Endocrinology Vol. 141, No. 6 1922-1925
Copyright © 2000 by The Endocrine Society
Perspective: Hexosamines and Nutrient Sensing
Luciano Rossetti
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
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Introduction
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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.
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Satiety signals at the cellular level
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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.
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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.
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Hexosamine pathway and insulin resistance
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In adipose cells and in skeletal muscle, following the transport
and phosphorylation of glucose to glucose-6-phosphate (Glc-6-P), the
latter is primarily used in two major pathways, i.e.
glycogen synthesis and glycolysis (4, 17). However, approximately
1–3% of the incoming glucose that is converted to
fructose-6-phosphate (Fru-6-P) enters the hexosamine biosynthetic
pathway (Fig. 1
), whose major end product,
UDP-N-acetyl-glucosamine (UDP-GlcNAc) serves as substrate
for multiple glycosylation reactions. Several recent studies have
demonstrated that increased flux of Fru-6-P into the hexosamine
biosynthesis pathway antagonizes the ability of insulin to stimulate
glucose uptake in vivo and in isolated cell systems (4, 5, 15, 18, 19, 20, 21, 22, 23, 24, 25, 26). The latter represents a likely
mechanism by which chronic hyperglycemia results in defective
stimulation of glucose transport by insulin (8).
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.
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Hexosamine pathway and regulation of gene expression
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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).
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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.
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Satiety signals at the whole body level
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It has long been recognized that a circulating "satiety
factor" plays a major role in the maintenance of energy homeostasis
in mammals. Lack of this factor leads to severe obesity in rodents
(32). In 1994, Zhang et al. (33) cloned this factor as a
16-kDa protein produced by adipose cells and later named it leptin. It
is now accepted that leptin exerts multiple behavioral, hormonal, and
metabolic actions mainly through its interaction with specific
hypothalamic receptors (1, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43). Many of leptin’s effects can be
interpreted as an attempt to limit excessive storage of energy into
lipid stores. This is accomplished via induction of satiety, increased
energy expenditure, and preferential oxidation of lipids.
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Hexosamine pathway and regulation of leptin biosynthesis
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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.
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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.
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Perspectives and conclusions
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The metabolic diseases of our era, obesity and type 2 diabetes
mellitus, share the common features of insulin resistance and early
onset of vascular diseases. Environmental triggers for these metabolic
syndromes have long been recognized and include the increased
availability and consumption of high calorie nutrients. However, it has
been difficult to identify the biochemical and molecular mechanisms,
which can mediate the complex effects of nutrients on metabolic
processes. The recent progress in our understanding of multiple
biochemical and molecular pathways responsive to nutrients is likely to
close the gap between epidemiological and clinical findings. The
hexosamine biosynthetic pathway is ideally positioned to function as a
prominent cellular sensor for the availability of carbohydrates and in
certain tissues of lipids. There is evidence for its pleiotropic roles
in the regulation of insulin action and gene transcription with
significant implications for the pathophysiology of insulin resistance,
obesity, and micro- and macrovascular complications of diabetes
mellitus. While the journey has just begun, this is a promising
direction. However, several issues remain quite confusing and
controversial. For example, the proposed role of this pathway in the
regulation of leptin biosynthesis and insulin resistance has to be
reconciled with the generally tight association of weight gain (which
theoretically should be prevented by leptin) and insulin resistance. A
failure of either nutrient-mediated stimulation of leptin secretion
and/or in leptin biological action has to be hypothesized (Fig. 3).
Indeed, the transgenic mice with GFAT overexpression are not lean
despite chronically increased levels of circulating leptin (50).
Finally, the molecular mechanisms responsible for the effects of the
hexosamine biosynthesis pathway on insulin action and gene expression
remain to be delineated.
Received April 4, 2000.
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Top
Introduction
Satiety signals at the...