Acute inflammation reduces kisspeptin immunoreactivity at the arcuate nucleus and decreases responsiveness to kisspeptin independently of its anorectic effects

Abstract

Tena-Sempere M. Acute inflammation reduces kisspeptin immunoreactivity at the arcuate nucleus and decreases responsiveness to kisspeptin independently of its anorectic effects. Am J Physiol Endocrinol Metab 299: E54 -E61, 2010. First published April 20, 2010 doi:10.1152/ajpendo.00081.2010.-Severe inflammatory challenges are frequently coupled to decreased food intake and disruption of reproductive function, the latter via deregulation of different signaling pathways that impinge onto GnRH neurons. Recently, the hypothalamic Kiss1 system, a major gatekeeper of GnRH function, was suggested as potential target for transmitting immune-mediated repression of the gonadotropic axis during acute inflammation, and yet key facets of such a phenomenon remain ill defined. Using lipopolysaccharide S (LPS)-treated male rats as model of inflammation, we document herein the pattern of hypothalamic kisspeptin immunoreactivity (IR) and hormonal responses to kisspeptin during the acute inflammatory phase. LPS injections induced a dramatic but transient drop of serum LH and testosterone levels. Suppression of gonadotropic function was associated with a significant decrease in kisspeptin-IR in the arcuate nucleus (ARC) that was not observed under conditions of metabolic stress induced by 48-h fasting. In addition, absolute responses to kisspeptin-10 (Kp-10), in terms of LH and testosterone secretion, were significantly attenuated in LPS-treated males that also displayed a decrease in food intake and body weight. Yet pair-fed males did not show similar alterations in LH and testosterone secretory responses to Kp-10, whose magnitude was preserved, if not augmented, during food restriction. In summary, our data document the impact of acute inflammation on kisspeptin content at the ARC as key center for the neuroendocrine control of reproduction. Our results also suggest that suppressed gonadotropic function following inflammatory challenges might involve a reduction in absolute responsiveness to kisspeptin that is independent of the anorectic effects of inflammation.Kiss1/kisspeptins; gonadotropin-releasing hormone; gonadotropins; lipopolysaccharide S IMMUNE/INFLAMMATORY CHALLENGES, such as those associated with severe bacterial infections, are commonly coupled with transient suppression of dispensable functions for individual survival, such as reproduction. Among a plethora of biological responses, administration of lipopolysaccharide S (LPS), a glycolipid of gram-negative bacteria, has been shown to disrupt puberty onset and gonadotropic function through deregulation of an array of signaling pathways, including different proinflammatory cytokines (IL-1, IL-6, TNF␣), growth factors, neurotransmitters (catecholamines, ␥-aminobutyric acid), and neuropeptides (corticotropin-releasing factor, arginine vasopressin, opioids) (1,10,16,28,33,35,37,39). However, although compelling evidence suggests that the above factors are variably involved in the suppression of the gonadotropinreleasing hormone (GnRH)/LH system by bacterial endotoxin (37,...

The roles of kisspeptin and gonadotropin inhibitory hormone in stress-induced reproductive disorders

“…Thereafter, we and other groups have vigorously evaluated the effects of stress on the kisspeptin system and the neuroendocrine mechanisms that underlie these effects. In agreement with the findings of our aforementioned study, the administration of LPS decreased hypothalamic Kiss1 mRNA expression and kisspeptin immunoreactivity, and the co-administration of kisspeptin partially restored serum LH levels in female rats [76]. In addition, other kinds of stress, such as psychosocial, unpredictable chronic (six randomly assigned stressors), and hypoglycemic stress, also reduced hypothalamic Kiss1 mRNA expression and kisspeptin neuron activity [77][78][79].…”

“…As a result, it was found that both the central administration of CRH and the peripheral administration of corticosterone reduced hypothalamic Kiss1 mRNA expression and kisspeptin neuron activity in female rats and mice, indicating that activation of the HPA axis is involved in the stressinduced suppression of the kisspeptin system [77,80]. Interestingly, relatively severe stress protocols were used in these studies; i.e., high-dose LPS (1-5 mg/kg) or repeated LPS administration protocols (three consecutive injections at 24-h intervals), to evaluate the effects of immune stress [75,76,81,82], and chronic (once per day for four weeks) or combined (restraint and isolation) protocols were used to evaluate the effects of unpredictable and psychosocial stress [78,79]. Similarly, we found that a subseptic dose (500 μg/kg) of LPS did not affect hypothalamic Kiss1 mRNA expression in female rats, indicating that only chronic or severe stress affects the kisspeptin system [81,82].…”

Food restriction during lactation suppresses Kiss1 mRNA expression and kisspeptin-stimulated LH release in rats

“…The results of other studies examining the effect of food restriction or fasting, and the associated decrease in circulating leptin concentrations, have provided no evidence of a reduction in the ability of kisspeptin to induce LH secretion. For example, in prepubertal fasted rats (Castellano et al 2005) and food-restricted male rats (Castellano et al 2010), i.c.v. kisspeptin administration has been shown to result in an increased release of LH compared with that in the AL-fed controls.…”

The involvement of gonadotropin inhibitory hormone and kisspeptin in the metabolic regulation of reproduction

“…The inhibitory effect of LPS on the expression of hypothalamic mRNA levels of Kiss1 and systemic levels of LH is fully reversed by indomethacin, a nonsteroidal anti-inflammatory drug. Moreover, it was observed that exogenous KP injection greatly increased systemic levels of LH in LPS-injected animals just like placebo animals (Iwasa et al 2008, Castellano et al 2010b). These results suggest that KP-containing cells are highly sensitive to immune/inflammatory challenges and convey these signals to the network of GnRH-containing neurons in the hypothalamus.…”

“…Lipopolysaccharide (LPS) administration has been shown to greatly decrease the hypothalamic levels of Kiss1 mRNA and reduce systemic levels of LH in gonadectomized rats (Iwasa et al 2008, Castellano et al 2010b. The inhibitory effect of LPS on the expression of hypothalamic mRNA levels of Kiss1 and systemic levels of LH is fully reversed by indomethacin, a nonsteroidal anti-inflammatory drug.…”