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Perspective: Hexosamines and Nutrient Sensing

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

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

	Introduction

Top Introduction Satiety signals at the... Hexosamine pathway and insulin... Hexosamine pathway and... Satiety signals at the... Hexosamine pathway and... Perspectives and conclusions References

 
The prevalence of obesity and type 2 diabetes mellitus has increased concomitantly with the introduction of nutrients with high caloric density and more sedentary lifestyle in western societies. The tight association between insulin resistance and weight gain is likely to play a pivotal role in this "epidemic." During the last decade, the relationship between nutrient availability and insulin action has been object of intense debate and novel hypotheses have emerged (1, 2, 3, 4, 5, 6, 7, 8, 9, 10). A common theme is that the availability of nutrients per se may modulate insulin action toward nutrient storage and disposal within the framework of a homeostatic system designed to regulate energy balance at the cellular and whole body level. Consistent with this view, insulin resistance is acquired as an "adaptation" to nutrient excess. This hypothesis rests on the existence of biochemical pathways capable of ‘sensing’ the availability of nutrients and activating the appropriate metabolic/endocrine responses. The current brief perspective is centered on the pleiotropic functions of one of these nutrient sensing pathways, the hexosamine biosynthesis pathway.

	Satiety signals at the cellular level

Top Introduction Satiety signals at the... Hexosamine pathway and insulin... Hexosamine pathway and... Satiety signals at the... Hexosamine pathway and... Perspectives and conclusions References

 
It has long been recognized that isolated cells have a remarkable ability to adapt to the nutritional environment. For example, cells cultured in the presence of very low glucose tend to up-regulate their basal transport system via increased expression of GLUT1. Similarly, the relative oxidation of lipids and carbohydrates is finely regulated by biochemical mechanisms pacing the rate of entry of long-chain CoAs into the mitochondria (the "malonyl CoA fuel sensing" system) (6, 9, 11, 12). Marshall et al. (4) first proposed that the metabolism of glucose by the hexosamine pathway generates a signal of "cellular satiety" (Fig. 1). In insulin target tissues, this signal leads to the desensitization of the glucose transport system to subsequent stimulation by insulin (4). In fact, prolonged incubation of cultured adipocytes in the presence of high glucose and insulin resulted in a marked decrease in insulin’s stimulation of glucose uptake. This effect of glucose was mimicked by incubation with glucosamine and was prevented by antagonism of the enzyme glutamine:fructose-6-P amidotransferase (GFAT), which catalyzes the first step in the metabolism of glucosyl units in the hexosamine pathway (4, 13). These observations supported the notion of nutrient sensing in isolated adipose cells. In the present issue of the journal, Crook et al. (14) report an interesting observation, which suggest a novel role of the hexosamine pathway in metabolic partitioning of substrates. Overexpression of GFAT in cultured fibroblasts resulted in decreased activity of glycogen phosphorylase (14) and therefore increased accumulation of glycogen (14, 15, 16). The latter can be interpreted as an attempt to maintain the hexose-phosphate pool at stable levels when a signal of "cellular satiety" is generated.

View larger version (25K): [in this window] [in a new window]   Figure 1. Schematic representation of the hexosamine biosynthesis pathway. Following its entry into muscle or adipose cells via the glucose transport system and its rapid phosphorylation to glucose-6-phosphate (Glc-6-P), glucose is primarily utilized by the pathways of glycogen synthesis and glycolysis. The hexosamine pathway receives approximately 1–3% of incoming glucose via the conversion of frustose-6-phosphate (Fru-6-P) to glucosamine-6-phosphate by the rate-limiting enzyme glutamine: fructose-6-phosphate amidotransferase (GFAT). The principle endproduct of this pathway, uridinediphosphoglucose-n-acetylglucosamine (UDP-GlcNAc) serves as substrate for virtually all glycosilation pathways.

	Hexosamine pathway and insulin resistance

Top Introduction Satiety signals at the... Hexosamine pathway and insulin... Hexosamine pathway and... Satiety signals at the... Hexosamine pathway and... Perspectives and conclusions References

In the presence of increased availability of FFA, the increased concentration of acetyl-CoA, derived in the mitochondria from the oxidation of FFA, decreases the rate of pyruvate oxidation via inhibition of pyruvate dehydrogenase (PDH) (7). Furthermore, the entry of fructose-6-P in the glycolytic pathway is also limited by the inhibition of phosphofructokinase (PFK) (Fig. 1). This in turn is expected to increase the availability of fructose-6-P for the formation of glucosamine-6-P. We hypothesized that an expanded fructose-6-phosphate pool, whether due to increased phosphorylation of glucose (e.g. hyperglycemia) or to decreased utilization of fructose-6-P via glycolysis (e.g. increased availability of FFA), would increase carbon flux into the glucosamine pathway and via increased concentration of its end products, UDP-N-acetyl-hexosamines, cause an impairment in glucose transport/phosphorylation. This notion is supported by the recent observation that prolonged exposure to high concentrations of FFA increases flux into the hexosamine biosynthetic pathway (3). It is noteworthy that these moderate elevations in the skeletal muscle concentrations of UDP-N-acetyl-hexosamines were sufficient to induce marked peripheral insulin resistance even in the absence of sustained hyperlipidemia (3, 21). Thus, the moderate increase in cellular hexosamines during lipid infusions preceded and was sufficient for the development of peripheral insulin resistance.

The evidence herein presented indicates that the glucosamine biosynthetic pathway may contribute to glucose- and fat-induced insulin resistance. Indeed, this quantitatively small pathway of glucose utilization may link the rates of glucose and FFA flux to the metabolic actions of insulin by functioning as a "fuel sensor" capable of decreasing the rate of glucose uptake when detecting increased availability of hexose-phosphates. This may provide a unifying hypothesis for both glucose- and fat-induced insulin resistance.

	Hexosamine pathway and regulation of gene expression

Top Introduction Satiety signals at the... Hexosamine pathway and insulin... Hexosamine pathway and... Satiety signals at the... Hexosamine pathway and... Perspectives and conclusions References

 
The discovery of the role of this biochemical pathway as a cellular mechanism for nutrient sensing has generated great interest in its possible participation in substrate regulation of gene transcription. It is noteworthy that carbohydrates and other nutrients regulate several genes. The activity of a growing number of "nutrient target" genes appears to be regulated by changes in the flux through the hexosamine biosynthesis pathway (27, 28, 29, 30). While the molecular mechanism(s) by which an increase in UDP-N-acetyl-hexosamine pool/flux leads to changes in transcriptional activity is still controversial, a major role of cytosolic O-linked glycosylation is likely (31). The enzyme O-glycosyltransferase (O-GTase) initiates the latter reaction by promoting the addition of a single molecule of UDP-GlcNAc on serine or threonine residues of cytosolic proteins. Several transcriptional factors involved in the regulation of gene expression by nutrients, including SP-1 (28), are among the substrates for O-Gtase (Fig. 2). Recent evidence supports the notion that this novel transcriptional mechanism plays a role in the complications of chronic hyperglycemia and in nutrient sensing at the cellular (4) and whole body level (10).

View larger version (23K): [in this window] [in a new window]   Figure 2. Schematic mechanism by which activation of the hexosamine pathway regulates gene transcription. Increased formation of UDP-GlcNAc results in enhaned O-GlyNAcylation of transcriptional factors such as SP-1. The increased glycosylation involves the addition of one molecule of GlcNAc on selective serine and threonine residues. This modification appears to stimulate the activity of specific promoters via increased activity of the transcriptional factor and via decreased targeting to the proteosome for degradation.

	Satiety signals at the whole body level

Top Introduction Satiety signals at the... Hexosamine pathway and insulin... Hexosamine pathway and... Satiety signals at the... Hexosamine pathway and... Perspectives and conclusions References

	Hexosamine pathway and regulation of leptin biosynthesis

Top Introduction Satiety signals at the... Hexosamine pathway and insulin... Hexosamine pathway and... Satiety signals at the... Hexosamine pathway and... Perspectives and conclusions References

 
The fat-derived hormone leptin plays a major role in the regulation of energy homeostasis. It is generally accepted that leptin is a mechanism for cross-talking between peripheral energy stores and hypothalamic centers regulating feeding behavior and metabolism. However, the specific biochemical mechanism(s), which regulate its biosynthesis, are still undefined. Schematically, there are two levels of regulation of leptin production. In the long term, leptin levels are proportional to fat mass (1, 35, 44, 45, 46), suggesting the operation of transcriptional and/or posttranscriptional mechanisms which coordinate this level of regulation. In the short term, leptin levels are nutritionally regulated with a meal-dependent peak in circulating levels occurring at approximately 0200 h in humans (47, 48, 49). The latter dynamic regulation of plasma leptin levels is consistent with and appears to require a rapid mechanism for nutrient sensing. Recent work from our laboratory (10) has shown that the stimulation of the hexosamine biosynthesis pathway results in increased leptin expression in adipose tissue and transient induction of the leptin gene in skeletal muscle. This effect was independent of the modalities by which hexosamine flux was enhanced and occurred in response to physiological increments in tissue hexosamine levels. In this issue of the journal, McClain et al. (50) provide an important validation of the role of the hexosamine pathway in the regulation of leptin gene expression. In fact, they report increases in plasma leptin and adipose tissue leptin messenger RNA levels in transgenic mice overexpressing GFAT in fat. Because these mice have a "satiety signal," the hexosamine pathway, constantly turned on they appear to have leptin levels that remain in the fed state independently of their nutritional status. Taken together, these findings (10, 50) indicate that the hexosamine biosynthesis pathway is a signal of satiety not only at the cellular level but also via regulation of leptin expression at the whole body level (Fig. 3). Based on these early observations one can speculate that alterations in cellular nutrient sensing are likely to contribute to the pathophysiology of weight gain and insulin resistance.

View larger version (21K): [in this window] [in a new window]   Figure 3. Hypothetical scheme of the role of nutrient sensing via the hexosamine pathway in the regulation of insulin action and body weight. Increased availability of nutrients promotes weight gain and insulin resistance both directly and via increased flux into the hexosamine pathway. However, the increased flux through the hexosamine pathway also stimulates the biosynthesis of leptin in adipose tissue and thus activates a biological response to both weight gain and insulin resistance. This response is largely mediated via the effects of leptin on the hypothalamus, which include changes in feeding behavior, substrate oxidation, and insulin action.

	Perspectives and conclusions

Top Introduction Satiety signals at the... Hexosamine pathway and insulin... Hexosamine pathway and... Satiety signals at the... Hexosamine pathway and... Perspectives and conclusions References

Received April 4, 2000.

	References

Top Introduction Satiety signals at the... Hexosamine pathway and insulin... Hexosamine pathway and... Satiety signals at the... Hexosamine pathway and... Perspectives and conclusions References

 

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