Abstract
The hormone leptin is secreted by adipose tissue in proportion to fat mass to signal the repletion of body energy stores to the neuroendocrine system. Leptin acts on neurons in the hypothalamus and elsewhere in the brain to decrease appetite and regulate the activity of the thyroid, adrenal, growth, gonadal, and lactational axes. Conversely, absence of leptin signaling initiates the neuroendocrine starvation response. Leptin mediates these effects by activating the long form (LRb) of its receptor. One LRb signal, STAT3, has recently been shown to play a critical role in the regulation of body weight and some elements of neuroendocrine function (thyroid, adrenal, lactation), although the participation of STAT3 in the gonadal and growth axes is negligible. We discuss these findings in the context of the hypothalamic neuroendocrine system as it is presently understood.
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Leptin and leptin action
Leptin production reflects body energy balance
Adipose cells are the primary source of leptin. Leptin production by fat cells in culture is stimulated by glucocorticoids and indicators of acute nutritional influx such as insulin and is inhibited by the counterregulatory hormones and their intracellular signaling mediators [1, 2, 3]. This regulation of leptin production by insulin (feeding→increased insulin→increased leptin) and counterregulatory hormones (fasting→increased counterregulatory hormones→decreased leptin) suggests that leptin serves as an indicator of energy balance, i.e., that increased energy stores yield increased leptin levels. Indeed, circulating leptin levels are strongly correlated with body adiposity and changes in acute nutritional status [4, 5, 6].
The stimulation of leptin production by glucocorticoids appears counterintuitive in this light, however, since circulating glucocorticoids are important mediators of the stress and starvation responses. Indeed, while plentiful data suggest that insulin is a critical mediator of increased leptin production in vivo, the diurnal pattern of leptin levels and numerous other data argue against an important role for circulating glucocorticoids in the stimulation of leptin production [7]. In contrast, adipocyte-produced autocrine- or paracrine-acting glucocorticoids may be involved, since the production of glucocorticoids by adipocytes increases with the accumulation of triglycerides, and mouse models with increased glucocorticoid production specifically in adipocytes have elevated leptin levels [8].
Integrating this information, then, circulating leptin levels reflect adipose mass (perhaps via the production of glucocorticoids, and reflecting long-term energy stores) modified by circulating levels of insulin (reflecting recent food intake) and counterregulatory hormones (reflecting lack of recent food intake). Leptin levels are also regulated by other factors, and are stimulated by infection and cytokines such as leukemia inhibitory factor, tumor necrosis factor, and interleukin-1, which may play a role in infection-induced weight loss [9, 10].
Leptin regulates body energy homeostasis and neuroendocrine responses to fasting
When energy stores are replete, leptin production is high; conversely, fasting and the depletion of fat mass inhibits leptin production [11, 12]. Leptin is thus well designed to communicate body energy status throughout the body. Indeed, low leptin levels enhance appetite and decrease energy utilization by initiating the endocrine starvation response [13]. Adequate leptin levels moderate appetite and permit normal growth and reproduction in addition to activating the thyroid axis and suppressing the production of adrenal corticosteroids (Fig. 1); leptin also activates the sympathetic nervous system [14].
Lack of the leptin signal in mice (and humans) genetically null for leptin (ob/ob mice) or the leptin receptor (LR; db/db mice) results in early-onset obesity secondary to increased feeding and decreased energy utilization [11, 12, 15, 16]. These mouse models also display a phenotype reminiscent of the neuroendocrine starvation response, including hypothyroidism, hypercorticosteronism, decreased growth, and infertility. Indeed, exogenous leptin replacement during food restriction normalizes each of these parameters as well as decreasing appetite [13]. Interestingly, while the evidence from humans supports the idea that leptin regulates appetite as well as thyroid, growth and gonadal function, the adrenal axis does not appear to be regulated by leptin in humans [17].
Leptin receptors and sites of leptin action
The primary LR transcript is alternately spliced to yield a number of isoforms; in the rodent, these are termed LRa–LRf [18, 19, 20]. A related transcript from within the LR genomic DNA produces no receptor, but the transcript (leptin receptor gene-related transcript) may regulate transcription from the leptin receptor promotor [21]. LRa–LRd and LRf contain identical extracellular leptin binding and transmembrane domains as well as the same first 29 intracellular amino acids, and diverge in sequence secondary to alternative splicing of 3′ exons [22]. LRe contains only the coding sequences for extracellular leptin binding domains and is secreted; proteolytic cleavage of the extracellular domains of at least some other isoforms also contributes to circulating LR. These circulating LR isoforms complex with circulating leptin and may regulate leptin availability [23].
LRa–LRd, and LRf, the isoforms containing transmembrane domains, fall into two classes: short, and long. The long form, LRb, is highly conserved among species and possesses an intracellular domain of approximately 300 residues [24, 25]. Of the short forms (LRa, LRc, LRd, LRf) only LRa is conserved across mammalian species, and the intracellular domains contain only 32–40 amino acids in the rodent. While the function of the short LR forms remains unclear, LRb is critical for leptin action. Indeed, the originally described db/db mice lack only LRb (as a consequence of a mutation that results in missplicing of the LRb message) but exhibit a phenotype indistinguishable from that of leptin-deficient ob/ob animals and of db 3J /db 3J mice (which are deficient in all LR isoforms) [11, 24, 25].
Much of the action of leptin is attributable to effects in the CNS, especially in the basomedial hypothalamus, the site of highest LRb expression [26, 27]. Indeed, transgenic replacement of LRb that is restricted to neurons in db 3J /db 3J animals attenuates the majority of the db/db phenotype [28]. While a saturable transport system has been shown to move leptin across the blood-brain barrier, the sites of highest LRb expression lie within extremely close proximity to the median eminence, and it is likely that leptin reaches these target hypothalamic neurons without requiring transport across the blood-brain barrier [29, 30]. In the hypothalamus leptin acts on neurons that regulate levels of circulating hormones (e.g., thyroid hormone, sex steroids, and growth hormone) [26, 31]. Leptin action on these hypothalamic neurons also regulates the activity of the autonomic nervous system, although direct leptin action on brainstem LRb-expressing neurons likely plays an important role as well [32, 33].
Leptin resistance and obesity
Over one-quarter of adult Americans are obese, and the incidence of obesity continues to rise in industrialized nations. Obesity is a major risk factor for type 2 diabetes, cardiovascular disease, and some forms of cancer [34]. Since administration of leptin to rodents decreases food intake and blocks the diurnal decrease in energy expenditure, resulting in loss of fat mass, leptin was initially hailed as a potential cure for obesity [11, 12, 24, 26, 31]. With the exception of humans with (rare) genetic leptin deficiency [15, 17], however, circulating leptin levels are correlated with body mass index and total body fat mass. Hence obese individuals have elevated circulating leptin levels, but this leptin fails to mediate weight loss, suggesting that most human obesity is a form of leptin resistance. It is not clear whether this leptin resistance is causative or represents feedback inhibition due to elevated circulating leptin in obesity, however. Indeed, although therapy with exogenous leptin does augment weight loss, the effects of leptin are modest under the conditions that have been tested [35].
A number of potential mechanisms have been postulated to underlie leptin resistance, including defects in leptin access into the brain, in LRb signaling, and in pathways/neurons that mediate downstream leptin action. Since leptin can likely access the appetite centers of the basomedial hypothalamus without relying on a specific transport mechanism, we favor the hypothesis that alterations in leptin signaling or in pathways downstream of leptin action in the hypothalamus mediate leptin resistance.
LR signaling
LRb mediates Jak2 activation
LRb belongs to the interleukin-6 receptor family of class 1 cytokine receptors which contain an extracellular ligand-binding domain, a single transmembrane domain, and a cytoplasmic signaling domain [24, 36]. As with other cytokine receptors, LRb does not contain intrinsic enzymatic activity but instead signals via a noncovalently associated tyrosine kinase of the Jak kinase family (Jak2 in the case of LRb) [37, 38, 39]. Unliganded LRb exists as a preformed homodimer; leptin binding alters the conformation of the LRb dimer, enabling transphosphorylation and activation of the intracellular LRb-associated Jak2 molecules [24, 40, 41]. The activated Jak2 molecule then phosphorylates other tyrosine residues within the LRb/Jak2 complex to mediate downstream signaling [42, 43].
Signaling by cytokine receptors requires a proline-rich “box 1” motif critical for Jak kinase interaction and activation; additional less-conserved sequences COOH-terminal to box 1 (sometimes referred to as “box 2”) are also important for Jak kinase interactions and likely function in Jak kinase isoform selectivity [36, 37, 39]. In the case of LRb intracellular residues 31–36 (i.e., immediately downstream of the alternative splice junction following amino acid 29) compose box 2 [39]. Homology between the box 2 regions of LRb and other Jak2-associated cytokine receptors suggests that a loosely conserved E/N-X0–2-E/N-X0–2-L/I motif mediates Jak2 association [39]. This motif is absent from all described short LR isoforms, explaining the inability of these molecules to mediate leptin action in db/db animals [24, 39, 42]. These data suggest that ability of LRa to activate extracellular signal regulated kinase (ERK) signaling in transfected cells likely represents an artifact of Jak2 overexpression [44].
Phosphotyrosine-dependent signaling by LRb
Tyrosine kinase-dependent signaling generally proceeds via the phosphotyrosine-dependent recruitment of signaling proteins that contain specialized phosphotyrosine-binding domains (e.g., Src homology, SH, 2 domains) [45]. Each SH2 domain isoform recognizes phosphotyrosine in a specific amino acid context. Thus, while tyrosine phosphorylation acts as a molecular switch to recruit SH2-containing proteins, each tyrosine phosphorylation site recruits only specific SH2 isoforms since they recognize the surrounding amino acids as well as the phosphotyrosine residue. For instance, the SH2 domain of the latent transcription factor, signal transducer and activator of transcription (STAT) 3, is recruited to phosphotyrosine in the context of a Y (P)XXQ motif [46, 47].
Understanding signaling by the LRb/Jak2 complex thus requires defining the tyrosine phosphorylation sites on LRb and Jak2 and the SH2 proteins that they recruit. There are three conserved residues on the intracellular domain of LRb Tyr985, Tyr1077, and Tyr1138 [24, 43, 42]. Tyr985 and Tyr1138 are phosphorylated upon leptin binding, while Tyr1077 is not phosphorylated and does not contribute to leptin signaling [43].
There are thus three primary intracellular signaling pathways that emanate from LRb (Fig. 2): Those originating directly from Jak2 tyrosine phosphorylation sites, from Tyr985 of LRb, and from Tyr1138 of LRb. The phosphorylation of Tyr985 creates a binding site for the COOH-terminal SH2 domain of the tyrosine phosphatase, src homology 2 containing phosphatase (SHP) 2. Recruitment of SHP-2 results in its tyrosine phosphorylation and recruitment of GRB2, the first step in the canonical p21ras→ERK signaling pathway. While Tyr985 thus mediates the majority of ERK stimulation during LRb signaling, a small amount of ERK activity occurs independently of LRb phosphorylation, presumably via tyrosine phosphorylation sites on Jak2 [39, 43, 48].
Phosphorylation of Tyr1138 recruits STAT3 to the LRb/Jak2 complex, resulting in tyrosine phosphorylation and subsequent nuclear translocation of STAT3 to mediate transcriptional regulation [42, 43]. Among other genes, STAT3 mediates the transcription of the SH2 domain containing feedback inhibitor, suppressor of cytokine signaling (SOCS) 3 [43, 49]. SOCS3 binds to Tyr985 of LRb to mediate inhibition of LRb→STAT3 signaling [50]. Jak2 tyrosine phosphorylation during LRb stimulation mediates some signals independently of tyrosine phosphorylation sites on LRb (e.g., a portion of ERK activation) [43]. Unfortunately, most Jak2 tyrosine phosphorylation sites have not been defined, impairing our understanding of the mechanisms by which Jak2-dependent signals are mediated. One Jak2-dependent pathway that is partially understood is the activation of the insulin receptor substrate protein/phosphatidylinositol 3 kinase pathway that is an area of crosstalk with insulin signaling [51, 52].
Leptin regulation of neural networks and neurophysiology
While LRb is expressed at other sites, the highest levels of LRb expression in the body are found in neurons of the nuclei of the basomedial hypothalamus, including the arcuate (ARC), dorsomedial hypothalamic, and ventromedial hypothalamic (VMH) nuclei and possibly in lower levels in the paraventricular nucleus [27]. Chemical or physical ablation of these nuclei results in increased feeding and neuroendocrine abnormalities that are similar to the phenotypes of db/db or ob/ob mice, suggesting that these hypothalamic nuclei that make up the so-called “satiety center” are critical sites of leptin action [26, 53].
Arcuate NPY and POMC neurons are major sites of leptin action
Within these nuclei of the basomedial hypothalamus LRb is expressed at its highest levels in the ARC. Within the ARC, LRb is found in at least two distinct populations of neurons: (a) neurons that coexpress neuropeptide Y (NPY) and agouti-related peptide (AgRP) and (b) neurons that express pro-opiomelanocortin (POMC) [26, 53]. POMC is processed to α-melanocyte stimulating hormone (αMSH) in the LRb/POMC neuron, which mediates a powerful anorectic (appetite-suppressing) signal via activation of melanocortin receptors (MC3R and MC4R). LRb stimulates the expression of POMC and activates the LRb/POMC neuron [53, 54]. AgRP is an antagonist of αMSH signaling, and NPY is itself an orexigenic (appetite-stimulating) hormone that also acts to suppress the central LRb growth and reproductive axes [55, 56, 57, 58]. Leptin acts via LRb to inhibit the NPY/AgRP neurons and to suppress expression of these neuropeptides. Thus leptin→LRb signaling stimulates the production of anorectic neuropeptides and suppresses levels of orexigenic peptides. Conversely, when leptin action is decreased or deficient (e.g., starvation, ob/ob, and db/db mice), appetite is stimulated via the suppression of anorectic neuropeptides (e.g., POMC) and by increased expression of orexigenic peptides (e.g., NPY and AgRP) [26, 53]. Other distinct populations of LRb-expressing neurons may also be found in the ARC [59].
Neuroendocrine control in the hypothalamus
The regulation of endocrine function begins in the hypothalamus, where neurons that synthesize releasing factors (e.g., thyrotropin-releasing hormone, TRH) secrete these factors in to the specialized portal circulation that carries these factors to the anterior portion of the pituitary gland. Within the pituitary the hypothalamic-releasing factors influence the synthesis of stimulating factors (e.g., thyrotropin) and their elaboration into the general circulation, where they regulate the activity of endocrine organs and the production of hormones (e.g., thyroid hormone) by these organs.
Much of the central control of thyroid and adrenal function occurs in the parvocellular neurons of the paraventricular hypothalamus (PVH) [60]. TRH neurons within the VMH release TRH to stimulate the secretion of thyrotropin in the pituitary and promote thyroid hormone production in the thyroid gland. Similarly, corticotropin-releasing hormone (CRH) neurons in the VMH elaborate CRH/corticotropin-releasing factor to promote the elaboration of corticotropin in the pituitary and the production of glucocorticoids from the adrenal cortex. Leptin acts to stimulate the thyroid axis by increasing the production and release of TRH. In mice, leptin also decreases circulating levels of corticotropin and corticosteroids, and these leptin effects are correlated with the inhibition of PVH CRH production by leptin [13].
The elaboration of growth hormone (GH) by the pituitary gland is regulated by numerous hypothalamic inputs, including the GH-releasing hormone GHRH that is secreted into the tubuloinfundibular system by ARC GHRH neurons to stimulate GH secretion, and somatostatin, which is secreted by ARC and periventricular neurons to block GH production. Leptin increases GHRH synthesis and secretion from the hypothalamus and inhibits somatostatin production and release [61, 62, 63]. The hypothalamic control of the release of pituitary gonadotropins is mediated in large part by the pulsatile secretion of gonadotropin-releasing hormone (GnRH) in the median preoptic area of the hypothalamus. Leptin increases the amplitude and frequency of GnRH pulses and the production of pituitary gonadotropins [64].
LRb→STAT3 Signaling in the regulation of physiology
LRb signaling via STAT3 mediates a subset of leptin actions
We have directly addressed the contribution of the LRb→STAT3 signaling pathway to the control of mammalian physiology by studying homologously targeted “knock-in” mice in which LRb is replaced by a mutant molecule (LRbS1138) that contains a substitution mutation of Tyr1138 (the STAT3 binding site) [58]. While LRbS1138 fails to mediate activation of STAT3 during leptin signaling, this mutant regulates all other LRb signaling pathways normally. Use of the “knock-in” approach ensured that the expression pattern and levels of LRbS1138 mirror that of wild-type LRb. As in the case of db/db animals, mice homozygous for LRbS1138 (s/s) display hyperphagia and decreased energy expenditure, resulting in massive early-onset obesity that is associated with increased serum leptin levels. The high circulating leptin levels in s/s animals are not only correlated with increased adipose mass in these mice but also indicate resistance to the energy homeostatic effects of leptin. Furthermore, as with db/db mice, s/s animals display elevated glucocorticoid and decreased thyroid levels (S.H. Bates and M.G. Myers Jr., unpublished observations). Although the role that LRb→STAT3 signaling plays in the leptin-mediated activation of the sympathetic nervous system is not yet known, phosphatidylinositol 3 kinase signaling is required for this leptin action, as it is for feeding [14, 51].
Important differences exist between the phenotypes of s/s mice (missing only the LRb→STAT3 signal) and db/db mice (devoid of all leptin signals), however [58]. While db/db animals are infertile and demonstrate decreased linear growth, s/s mice retain relatively normal gonad function and actually demonstrate increased linear growth compared to wild-type animals. Hence LRb→STAT3 signaling is central to the regulation of energy balance and the neuroendocrine thyroid and adrenal axes but is dispensable for regulation of the hypothalamic control of the gonadal and growth axes.
Interestingly, although s/s animals are fertile, the offspring of s/s females die within 48 h after birth without milk in their stomachs, although it is possible to foster them to wild-type females. Similarly, leptin-deficient ob/ob females rendered fertile by leptin treatment fail to lactate if leptin is withdrawn at the onset of pregnancy, but lactate normally if leptin therapy is continued, suggesting that leptin provides a permissive signal to the control of lactation [65, 66]. To investigate the hormonal basis for this defect we assayed prolactin levels in wild-type and s/s females immediately postpartum and found that circulating prolactin was undetectable in the s/s mothers (Fig. 3). Thus, although LRb→STAT3 signaling is not required for fertility, it is required in a pathway that mediates the elaboration of prolactin and lactation.
LRb→STAT3 signaling and the regulation of ARC neuropeptides
Analysis of hypothalamic neuropeptide expression reveals that, as with db/db mice, s/s mice have decreased POMC and increased AgRP mRNA levels in the hypothalamus [58]. In contrast, while db/db animals display dramatic induction of hypothalamic NPY mRNA, levels of NPY message are near normal in s/s animals. These data suggest that LRb→STAT3 signaling is a critical regulator of hypothalamic melanocortin action, and that dysregulated melanocortin signaling (as opposed to alterations in NPY) accounts for the obesity of s/s animals. Additionally, non-STAT3 LRb signals are critical regulators of NPY expression in the LRb/NPY neuron.
An integrated model for the control of hypothalamic neuroendocrine function by leptin
Our analysis of s/s animals that display severe impairment of the melanocortin system with relative preservation of NPY regulation suggests a model in which melanocortin signaling is dominant signal in the control of feeding, although the slightly decreased feeding in s/s than in db/db animals suggests a role for other pathways, such as NPY (Fig. 4). Indeed, the feeding and weight gain phenotype of s/s animals closely mirrors that of ob/ob animals genetically devoid of NPY (ob/ob, Npy --/--) [57].
In the growth axis arcuate NPY blocks GHRH and stimulates somatostatin, effectively inhibiting GH elaboration from the hypothalamus [67] The suppression of ARC NPY action by leptin may mediate the permissive effect of leptin on this axis [63, 68]. Similarly, much of the leptin effect on the gonadal axis may be mediated via blockade of NPY action by leptin, as NPY provides a powerful block on GnRH secretion [68, 69]. The phenotype of s/s animals is consistent with the proposed role for NPY in suppressing the hypothalamic growth and gonadal axes; thus the increased NPY signaling in ob/ob and db/db mice may only modestly increase feeding, but may be responsible primarily for infertility and growth retardation in these mouse models. Indeed the phenotype of ob/ob, Npy −/− animals displays important similarities with the s/s phenotype [70]. Both display restoration of the hypothalamic/gonadal axis and increased linear growth with only modestly attenuated obesity compared to ob/ob and db/db mice.
Similarly, numerous data suggest that melanocortin action is dispensable for reproduction and growth. Comparison to the dramatic effects observed with manipulation of the NPY system, pharmacological, or genetic manipulation of hypothalamic melanocortin action does not appreciably alter fertility or its hypothalamic control [68, 71]. Furthermore, acute blockade of the melanocortin system does not alter growth or the hypothalamic control of the growth axis but chronic attenuation of melanocortin function (as in MC4R−/− and s/s mice) actually increases the activity of the growth axis, presumably by increasing adiposity (and thus leptin levels) and exaggerating the (STAT3-independent) inhibition of ARC NPY neurons by leptin.
The mechanisms by which leptin regulates the thyroid and adrenal axes have been more difficult to dissect. LRb is expressed at very low levels within the PVH (where TRH and CRH neurons are found), suggesting that much of this regulation is indirect [29, 31]. Indeed, while some data suggest a direct role for leptin on TRH neurons, many data point to a critical role for αMSH and NPY projections from the ARC in the regulation of TRH [17, 72, 73]. Our unpublished observations suggest that thyroid function is similarly suppressed in s/s and db/db animals, which is consistent with the notion that melanocortin action is a critical mechanism by which leptin controls thyroid function.
The mechanism by which leptin regulates the CRH neurons of the PVH is unclear; although both melanocortin agonists and NPY may modulate CRH levels and activity, no arcuate NPY or POMC projections have yet been mapped onto these neurons. Furthermore, the PVH CRH neuron may be regulated divergently by leptin in different species, as leptin increases CRH expression in the PVH in the rat [74, 75]. Recall, as well, that the adrenal axis does not appear to be altered in humans that lack leptin [17].
Perhaps the least understood of all of the neuroendocrine systems regulated by leptin is lactation, however. Since lactation is blocked in s/s animals, NPY is not likely to be the hypothalamic regulator of PRL secretion. Furthermore, it is clear that melanocortin action is dispensable for lactation, as animals that overexpress the agouti melanocortin antagonist or that lack melanocortin receptors are fertile and suckle their young normally [71, 76]. Identifying the leptin-regulated neuron that controls prolactin secretion and lactation will clearly be an important step in understanding this process.
Summary
Models of disrupted leptin signaling have provided important tools in the investigation of leptin physiology, it is clear however, that there are many issues that remain to be explored regarding leptin signals in the control of physiology and especially in s/s mice. The regulation of a number of neuropeptides has yet to be explored in s/s animals (including CART and GALP, among others). Also the development of the LRb-expressing neurons and the ability of leptin to control membrane potential in these animals need to be investigated. The physiological roles of most other intracellular LRb-mediated signals have yet to be investigated, as well.
Abbreviations
- AgRP :
-
Agouti-related peptide
- ARC :
-
Arcuate nucleus
- CRH :
-
Corticotropin-releasing hormone
- ERK :
-
Extracellular signal regulated kinase
- GH :
-
Growth hormone
- GHRH :
-
Growth hormone releasing hormone
- GnRH :
-
Gonadotropin-releasing hormone
- LR :
-
Leptin receptor
- MCR :
-
Melanocortin receptor
- MSH :
-
Melanocyte stimulating hormone
- NPY :
-
Neuropeptide Y
- POMC :
-
Pro-opiomelanocortin
- PVH :
-
Paraventricular hypothalamus
- SH :
-
Src homology
- SHP :
-
Src homology 2 containing phosphatase
- SOCS :
-
Suppressor of cytokine signaling
- STAT :
-
Signal transducer and activator of transcription
- TRH :
-
Thyrotropin-releasing hormone
- VMH :
-
Ventromedial hypothalamus
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Acknowledgements
This research was supported by NIH DK56731 and DK 57768 and grants from the American Diabetes Association (to M.G.M.) and an American Diabetes Association/European Association for the Study of Diabetes Transatlantic Fellowship (to S.H.B.). We thank Michael Schwartz, M.D. for helpful discussions.
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Bates, S.H., Myers, M.G. The role of leptin→STAT3 signaling in neuroendocrine function: an integrative perspective. J Mol Med 82, 12–20 (2004). https://doi.org/10.1007/s00109-003-0494-z
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DOI: https://doi.org/10.1007/s00109-003-0494-z