The Hypocretin System In Peripheral Endocrine Tissues

The presence of the hypocretin system is not restricted to the central nervous system (CNS). In the periphery, hypocretin peptides and receptors are widely expressed, especially in endocrine tissues.

Hypocretins are expressed in the rat and human pituitary.65-67 In human adenohypophysis Hcrt1 is present in lactotropes, thyrotropes, somatotropes, gonadotropes (FSH and LH) but not in corticotropes. In contrast, Hcrt2 was found in all corticotropes of the anterior pituitary.67 These findings could suggest a paracrine role for hypocretins in human pituitary cell function. Finally, in addition to innervation of neuroendocrine centres in the hypothalamus, hypocretin-positive fibers are present in both the internal and external layers of the median eminence.65 Hypocretin receptors have also been shown to be present in the rat and human pituitary.65,68,69 Both Hcrtr1 and Hcrtr2 mRNAs are highly expressed in the intermediate lobe of rat pituitary, whereas in the anterior lobe, the Hcrtr1 is more markedly expressed than the Hcrtr2. The two receptors mRNAs are also found in the posterior lobe of rat pituitary.65 In human pituitary Hcrtr1 is expressed by somatotrope cells and Hcrtr2 by corticotrope cells68 (Fig. 1A and 1B). All these data suggest direct neuroendocrine actions of hypocretins on the pituitary gland, in addition to their possible neuromodulatory role in the hypothalamus.

The hypocretin system is highly expressed in the adrenal gland and shows a species-specific pattern of expression. Thus, while no expression of prepro-Hcrt has been detected in the rat adrenal gland,69,70 immunoreactivity for prepro-Hcrt and Hcrt1 has been described in human adrenal gland.71,72 Hypocretin receptors have been described in the adrenal cortex and/or in the adrenal medulla of rat,66,70,73 pig74 and human71,75-77 (Fig. 1C and 1D).

Hypocretin and Hcrtr1 mRNA expression, but not Hcrtr2 mRNA, has been detected in the rat testis,7,66,70,78 with presence of prepro-Hcrt signal in interstitial Leydig cells and seminiferous tubules, and predominant location of Hcrtr1 mRNA in the tubular compartment of the testis78 (our unpublished data). In contrast, in humans prepro-Hcrt is only expressed in the epididymis and penis whereas both Hcrtrs are present in testis, epididymis, seminal vesicle and penis.79

In the gastrointestinal tract the hypocretin system is highly expressed in endocrine cells. Thus, Hcrt1 immunoreactivity is detected in numerous endocrine enterochromaffin (EC) cells of the gastric and intestinal mucosa as well as in the a and p cells of the pancreas.72,80-83 Both Hcrtrs were also found in endocrine cells in the gut and in the pancreas, suggesting a role for hypocretins in the control of gastrointestinal and pancreatic function.80,82

Low levels of hypocretin and hypocretin receptors have been detected in other peripheral tissues. In humans prepro-Hcrt is expressed in the stomach, kidney, colon, colorectal epithelial cells and placenta.72 In the rat, Hcrtr1 mRNA has been detected in the kidney, thyroid, ovary and placenta66 (our unpublished data). In addition, Hcrtr2 mRNA has been found in rat lung, placenta66 (our unpublished data) and pineal gland.84

Finally, it is interesting to note the presence of Hcrt1 in plasma in the human85-92 and rat.83'93 The exact source of these circulating hypocretins is unknown; although the hypothalamic hypocretin neurons project to the median eminence65 their plasma levels are too high to be explained by a unique central origin. In addition, no differences in plasma hypocretin levels are detected between men and women suggesting that a testicular origin for plasma hypocretins is unlikely.85 A gut origin has been proposed for circulating Hcrt.45'80'85 However, the fact that Hcrtl plasmatic levels are increased after fasting in both humans85,86 and rats83 and that glucose levels regulate its pancreatic secretion83 suggest that Hcrtl could be secreted by the pancreas.83 In any case, independent of their origin, the presence of hypocretins in the circulation and the widespread distribution of hypocretin receptors in the periphery suggest the existence of direct endocrine actions (not mediated through the hypothalamus-pituitary unit) of these peptides, acting like true hormones.

A Hcrtrl GH DoUble C

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A Hcrtrl GH DoUble C

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B Double D

Hcrtr2 ACTH

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Hcrtr2 ACTH

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Figure 1. Hypocretin receptors immunoreactivity in endocrine tissues of human and rat. A.

Colocalization of Hcrtrl and GH in the human pituitary. Double immunofluorescence for Hcrtrl and GH. Hcrtrl expressing cells are identified by tetramethylrhodamine isothiocyanate (TRICT) immunofluorescence (red) and GH positive cells are identified by fluorescein isothiocyanate (FICT) immunofluorescence (green). Colocalization of both Hcrtrl and GH in the same cells is illustrated by the yellow colour obtained using the double exposure method of photomicrography. (225X). B. Colocalization of Hcrtr2 and ACTH in the human pituitary. Double immunofluorescence for Hcrtr2 and ACTH. All Hcrtr2 displaying cells (Cy3 immunofluorescence, red) are also positive for ACTH (FICT immunofluorescence, green). Coexpression is confirmed by the double exposed microphotography (yellow). (250X). C. Hcrtrl in the adrenal medulla of the rat (4X). D. Hcrtr2 in the adrenal medulla of the rat (4X).

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