1 Departments of Medicine and Physiology, University of Alberta, Edmonton, Alberta, Canada T6G 2S2; and 2 Laboratory of Molecular Endocrinology, Massachusetts General Hospital, Howard Hughes Medical Institute and Harvard Medical School, Boston, Massachusetts 02114
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ABSTRACT |
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The prevalence of obesity and related
diabetes mellitus is increasing worldwide. Here we review evidence for
the existence of an adipoinsular axis, a dual hormonal feedback loop
involving the hormones insulin and leptin produced by pancreatic
-cells and adipose tissue, respectively. Insulin is adipogenic,
increases body fat mass, and stimulates the production and secretion of leptin, the satiety hormone that acts centrally to reduce food intake
and increase energy expenditure. Leptin in turn suppresses insulin
secretion by both central actions and direct actions on
-cells.
Because plasma levels of leptin are directly proportional to body fat
mass, an increase of adiposity increases plasma leptin, thereby
curtailing insulin production and further increasing fat mass. We
propose that the adipoinsular axis is designed to maintain nutrient
balance and that dysregulation of this axis may contribute to
obesity and the development of hyperinsulinemia associated with diabetes.
insulin secretion; diabetes
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OVERVIEW |
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The ob/ob and db/db mouse strains are both characterized by the development of obesity, hyperinsulinemia, and hyperglycemia, a syndrome resembling type 2 diabetes mellitus (28, 29, 43, 62, 63, 79). By a series of parabiosis experiments thirty years ago, in which the circulations of two animals became partially fused (ob/ob with db/db; ob/ob with +/+; db/db with +/+), Coleman (29) predicted that the ob/ob mice could respond to an appetite-suppressing hormone that it could not produce itself, whereas the db/db mice could produce this satiety factor but could not respond to it. The ob gene was identified in 1994 by use of positional cloning techniques; it encodes a 167-amino acid product termed leptin (188), which is comprised of a four-helical bundle similar to that of the long-chain helical cytokine family (97, 187). It was discovered that mutations in the ob gene of ob/ob mice prevent the synthesis of a functional leptin protein (188).
Although leptin is expressed at low levels in gastric epithelium (6), placenta (120), muscle (178), and possibly the central nervous system (46, 113), it is predominantly produced by and secreted from adipose tissue (188). As a consequence of this circumstance, plasma leptin levels are directly proportional to fat mass (33, 36, 42, 77, 104, 118, 121). It now appears that leptin is the long-sought-after hormone that communicates information about adipocyte metabolism and body weight to the appetite centers in the hypothalamic regions of the brain. Treatment of leptin-deficient ob/ob mice with recombinant leptin markedly increases energy expenditure and decreases food intake, body weight, and adiposity (17, 69, 135, 166, 182). The exogenous administration of leptin to mice also attenuates the neuroendocrine responses to food restriction, indicating that leptin may also play an important role in signaling nutritional status during periods of food deprivation (1).
The leptin receptor was first isolated from the mouse by the expression
cloning of complementary DNA prepared from the choroid plexus (171).
Positional cloning of the leptin receptor gene (db) revealed
that it encodes five alternatively spliced forms of mRNAs (110). As had
been predicted earlier from the parabiosis experiments, abnormal
splicing of the mRNA transcribed from the leptin receptor gene in
db/db mice results in a truncated version of the otherwise
longer signaling isoform (ObRb) (110). Therefore ObRb, the so-called
long form of the leptin receptor, is essential for the weight-reducing
effects of leptin. The functions of the other isoforms of the leptin
receptor remain unclear. Notably, however, it is now recognized that
leptin receptor isoforms are widely distributed throughout peripheral
organs (52, 66, 80, 115). These observations support the concept that
leptin has peripheral actions independent of its actions on the central
nervous system. In particular, the ObRb leptin receptor is expressed in the pancreatic -cells that produce insulin, raising the possibility that leptin directly regulates insulin release (94). Because the
adipogenic actions of insulin are well known, the idea was postulated
that leptin may suppress insulin release as part of a bidirectional
adipoinsular axis (94).
The reader is referred to several comprehensive reviews of leptin biology (5, 19, 32, 56, 61, 170). In this review we present the evidence that supports the existence of an adipoinsular axis in which leptin suppresses insulin production and secretion. The other limb of the proposed adipoinsular axis, the stimulation of leptin production and secretion in adipose tissue by insulin, seems to be well established and will only be reviewed briefly. To place the concept of the adipoinsular axis into a comprehensible body of understanding, it is helpful to describe briefly the biology of the endocrine pancreas and adipose tissue.
The Endocrine Pancreas
The endocrine pancreas consists of circumscribed clusters of endocrine tissue (islets of Langerhans) imbedded in the exocrine tissue of the pancreas. The islets are composed of at least four major phenotypically specific hormone-producing cells: theIt is important to appreciate that the factors involved in the regulation of the secretion of insulin and glucagon in response to meals are complex. The temporal aspects and the relative amounts of insulin secreted in response to a meal involve precise timing. These temporal and quantitative aspects of insulin secretion are orchestrated not only by absorbed nutrients, but also by complex neural and hormonal factors that are activated by feeding. Changes in sympathetic and parasympathetic tone in the autonomic nervous system, which enervates the islets, are of critical importance. Likewise, the secretion of intestinally derived hormones, so-called incretins, such as glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), are of paramount importance in the modulation of meal-induced insulin secretion. The intestinal incretin hormones augment glucose-dependent insulin secretion in response to the ingestion of nutrients. Therefore, there are multiple regulatory systems to ensure appropriate secretion of insulin and glucagon so as to maintain plasma glucose levels within a narrow range.
Adipose Tissue
There are two distinct types of adipose tissue, white and brown, which have entirely separate physiological functions. Brown adipose tissue resides in the central axis of the body and functions to dissipate energy and provide heat, i.e., brown adipose is a thermogenic organ. Brown adipose tissue plays a major role in the regulation of body temperature in small animals such as mice and rats, which have a high surface area to body volume and require hormonal regulation (adrenergic) of thermogenesis to maintain body temperature. In human infants, brown adipose tissue may provide a similar role. However, with aging, brown adipose atrophies, and thus the importance of brown adipose tissue in humans remains to be identified.White adipose tissue is widely distributed throughout the body and serves as a major depot of stored energy in the form of triglycerides. The triglycerides are stored during periods of excess energy availability and are mobilized during periods of energy deprivation. Thus white adipose tissue is unique in that it has enormous potential for changes in volume (and hence mass). Over the long term, adipose mass reflects the net balance between energy expenditure and energy intake. Remarkably, total adipose mass remains relatively stable in most individuals. It is now evident that the hormone leptin, produced and secreted predominantly by white adipose tissue, plays a key role in signaling to the hypothalamic centers controlling food intake and energy expenditure to maintain this balance.
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REGULATION OF LEPTIN PRODUCTION BY INSULIN |
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Because leptin is produced and secreted from adipocytes, and the
relative body mass of most individuals is determined to a large extent
by the fat mass, circulating leptin levels correlate directly with body
mass index (BMI) (33, 36, 42, 77, 104, 118, 121). Those individuals
with higher BMIs typically have a higher adipose tissue mass and
therefore higher levels of circulating leptin. This direct relationship
between BMI and plasma leptin levels has been verified by correlating
circulating leptin to body fat content (42, 104, 118). It is worth
noting that the regression between body weight or body fat content and
circulating leptin is not complete, in the range of 0.7-0.8, with
a correlation, or r2, of 0.5-0.6 (3),
indicating that other factors must also be involved in leptin
regulation. Furthermore, plasma leptin levels and leptin gene
expression increase at night and decrease acutely during fasting (33,
98, 118, 150, 160). These observations cannot be adequately accounted
for by corresponding changes in body fat content. In this regard a role
for nutrients, hormones, and neurotransmitters in the regulation of
leptin expression and secretion is emerging. For example, leptin
production by white adipose tissue is stimulated by insulin and
cortisol and attenuated by -adrenergic agonists, cAMP, and thiazolidinediones.
Insulin has been considered to be a potential regulator of leptin, because plasma insulin concentrations decrease during fasting and increase after refeeding in parallel with plasma leptin levels. Current evidence suggests that insulin plays a chronic role in the regulation of leptin gene expression and production by white adipose tissue. Hyperinsulinemia increases plasma leptin levels and gene expression in white adipose tissue after many hours in rodents and humans (34, 99, 100, 119, 149, 150, 174, 176). Plasma leptin levels and leptin mRNA are also increased in subjects with insulinoma, and plasma leptin levels return to normal after removal of the insulinoma (35, 138). Insulin deficiency induced by streptozotocin results in diminished plasma leptin levels and leptin mRNA, and this suppression is rapidly reversed by treatment with insulin (11, 78, 86, 117, 134, 162). This action of insulin appears to be mediated, at least in part, directly at the level of adipocytes, because insulin also increases leptin secretion and mRNA levels in vitro (8, 64, 70, 99, 111, 129, 143, 148, 164, 177, 185), perhaps due to increased glucose transport and metabolism (126). A candidate transcription factor, adipocyte determination differentiation dependent factor 1/sterol regulatory element binding protein 1 (ADD1/SREBP1), linking changes in insulin levels to ob gene expression in mice, was recently reported (96). ADD1/SREBP1 expression increases upon treatment of adipocytes with insulin, and the increased ADD1/SREBP1 transactivates the leptin gene (96). Undoubtedly other transcription factors, including members of the C/EBP and PPAR families, are involved in the regulation of leptin gene expression by hormones such as insulin (47, 85). For additional reviews on the regulation of leptin production, see the following references (3, 31, 83, 85).
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RATIONALE FOR PROPOSING AN ADIPOINSULAR AXIS |
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The hypothesis for the presence of an adipoinsular axis, or feedback
loop (see Fig. 1) between adipose tissue
and the endocrine pancreas (94), was generated on the basis of existing
literature on the leptin-deficient or -resistant ob/ob or
db/db mouse, respectively. Studies spanning three decades have
reported that in both of these obese, diabetic mouse models,
hyperinsulinemia precedes the development of both obesity and insulin
resistance (22, 25, 30, 43, 55, 62, 63, 68, 114). It seemed reasonable
that, if in the absence of a functional leptin signal, the first
metabolic abnormality observed is hyperinsulinemia, then perhaps in
normal circumstances leptin acts to curtail insulin release.
Physiologically such a pathway would be important in the regulation of
fat deposition. Insulin is a major adipogenic hormone. Therefore, as
fat stores increase, rising plasma leptin concentrations would reduce
insulin levels, thereby directing less energy to the formation of
adipose tissue. In the event that adipose stores diminish, falling
plasma leptin levels would permit increased insulin production, thereby resulting in the deposition of additional fat. Therefore, it was postulated that leptin might be considered as a thermostat or set point
to appropriately regulate insulin levels according to the extent of
adiposity (94). Such a putative feedback loop must be superimposed on
the well-established enteroinsular axis, whereby insulin secretion is
acutely regulated during meals by way of the secretion of intestinal
incretin hormones.
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In support of the hypothesis that leptin may directly suppress insulin
release from pancreatic -cells are the observations that the
administration of leptin for 5-30 days, either via injection, osmotic mini-pump, or gene therapy, lowers plasma insulin levels in
ob/ob mice (112, 128, 135, 151, 166, 182). In a recent study, a
single injection of leptin reduced plasma insulin levels in
ob/ob mice by ~75% after only 24 h (152). Furthermore, a
significant reduction in plasma insulin levels occurs within 10 min
after the administration of leptin to ob/ob mice (103). This
acute fall in plasma insulin levels is accompanied by a concomitant increase in plasma glucose levels. By 2 h after a leptin injection, the
plasma glucose excursion after an oral glucose challenge was significantly increased relative to saline-treated animals (71). Therefore, the acute reduction in plasma insulin levels after leptin
treatment does not appear to be secondary to either diminished body
weight or a fall in plasma glucose concentrations. Notably, however,
leptin treatment for longer periods of time appears to normalize plasma
glucose levels in hyperglycemic rodents (69, 72, 112, 128, 135, 151,
152, 166, 182). This effect of leptin appears to be mediated by an
increase in insulin sensitivity at the levels of the liver and
peripheral tissues (9, 13, 26, 92, 147, 154, 163, 179). Thus reductions
in circulating insulin levels after several hours or days of leptin
treatment likely result from both increased insulin sensitivity and a
direct leptin-mediated reduction in insulin secretion.
The autonomic nervous system likely contributes to the inhibitory
effect of leptin on insulin secretion. The administration of leptin in
vivo inhibits neuropeptide Y (NPY) gene expression (151, 166) and
secretion (166), which in turn could result in reduced insulin
secretion by either inhibiting the parasympathetic or activating the
sympathetic nervous system. In support of this notion, insulin levels
are reduced by one-half in ob/ob mice deficient in NPY (45).
Direct evidence has been obtained for the regulation by leptin of
sympathetic inputs to pancreatic -cells (123). In vagotomized rats,
leptin significantly suppresses the increase in plasma insulin levels
after an intravenous glucose injection. However, the effect of leptin
in vagotomized rats is abolished after chemical sympathicectomy (123).
Therefore, it appears that leptin can regulate insulin secretion
through the autonomic nervous system. However, there is now abundant
evidence to support the hypothesis that leptin also directly modulates
insulin secretion by actions on leptin receptors on pancreatic
-cells.
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DETECTION OF LEPTIN RECEPTORS IN ISLETS |
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There are multiple isoforms of leptin receptors (60, 110, 170). Although the short isoform of the receptor (ObRa) is capable of signaling (15, 127), the long isoform (ObRb) is currently believed to convey most of the physiological actions of leptin. The db/db strain of mice has a genetic defect that results specifically in the absence of expression of ObRb, whereas other isoforms of the receptor are not altered (21, 27, 110). Given that the resultant phenotype closely resembles that of the leptin-deficient ob/ob mice, including the presence of hyperinsulinemia, it seems probable that the actions of leptin on pancreatic islets are mediated largely by ObRb. This concept is substantiated by the observation that leptin has no insulin-lowering action either in vivo or in vitro in db/db mice, whereas leptin lowers plasma insulin levels in ob/ob mice studied in parallel (44, 103, 151).
To support the hypothesis of direct actions of leptin on pancreatic
-cells, evidence must be provided for the presence of leptin
receptors on these cells. On the basis of results of tissue surveys, it
is often argued that the only tissue where ObRb is found in high
abundance is the hypothalamus, raising doubts as to the possibility of
peripheral actions of leptin (60, 170). It is important to consider,
however, that pancreatic islets comprise only 1-2% of the entire
pancreas; the majority of the pancreas consists of an exocrine organ in
which large quantities of digestive enzymes are synthesized. Therefore,
pancreatic islet RNA represents a minor fraction of total pancreatic
RNA. Yet of 21 tissues examined by sensitive RNase protection assay,
total pancreas appears to have the most abundant proportion of ObRb
mRNA relative to ObRa mRNA of all the peripheral tissues examined, and
it is only second in amount to the brain and hypothalamus overall (11%
ObRb vs. 18 and 36%, respectively) (66). Thus, just as the proportion of ObRb mRNA is considerably enriched in hypothalamic preparations compared with total brain, the same is true of islet ObRb mRNA compared
with total pancreas. Messenger RNA for ObRb has been found in
relatively high abundance in murine pancreatic islets but was not
detected in whole pancreas by RNA blot hybridization because of the
limited sensitivity of the technique used and the dilution of
islet-specific RNA by exocrine pancreas RNA (44).
By use of a probe common to all leptin receptor isoforms, leptin
receptor mRNA was detected in rat islets in greater abundance than was
found in total brain (94). Leptin receptor mRNA was also observed by
RT/PCR in rat islets and the tumor-derived -cell line
TC3 (94).
Expression of a functional protein was confirmed by the observation
that
TC3 cells bind 125I-labeled leptin (94). These
initial observations support the hypothesis of the existence of an
adipoinsular axis. The presence of leptin receptors in pancreatic
islets has since been confirmed by a variety of techniques. Although
shorter isoforms of the leptin receptor may predominate, clearly ObRb
is expressed in pancreatic
-cells (44, 51, 89, 95, 101, 103, 107,
133, 136, 157, 169, 189). The distribution of leptin receptors within rat pancreatic islets was examined using antisera generated against an
extracellular epitope of the leptin receptor. Leptin receptor immunoreactivity was observed on the majority of
- and
-cells, but not on glucagon-producing
-cells (95). Similar results were
obtained using leptin tagged with the fluorescent compound iodocarbocyanine (Cy3) (95). The function of leptin receptors expressed
on somatostatin-secreting
-cells remains to be determined.
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ACTIONS OF LEPTIN ON PANCREATIC ISLETS |
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Insulin Secretion
The effects of leptin on insulin secretion have been studied in several different experimental settings, with variable and sometimes apparently conflicting results. The pancreatic islets (The application of leptin (6.25-100 nM) for 1-2 h to pancreatic islets isolated from ob/ob mice reduces insulin secretion from ~13 to almost 80% (44, 95). Leptin also significantly reduces insulin release from the perfused pancreas of ob/ob mice (44), a standard, reliable model to assess islet function. Notably, in ob/ob islets, the suppressive effect of leptin may be reduced at higher glucose levels and is absent in the presence of the incretin hormone GLP-1 (24, 95). One explanation for this observation is that leptin acts primarily during fasting to dampen insulin secretion and that this tonic inhibition is overcome by the nutrient and incretin signals (e.g., glucose and GLP-1) that accompany feeding (95). Leptin attenuates insulin release from ob/ob islets stimulated by either acetylcholine or the phorbol ester phorbol-12-myristate 13-acetate (PMA), both activators of protein kinase C (PKC) (24). At concentrations as low as 2.5 nM, leptin partially constrained acetylcholine-induced insulin secretion from islets of ob/ob mice, with an IC50 (effective concentration) of ~5 nM. The finding that leptin curtails acetylcholine-induced insulin secretion may in part explain why islets from leptin-deficient ob/ob mice have enhanced sensitivity to PKC-stimulated insulin secretion (22, 23).
In contrast to -cells of leptin-deficient ob/ob mice, the
-cells in normal rodents are continually exposed to leptin and therefore may be expected to be less sensitive. Overall, the reports regarding the effect of leptin on insulin secretion in normal rodents
are conflicting. There were no significant effects of leptin
(0.625-100 nM) on insulin release from isolated rat or mouse
islets at glucose concentrations ranging from 1.7 to 16.7 mM
(93, 136) or the perfused rat pancreas with 8.3 mM glucose and leptin
at either 1.0 nM (107) or 10.0 nM (108, 109). In one study, leptin (1 nM) stimulated insulin release from isolated rat islets incubated in 5 mM glucose (169). However, in the majority of studies, leptin
(1-20 nM) significantly reduced insulin release from the perfused
rat pancreas and isolated rat or mouse islets in the presence of either
low (2.8-3.3 mM) (51, 123), normal (5.5-8.0 mM) (87, 103), or
high (10.0-20.0 mM) glucose (44, 51, 123, 132, 133, 144). There
are no clear answers for these disparate observations.
Insulin secretion stimulated by agents that elevate cellular
concentrations of cAMP, such as glucose + IBMX, a phosphodiesterase inhibitor, or forskolin and GLP-1, is inhibited by leptin during both
static incubations and perifusions of mouse or rat islets (49, 136,
189). These observations suggest that in normal rodents, leptin
antagonizes cAMP signaling. Leptin also suppresses the elevations of
cellular cAMP levels that occur in response to exposure of -cells to
GLP-1 or to forskolin (189). A mechanism proposed to explain this
action of leptin on cAMP levels is a phosphoinositide 3-kinase (PI
3-kinase)-dependent activation of phosphodiesterase 3B (PDE3B) and
subsequent reduction of the intracellular cAMP (189). Notably, leptin
restrains insulin secretion from both mouse ob/ob islets (24)
and rat islets (132) induced by PMA, a PKC activator. Therefore, it
appears that leptin may antagonize insulin secretion from
-cells by
interacting with both cAMP-dependent protein kinase A (PKA) and PKC
signaling pathways.
Studies of cultured human islets in vitro indicate that they respond to leptin in a manner similar to that of mouse and rat islets. Leptin suppresses insulin secretion from human islets at concentrations as low as 0.01 nM (48, 103, 153). Thus it appears from these findings in studies of human islets that humans are likely to have a functional adipoinsular axis.
The effects of leptin on insulin secretion have also been investigated
in various -cell lines derived from islet cell tumors (insulinomas).
The results obtained in different insulinoma cell lines have been
contradictory and less consistent than those of studies in cultured
islets and the perfused pancreas. In mouse MIN6 cells and hamster
HIT-T15 cells, murine leptin increased insulin secretion (157, 169). In
contrast, in other studies, leptin (2 nM) inhibited both glucose and
GLP-1-stimulated insulin secretion from HIT-T15 (189), rat RIN5AH, rat
RINm5F, and mouse
TC6 cells (103). The inhibition of insulin
secretion by leptin in
TC6 cells was observed at 10 min and achieved
a maximum by 60 min. In the rat insulinoma cell line INS-1, leptin
significantly reduced insulin secretion stimulated by agents that
increase intracellular content of cAMP (i.e., GLP-1), but not insulin
secretion stimulated by activators of PKC (i.e., carbachol) (2, 49).
These latter observations suggest that, in the INS-1 cell line, the
cAMP-PKA signal transduction pathway is a target by which leptin may
inhibit insulin secretion. A proliferative response to leptin was
observed in RINm5F cells and mouse MIN6 cells, as measured by
[3H]thymidine incorporation (89, 168). Notably,
however, incubation of mouse islets with 100 nM murine leptin for 48 h
had no effect on islet cell replication, as assessed by the same
[3H]thymidine incorporation assay (93). Thus
leptin responses in transformed cell lines may not necessarily reflect
the response of native
-cells.
Insulin Gene Expression
In a few studies, leptin had no effect on insulin biosynthesis (93, 144), and in one other study (157) leptin (unreported source) treatment increased preproinsulin mRNA levels in HIT-T15 cells. However, leptin has been shown to suppress preproinsulin mRNA expression in isolated rat islets (103, 133), in mouseIncubation of INS-1 cells with leptin (0.625 nM or 6.25 nM) for 16 h significantly reduces preproinsulin mRNA expression when incubated at 25 mM glucose, but not 5.6 or 11.1 mM glucose (152). These findings indicate a dependence of leptin-mediated reductions of preproinsulin mRNA expression on glucose augmentation. However, as with human islets, the stimulation of preproinsulin mRNA expression by GLP-1 (10 nM) is also inhibited by leptin (6.25 nM) at both 5.6 and 11.1 mM glucose (152). Of note, there was no effect of leptin on steady-state levels of preproinsulin mRNA after a 6-h incubation.
The effect of leptin on the transcriptional activity of the insulin gene promoter has been examined. A reporter vector expressing the luciferase gene under control of 410 bp of the rat insulin I gene promoter was transfected into INS-1 cells. Leptin (6.25 nM) inhibited reporter gene expression at 25 mM glucose by 50%, but no such inhibition was observed at 5.6 or 11.1 mM glucose (152). However, the induction of transcriptional activity by GLP-1 (10 nM) in the presence of 11.1 mM glucose was nearly completely inhibited by leptin. These observations indicate that activation of transcription by either GLP-1 or high glucose (25 mM) restores the inhibitory actions of leptin on rat insulin I promoter activity at a glucose concentration (11.1 mM) in which leptin alone fails to reduce insulin promoter activity (152).
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MECHANISM OF LEPTIN ACTION ON ![]() |
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The leptin receptor gene encodes multiple splice variants of the leptin
receptor (ObRa-ObRf), which closely resemble the class I cytokine
receptors (110, 170, 171). The longest form of the leptin receptor,
ObRb, contains intracellular consensus motifs for interaction with
cytoplasmic protein kinases, known as JAKs (Janus kinase), and protein
transcription factor kinase substrates of the signal transducers and
activators of transcription (STAT) family. Leptin appears to interact
with homo-oligomerized ObRb (10, 183, 184), resulting in activation of
JAK2 (65), which phosphorylates a number of substrates, including ObRb.
When phosphorylated, ObRb serves as a scaffold for recruitment of STATS
(10, 15, 66, 175). STATS themselves are also substrates for JAK, and when activated, either homo- or heterodimerize and translocate to the
nucleus, where they modulate the transcription of target genes (37).
STATS 1, 3, 5, and 6 are all reportedly activated by leptin (10, 66,
125, 146, 158, 175). Signaling capabilities have also been reported for
short (ObRa) isoforms of the leptin receptor (15, 127). However,
because leptin has no effect on islets isolated from db/db
mice, which harbor mutations resulting in aberrant mRNA that encodes
only a shortened form of ObRb (21, 110), the direct effects of leptin
on -cells are likely mediated via ObRb.
A brief review of intracellular signaling pathways within pancreatic
-cells is required to interpret possible pathways involved in leptin
signaling. Insulin secretion from pancreatic
-cells is controlled in
part by the activity of KATP channels. Closure (inactivation) of KATP channels in response to glucose or
other insulin secretagogues depolarizes
-cells, resulting in the
activation of voltage-dependent Ca2+ channels, a rise in
cytosolic calcium concentration
([Ca2+]i), and insulin secretion
(4). Glucose metabolism within
-cells also results in an elevation
of fatty acyl-CoA esters, which synergize with rises in
[Ca2+]i to cause induction of
insulin release (139). Glucose-induced insulin secretion is further
potentiated by hormone-mediated elevation of the intracellular second
messengers cAMP/PKA (81) and phospholipase C/PKC (186). Thus there are
multiple potential sites for leptin signaling to influence insulin secretion.
Clues to the cellular mechanisms by which leptin suppresses insulin
release come from earlier studies utilizing ob/ob and db/db mouse islets. Notably, over two decades ago it was
reported that islets from db/db mice are partially depolarized,
even in the absence of glucose (122). This circumstance is associated with elevated basal insulin release and unresponsiveness to further elevation of the glucose concentration (122). The K+
permeability of both ob/ob and db/db islets is
relatively insensitive to changes in glucose (12, 59, 145), yet this
insensitivity does not appear because of a failure of the cells to
express functional KATP channels (58, 102). Because these
phenotypes both result from the absence of leptin signaling, it was
postulated that leptin may normally open (activate) KATP
channels on -cells and thereby hyperpolarize the membrane. Such a
mechanism would be consistent with the observations that leptin reduces
insulin secretion (95).
Patch-clamp electrophysiological analyses on both normal and
ob/ob mouse -cells show that the application of leptin
(1-10 nM) to single mouse
-cells (95) or the CRI-G1 cells (75, 76) consistently results in hyperpolarization, consistent with an
inhibitory action of leptin on insulin secretion. The effect of leptin
is delayed by 10-15 min, similar to that observed previously for
potassium channel activation by janus kinase-associated prolactin receptors in Chinese hamster ovary cells (140). Leptin also increases membrane conductance, consistent with the opening (activation) of
ATP-sensitive K channels (KATP channels). The activation of KATP channels by leptin is further supported by the
observations that the leptin response is sensitive to the application
of the sulphonylureas tolbutamide and glibenclamide, selective blockers of KATP channels. Leptin-induced increases in membrane
conductance and the resulting hyperpolarization are immediately and
completely reversed by the application to
-cells of tolbutamide (100 µM) or glibenclamide (0.5 µM) (73, 75, 76, 95). Notably, in single
ob/ob mouse
-cells, the increase in conductance is biphasic in nature (95). The reversal potential associated with the increase in
cell conductance in response to leptin is characteristic of the
activation of a potassium current (75, 76, 95).
A confirmation of the KATP channel as the molecular target
for action of leptin in -cells was obtained from single-channel recordings. Application of leptin (1-10 nM) induces an increase in
the activity of single potassium channels that are sensitive to ATP and
sulphonylureas (76, 95). Leptin increases the KATP open
channel probability with no significant effect on open times (95).
Notably, the activation of KATP channels in CRI-G1 cells by
leptin is reversed by nanomolar concentrations of insulin (74). This
effect is specific for leptin, because insulin fails to prevent opening
of KATP channels by diazoxide (74). These observations suggest that leptin suppresses insulin secretion during fasting, when
ambient insulin levels are low (74). However, during feeding, the
resultant increases in insulin levels inhibit the opening of
KATP channels by leptin and prevent the inhibition of
insulin secretion. Such a model could explain in part the apparent
resistance to leptin actions observed in obese individuals who are
typically hyperinsulinemic, even during fasting.
Given the important role of KATP channels in determining
[Ca2+]i in -cells, it is
anticipated that application of leptin to
-cells results in a
decrease in [Ca2+]i. A fall in
[Ca2+]i occurs in both mouse and
human single
-cells after application of leptin (6.25 nM) (95, 153).
Notably, this fall in [Ca2+]i is
reversed by co-incubation of the
-cells with 20 mM glucose and GLP-1
(10 nM) (95). A 15-min preincubation of INS-1 cells with leptin reduces
the subsequent rise in [Ca2+]i in
response to either forskolin (1 µM) or GLP-1 (10 nM) (49). Leptin (10 nM) also attenuated glucose-induced elevations in
[Ca2+]i in mouse islets (51). Of
note, leptin also hyperpolarizes glucose-receptive hypothalamic neurons
via opening (activation) of KATP channels (165). Therefore,
the KATP channel may function as the molecular end point of
the leptin signaling pathway in both hypothalamic neurons and
pancreatic
-cells.
By what mechanisms might leptin open KATP channels and thereby lower [Ca2+]i and inhibit insulin secretion? Dialysis with AMP-PNP, a nonhydrolyzable analog of ATP that does not serve as a substrate for protein kinases, prevents leptin activation of KATP channels, indicating that phosphorylation or dephosphorylation is involved (75). The serine/threonine-specific protein phosphatase inhibitors okadaic acid (50 nM) and cyclosporin A (1 µM) fail to block activation of KATP channels by leptin (75). In contrast, whole cell dialysis with the tyrosine phosphatase inhibitor orthovanadate (500 µM) prevents the actions of leptin, suggesting that protein phosphorylation of tyrosine, but not serine/threonine, residues underlies actions of leptin in CRI-G1 cells. Furthermore, inhibition of tyrosine kinase activity by application of genistein (10 µM), tyrphostin B42 (10 µM), or herbimycin A (500 nM) mimics the leptin-induced hyperpolarization and increase in K+ conductance (75). Therefore, the mechanism underlying the opening of KATP channels by leptin may involve inhibition of tyrosine kinases or activation of tyrosine phosphatases and subsequent tyrosine dephosphorylation. Because the opening of KATP channels by leptin is blocked by wortmannin (1-10 nM) and LY-294002 (10 µM), inhibitors of PI 3-kinase, the mechanism underlying leptin activation of KATP channels appears to involve dephosphorylation of cytosolic proteins before activation of PI 3-kinase (74).
Further support for the concept that leptin activates PI 3-kinase is provided by the findings that treatment of insulinoma HIT-T15 cells with murine leptin (2 nM) for 30 min results in a threefold activation of PI 3-kinase (189). PDE3B, which reduces the cellular content of cAMP, is also activated by leptin. Thus, in HIT-T15 cells, leptin (1-5 nM) suppresses the elevation of cAMP induced by GLP-1 (5 nM) (189). This suppression is a PI 3-kinase-dependent process, because the addition of the PI 3-kinase inhibitors wortmannin (20 nM) or LY-294002 (2 µM) abolishes the activation of PDE3B by leptin and the inhibitory effect of leptin on glucose- and GLP-1-stimulated insulin secretion from the HIT cells (189). Furthermore, treatment of HIT cells with either milrinone (1 µM) or enoximone (1 µM), selective inhibitors of type 3 PDE, completely blocked the inhibitory effect of leptin on glucose- or GLP-1-potentiated insulin secretion. These findings suggest that the inhibitory actions of leptin on insulin secretion are primarily mediated through the PI 3-kinase-dependent activation of PDE3B and a subsequent reduction of the intracellular cAMP (189). Because cAMP potentiates insulin secretion in part by closing (inactivating) KATP channels (81, 82), a reduction of cAMP by leptin is consistent with the activation of KATP channels by leptin.
Another mechanism by which leptin may open KATP channels is
through lipid metabolism in -cells. It has been proposed that leptin
increases the storage of triglycerides in adipocytes to maintain a
constant level of intracellular triglycerides in nonadipocytes, such as
-cells (173). Culture of isolated islets with leptin depletes the
content of triglycerides and increases the oxidation of free fatty
acids (101, 156). This lipopenic action of leptin is not observed in
islets isolated from leptin-resistant fa/fa Zucker diabetic
fatty rats but is reestablished upon the restoration of expression of
the leptin receptor (ObRb) in the islets (155, 180, 181). This action
of leptin appears to be dependent on formation of fatty acyl-CoA.
Remarkably, long-chain acyl-CoA esters (LC-CoA), the metabolically
active form of free fatty acids, bind to and open KATP
channels in pancreatic
-cells (16, 105). Therefore, it is possible
that elevations in LC-CoA within
-cells after exposure to leptin
result in activation of KATP channels and thereby
inhibition of insulin secretion.
The inhibitory effects of leptin on preproinsulin gene expression appear to be independent of the activation of KATP channels. Diazoxide, which also opens KATP channels, has no effect itself on preproinsulin mRNA levels in INS-1 cells and does not alter the suppressive effect of leptin (152). Furthermore, inhibition of insulin promoter activity in INS-1 cells at 25 mM glucose was detected in both the presence and absence of KATP channel activation by diazoxide (152). These findings indicate that inhibition of preproinsulin gene expression by leptin is independent of the opening of KATP channels and suggests that the molecular mechanisms underlying inhibition of insulin secretion and preproinsulin mRNA by leptin are mediated by different intracellular signaling pathways.
Activation of STAT proteins in -cells after leptin treatment is
clearly a candidate pathway for the mechanism of action of leptin on
insulin gene expression. Treatment of RINm5F cells and isolated rat
islets with leptin induces the binding of STATs to a labeled
oligonucleotide containing a high-affinity binding element for STAT1
and STAT3 (124). This binding is not altered by treatment with
plasminogen activator (PMA, a PKC activator; 100 nM) but is reduced by
treatment with acetylcholine (10 µM), ionomycin (calcium ionophore; 1 µg/ml), forskolin (adenylyl cyclase activator; 10 µM), and IBMX
(cAMP phosphodiesterase inhibitor; 50 µM). The activation of STAT3 is
suggested by the observation that treatment of rat pancreatic islets
with leptin produces an increase in the tyrosine phosphorylation of
STAT3 (124). Similarly, in MIN6 cells, leptin (5 nM) increases tyrosine
phosphorylation of STAT1 and STAT3, but not STAT5 (168). Leptin also
increases the transcriptional activation of reporter plasmids
containing STAT3 binding elements, but not the STAT5 consensus element,
in RINm5F cells (124). These observations implicate STAT3 as a
potential mechanism by which leptin regulates gene expression in
-cells. Furthermore, the STAT3 pathway appears to be antagonized by
elevations of [Ca2+]i and cAMP.
That STAT proteins may mediate the inhibition of insulin gene
expression after leptin treatment was shown by DNA-binding assays in
which sequences between 307 and
410 bp of the rat insulin I gene promoter bind multiple protein complexes contained in nuclear extracts from leptin-treated ob/ob islets. One of the complexes contained STAT5b, which formed on a previously described consensus STAT
binding site (152). Although STAT proteins are generally considered to
be activators of gene transcription, they may also be inhibitory,
depending on the promoter context and cell type. For example, STAT5b
stimulated by prolactin induces the
-casein promoter but inhibits
the interferon regulatory factor-1 promoter (116).
In addition to activating a STAT pathway within pancreatic -cells,
the leptin receptor appears to be coupled to a mitogen-activated protein kinase (MAPK) pathway in MIN6 and RINm5F cells (124, 168). The
phosphorylation of MAPK in response to leptin was observed with 0.3 nM
leptin and was maximal with 5 nM leptin (168). However, the activation
of MAPK by leptin may be limited to tumor-derived
-cell lines,
because treatment of rat islets with concentrations of leptin up to 100 nM did not result in activation of MAPK (124). Please see Fig.
2 for a summary of leptin signaling
pathways within pancreatic
-cells.
|
![]() |
CONCLUDING REMARKS |
---|
Leptin is an important controller of food intake and energy expenditure
by its actions on receptors located in regions of the hypothalamus that
regulate feeding behavior. There is now growing evidence that leptin
also acts to suppress insulin production from pancreatic -cells.
Because insulin is adipogenic and increases the expression of leptin,
there is a bidirectional feedback loop between adipose tissue and
pancreatic islets, termed the adipoinsular axis. The majority of
evidence in support of an adipoinsular axis has come from studies in
rodents or cell lines, but there is also evidence to suggest that a
similar pathway exists in humans. Given the well-known direct
relationship between increased adiposity (leptin) and increased insulin
levels (7, 88, 137, 167), it has been questioned whether leptin
inhibits insulin release in humans (18). If it did, why would obese
hyperleptinemic individuals be hyperinsulinemic?
It is generally believed that hyperinsulinemia is simply a compensatory
response to insulin resistance (20, 38, 39, 53, 67, 90, 91, 131, 141,
142, 172). Hyperglycemia is believed to occur when -cells can no
longer compensate adequately for insulin resistance, resulting in the
development of diabetes. However, many recent studies challenge this
dogma because of the observations that hyperinsulinemia appears to
precede decreases in insulin sensitivity and perhaps even the
development of obesity in humans, thus arguing against the belief that
obesity-induced insulin resistance fully explains the development of
type 2 diabetes (54, 106, 130, 159). Hyperinsulinemia promotes
adipogenesis and may initiate a cycle of increasing insulin resistance,
compensatory hyperinsulinemia, and a progression to the diabetic state.
In obese individuals, sustained elevated levels of plasma leptin are
proposed to uncouple leptin actions on its receptors in the
hypothalamus, thereby attenuating signal transduction pathways that
exert the effects of the hormone on satiety and energy expenditure (14,
57). Given that leptin suppresses insulin secretion by autonomic
outputs originating in hypothalamic circuitry, breakdown of the central
leptin signal may contribute to hyperinsulinemia. By analogy to leptin
actions on the hypothalamus, in conditions of increasing adiposity and
prolonged elevated plasma leptin levels, the leptin signaling system in
pancreatic -cells may become unresponsive. Such a putative loss of
leptin reception by
-cells could result in dysregulation of the
adipoinsular axis and a corresponding failure to suppress insulin
secretion, resulting in chronic hyperinsulinemia. Additionally, the
hyperinsulinemia exacerbates the obesity by increasing adipogenesis and
increasing leptin production. This positive feedback loop of leptin
desensitization at both the hypothalamus and pancreatic
-cells may
result in hyperphagia and hyperinsulinemia, respectively, and thus may
be an important factor in the pathogenesis of obesity-associated
diabetes mellitus. Furthermore, it has recently been proposed that such
dysregulation of the adipoinsular axis may occur independently of
obesity in subjects who are susceptible to the development of diabetes
(88). Thus investigation of the adipoinsular axis dysregulation
hypothesis may lead to the identification of determinants of both human
obesity and diabetes.
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ACKNOWLEDGEMENTS |
---|
We are grateful to Townley Budde for assistance in the preparation of this manuscript. T. J. Kieffer acknowledges support from the Alberta Heritage Foundation for Medical Research, the Medical Research Council of Canada, and the Canadian Diabetes Association. J. F. Habener is an Investigator with the Howard Hughes Medical Institute.
![]() |
FOOTNOTES |
---|
Please address correspondence and reprint requests to either T. J. Kieffer, Div. of Endocrinology and Metabolism, 370 Heritage Medical Research Centre, Univ. of Alberta, Edmonton, AB, Canada T6G 2S2 (E-mail: tim.kieffer{at}ualberta.ca); or J. F. Habener, Laboratory of Molecular Endocrinology, Massachusetts General Hospital, 55 Fruit St., WEL320, Boston, MA 02114 (E-mail: jhabener{at}partners.org).
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