provide new insights into how diet can nutritionally influence such diverse diseases as diabetes, obesity, and cancer.

Components and functions of the mTOR signaling pathway

The first component of the mTOR signaling pathway is the tuberous sclerosis complex (TSC), which comprises two interacting proteins that form a stable heterodimeric complex (6264). TSC2 (or tuberin) functions as a specific guanosine triphosphatase (GTPase) activating protein (GAP) that inhibits Rheb (Ras homolog enriched in brain), whereas TSC1 (or hamartin) has no apparent catalytic activity. Both proteins are essential, because mutations in either protein lead to an autosomal dominant disorder characterized by the development of hamartomas (benign tumors) in multiple tissues (6568). These findings indicate that TSC functions as a negative regulator of cell growth (in other words, as a tumor suppressor protein). TSC also integrates information from the insulin signaling cascade and the AMPK signaling pathway. Specifically, several kinases within the insulin-signaling pathway inhibit TSC2 through a phosphorylation-mediated mechanism. These include extracellular signal-regulated kinase 1 and 2 (ERK1/2) and ribosomal S6 kinase 1 and 2 (RSK1/2) from the mitogen-activated protein kinase (MAPK) branch of the insulin signal cascade, as well as Akt from the phosphatidylinositol 3-kinase (PI3K) branch. Because TSC constitutively inhibits Rheb (69), signals from the insulin-signaling pathway actually stimulate protein synthesis by inhibiting TSC activity.

The immediate downstream target of TSC is Rheb, a member of the Ras superfamily of small GTP-binding proteins that functions to activate mTOR kinase (64, 69). This protein can be converted to a lipophilic protein through the enzymatic addition of a farnesyl group, and this modification appears to be functionally important because farnesyltransferase inhibitors can block insulin-mediated activation of the mTOR signaling pathway (69, 70).

The central component of the mTOR signaling pathway is mTOR itself, which is a relatively large (290 kD) serine-threonine kinase that contains several regulatory domains (5661, 71, 72). These include the mTOR catalytic domain, which binds an associated protein (GβL), a FKBP12-rapamycin–binding (FRB) domain, a FAT (FRAP-ATM-TRAPP2) domain, and a smaller FATC domain that is believed to act in concert with the FAT domain to influence kinase activity by facilitating protein-protein interaction. Within the N-terminal half of mTOR lies a series of HEAT [huntingtin elongation factor 1A–protein phosphatase 2A (PP2A) A subunit–TOR] repeats that bind cytosolic proteins such as raptor and rictor (rapamycin-insensitive companion of mTOR) in a mutually exclusive manner. When raptor is bound, mTOR kinase activity can be inhibited by rapamycin and stimulated by Rheb. Upon activation of the mTOR-GβL-raptor complex (called mTORC1), two downstream targets are phosphorylated: eukaryotic initiating factor 4E binding protein 1 (4E-BP1) and S6 kinases 1 and 2 (S6K1/2). These events then trigger a cascade that culminates in the regulation of protein synthesis, ribosomal biogenesis, and autophagy. Information regarding the function and regulation of the mTOR-GβL-rictor complex (called mTORC2) is less extensive, but recent studies have shown that this complex plays a role in actin organization (73) and mediates the phosphorylation and activation of Akt (7476). Whether the mTOR-rictor complex is controlled by nutrients and AMP levels in the same manner as the mTOR-raptor complex remains to be determined.

From a regulatory and functional perspective, the mTOR pathway is relatively complex. For example, multiple mechanisms are used to regulate mTOR signaling. These include protein phosphorylation (of TSC and mTOR), protein localization, and control of mTOR activity through the binding of auxiliary cytosolic proteins (such as raptor, rictor, and GβL). Moreover, these regulatory mechanisms are under the control of various sensors (and signaling pathways) that detect changes in nutrient availability (amino acids), changes in intracellular energy levels (input from the AMPK signaling pathway), and changes in the external environment (originating from insulin, leptin, and adiponectin binding to cell surface receptors). In other words, multiple signals converge on the mTOR signaling pathway.

Complexity is also manifested in the diversity of cellular functions. One recognized function of the mTOR signaling pathway is to couple energy availability to the rate of protein synthesis and cell growth. This is achieved through regulatory input received from the AMPK signaling pathway. Another function is to sense amino acid availability and glucose availability (through insulin binding and signal transduction) and then link nutrient availability to the rate of protein synthesis and cell growth. This makes sense, given that protein synthesis requires a constant supply of amino acids (as precursor products) and a source of glucose to provide the necessary metabolic energy.

The AMPK Signaling Pathway

AMPK is a heterotrimeric serine-threonine kinase that senses depletion of intracellular energy and responds by stimulating catabolic pathways that generate ATP. A synergistic response entails inhibition of anabolic pathways that mediate the synthesis of macromolecules such as proteins, fatty acids, lipids, cholesterol, and glycogen (72, 7782). The net result of these two regulatory actions is replenishment of cellular ATP levels and restoration of energy homeostasis.

One mechanism for sensing cellular energy levels involves allosteric activation of the kinase activity of AMPK. Under conditions in which cellular energy demands are increased (such as enhanced cell work or cell stress) or when fuel availability is decreased (because of a reduced rate of glucose uptake), intracellular ATP is reduced and AMP levels rise. AMP then allosterically activates AMPK and triggers a phosphorylation cascade that regulates the activity of various downstream targets, including transcription factors, enzymes, and other regulatory proteins. At least two downstream targets of AMPK lie within the mTOR signaling pathway (TSC2 and mTOR). The phosphorylation of these targets plays a key role in restoring ATP levels by slowing the energy-consuming process of protein synthesis and cell growth.

In addition to allosteric activation, AMPK activity can be regulated by a mechanism involving covalent modification through the addition of a phosphate group. It is noteworthy that each mechanism is interactive and is tightly integrated in the overall regulation of kinase activity. Leptin and adiponectin are two metabolic hormones that regulate the phosphorylation state of AMPK by binding to cell surface receptors and triggering a receptor-mediated transduction cascade (33, 34, 47, 83). Another route through which AMPK can be regulated is through the action of a recently identified serine-threonine kinase called LKB1 (80, 8487). This kinase is active only when associated with two proteins called Mo25 and STE20-related adaptor (STRAD). Given that 80% of cancer patients with Peutz-Jeghers syndrome harbor inactivating mutations in LKB1, this enzyme complex appears to function as a tumor suppressor (86, 88, 89). Although AMPK is the most widely recognized target of LKB1, convincing evidence now indicates that LKB1 may phosphorylate additional target proteins that play a role in controlling energy metabolism, chromatin remodeling, cell cycle arrest, cell polarity, and Wnt signaling (86, 9093). Clearly, additional studies are required to map all the regulatory elements of the AMPK signaling pathway, identify the full gamut of its regulatory actions, and elucidate how this pathway functionally integrates with other intracellular signaling pathways and cellular actions.

Nutrient-Sensing Pathways as Components of a Larger "Metabolic Regulatory Network"

The growing realization that nutrients serve as important signaling molecules that regulate various nutrient signaling pathways is rapidly changing our view on the role of nutrients in intermediary metabolism. No longer can nutrients be viewed simply as metabolic fuel or precursor substrates; accumulating evidence indicates that glucose and amino acids play a direct and active role in regulating metabolism. In many respects, nutrients take on the attributes of hormones in that they circulate in the blood, their levels vary depending on prevailing physiological conditions (fed state versus fasting), they bind to cell surface proteins (glucose and amino acid transporters) before undergoing internalization, and they act within cells to alter signal transduction pathways and cellular metabolism. Thus, the common perception that hormones play the dominant role in controlling fuel metabolism, energy homeostasis, and blood glucose levels requires some revision. Specifically, the classical view of the metabolic endocrine system needs to include the role of nutrients as signaling molecules and key regulators of intermediary metabolism. Control of intermediary metabolism should be viewed as a dynamic equilibrium between hormonal regulation of fuel metabolism and nutrient control of cellular metabolism through nutrient signaling pathways.

The various nutrient signaling pathways do not function in isolation. Rather, it appears that nutrient signaling pathways are interconnected at multiple levels and also affect (and are affected by) the secretion of metabolic hormones from adipose tissue (Fig. 1). For example, the AMPK signaling pathway is linked to the mTOR signaling pathway through the ability of AMPK to inhibit mTOR signaling (by phosphorylating TSC and mTOR). Thus, the energy demands of protein synthesis can be reduced when cellular energy levels are diminished. There also appear to be multiple links between the hexosamine signaling pathway and the AMPK signaling pathway.

At the substrate level, the hexosamine signaling pathway controls the sensitivity and responsiveness of the insulin-regulated glucose transport system. Because glucose uptake plays a major role in generating ATP and cellular energy, changes in glucose uptake would be expected to affect signal transduction through the AMPK signaling pathway. At the hormonal level, the hexosamine signaling pathway controls the synthesis and release of leptin and adiponectin from adipose tissue. When these two hormones are released to the blood, they influence fuel metabolism in the liver and muscle through a receptor-mediated cascade that directly regulates AMPK activity.

On the basis of the extensive interactions between nutrient signaling pathways and insulin signaling, we postulate that nutrient signaling pathways and aspects of the endocrine system constitute components of a larger "metabolic regulatory network." This network appears to function in an integrated manner to assess nutrient availability and energy status at both the cellular and whole-body levels and then to coordinately regulate whole-body energy homeostasis to ensure that vital organs and tissues receive sufficient fuel (and energy) to meet basic metabolic needs and perform specialized functions essential for the survival and benefit of the organism.

A major difference between single-cell organisms and cells of complex organisms (such as humans) involves the route of nutrient delivery. Single cells extract nutrients directly from the environment, whereas the cells of tissues and organs must absorb nutrients from the circulatory system after consumption of a meal. Although all organisms must adapt to changes in nutrient availability (feast or famine), the evolution of the digestive and circulatory systems presented new survival challenges that required a more complex and advanced metabolic regulatory system. For example, intermittent food consumption by humans results in two functionally different nutritional states: (i) the absorptive state, in which nutrients are released to the blood during digestion, and (ii) the postabsorptive state (occurring between meals) in which nutrients in the gastrointestinal tract are depleted. In the latter state, energy needs must be met from the release of nutrients stored in the liver (as glycogen) and adipose tissue (as triglyceride). Although most peripheral tissues can metabolize alternative nutrients for energy generation (including glucose, fatty acids, and amino acids), a notable exception is the brain, which uses glucose as its sole metabolic fuel. Thus, maintenance of blood glucose levels within a relatively narrow range is crucial to survival and constitutes an important regulatory endpoint of the metabolic regulatory network. Clearly, an integrated network is required to orchestrate the cellular and organ changes necessary to maintain fuel and energy homeostasis under the constantly changing conditions associated with intermittent food intake.

Therapeutic Implications

Metabolic diseases

Type 2 diabetes is a serious metabolic disease characterized by insulin resistance, variable insulin secretion, and hyperglycemia. Because of the aging of populations and recent lifestyle and cultural changes, especially in developing countries, the prevalence of diabetes is rapidly increasing. This diabetes pandemic has devastating consequences for the individual, in the form of hyperglycemia-induced secondary complications, and places an enormous financial burden on both U.S. and global health care systems.

Although the cellular and genetic basis of type 2 diabetes mellitus is not well understood, it is generally believed that initiation and progression of the disease involves the induction of insulin resistance mediated by the interaction of various genes with environmental factors such as diet, obesity, exercise, stress, and age. In the early stages of disease progression, blood glucose concentration remains relatively normal because of enhanced insulin secretion; however, at later stages, impaired pancreatic function leads to hyperglycemia. The ensuing hyperglycemia worsens the diabetic state by increasing insulin resistance. This idea is encompassed in the broader glucose toxicity concept, which states that acute and chronic hyperglycemia leads to a cascade of events that culminates in impaired insulin action and secretion. Glucose toxicity also underlies the progressive development of diabetic complications, which include retinopathy, nephropathy, neuropathy, and other microvascular and macrovascular disorders.

The hexosamine signaling pathway has been implicated in glucose-induced insulin resistance, and accumulating evidence indicates that increased flux through the hexosamine signaling pathway may be a contributing factor in the development of secondary diabetic complications (94, 95). Therefore, it is important to understand the sequence of events from initial influx of glucose to the phenotypic abnormalities linked to hyperglycemia. Because nutrient signaling pathways are tightly interrelated, a mechanistic explanation for the cellular and molecular basis of glucose toxicity may include abnormalities in other nutrient signaling pathways. In other words, the search for the cellular basis of hyperglycemia-induced glucose toxicity will require a broader perspective that encompasses possible dysfunction of other components of the "metabolic regulatory network."

Obesity is another multifactorial metabolic disorder with numerous genetic and environmental contributing factors. Ultimately, these contributing factors lead to caloric intake that exceeds daily caloric expenditure. This imbalance results in the gradual accumulation of excess body fat. The health consequences of obesity encompass both the psychological and physical burden of increased body weight and the progressive development of secondary disorders and risk factors. The constellation of associated disorders includes the induction of insulin resistance (and its own associated risk factors), dyslipidemia, hypertension, cardiovascular disease, inflammation, and a heightened risk of cancer. Although the molecular mechanisms linking obesity to these abnormalities remain elusive, at least two possibilities can be envisioned. First, the chronic and excessive intake of nutrients needed to acquire and maintain increased adiposity may have a direct and detrimental impact on the homeostatic functioning or adaptive ability of one or more nutrient signaling pathways. Alternatively, the increased size and mass of adipose tissue may lead to adipocyte dysfunction, including pathogenic release of various hormones and cytokines. Clearly, additional studies are required to elucidate the causes and consequences of obesity and to assess how obesity affects individual nutrient signaling pathways and the "metabolic regulatory network."

Diabetes and obesity are etiologically distinct metabolic diseases; however, extensive overlap exists in causative factors and the development of secondary disorders and risk factors. Insulin resistance plays a prominent role in both diseases, as illustrated by the finding that a high percentage of type 2 diabetics are both insulin-resistant and obese, and a high percentage of obese individuals are insulin-resistant and go on to develop type 2 diabetes mellitus. In general, the cellular and molecular mechanisms that link metabolic diseases with common underlying abnormalities and risk factors are poorly understood. However, by viewing the hexosamine signaling pathway and other nutrient signaling pathways as components of an integrated metabolic network and assessing how nutrient excess and the onset of other metabolic diseases could alter these pathways, it may be possible to derive new insights into the etiology and pathogenesis of metabolic diseases and the resulting secondary disorders and complications.


Cancer typically arises as a consequence of mutations in somatic cells that cause or predispose an individual to develop a specific type of cancer. Interestingly, there is a growing realization that signaling abnormalities within nutrient signaling pathways can lead to abnormal cell growth and cancer. For example, loss-of-function mutations in the LKB1 tumor suppressor protein (within the AMPK signaling pathway) and mutations in the TSC tumor suppressor protein (within the mTOR signaling pathway) are associated with several types of related cancers (67, 72, 86, 9699). Similarly, a dysfunctional PTEN (phosphatase and tensin homolog on chromosome 10) tumor suppressor protein within the insulin-signaling pathway is associated with abnormal cell growth (67, 72, 100). In addition, overexpression of proto-oncogene proteins in the insulin action cascade (Ras and Raf) results in uncontrolled signal transduction and the development of cancer (101, 102). These findings are not unexpected, given that one function of the metabolic regulatory network is to integrate glucose metabolism, amino acid availability, and energy balance with the growth, proliferation, and survival of cells.

New opportunities in drug discovery

The therapeutic leap from understanding nutrient signaling pathways to the discovery of drugs for the treatment of metabolic diseases and cancer is neither simple nor direct; it requires the progressive accumulation of new knowledge and insights.

The idea that fuel metabolism, energy homeostasis, and several human diseases appear to be interrelated provides a conceptual framework for the evaluation of new information and the generation of novel strategies for drug discovery. Thus, new insights into the regulation and functioning of hormone and nutrient signaling pathways may lead to the identification of new therapeutic targets and the discovery of novel drugs. Such drugs could be used to prevent or slow the onset of various metabolic diseases (such as diabetes and obesity) or prevent the development of secondary complications and disorders associated with hyperglycemia and obesity. Along these lines, it is interesting to note that metformin, a drug currently used to treat type 2 diabetes mellitus, acts within the AMPK signaling pathway as an activator of AMPK (103, 104).

Given the likelihood that nutrient availability, nutrient signaling pathways, and hormone signaling pathways are tightly linked to cell proliferation and survival, a greater understanding of the "metabolic regulatory network" may shed additional light on the relationship between nutrition and the development of cancer (105). With this knowledge, innovative avenues of pharmaceutical investigation could be pursued that would ultimately lead to the discovery of drugs to prevent, slow, or halt unregulated growth in cancerous cells.


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