Introduction: While the vast majority of research investigating the role of ghrelin or its receptor, GHS-R1a, in growth, feeding, and metabolism has been conducted in male rodents, very little is... Show moreIntroduction: While the vast majority of research investigating the role of ghrelin or its receptor, GHS-R1a, in growth, feeding, and metabolism has been conducted in male rodents, very little is known about sex differences in this system. Furthermore, the role of GHS-R1a signaling in the control of pulsatile GH secretion and its link with growth or metabolic parameters has never been characterized. Methods: We assessed the sex-specific contribution of GHS-R1a signaling in the activity of the GH/IGF-1 axis, metabolic parameters, and feeding behavior in adolescent (5-6 weeks old) or adult (10-19 weeks old) GHS-R KO (Ghsr-/-) and WT (Ghsr+/+) male and female mice. Results: Adult Ghsr-/- male and female mice displayed deficits in weight and linear growth that were correlated with reduced GH pituitary contents in males only. GHS-R1a deletion was associated with reduced meal frequency and increased meal intervals, as well as reduced hypothalamic GHRH and NPY mRNA in males, not females. In adult, GH release from Ghsr-/- mice pituitary explants ex vivo was reduced independently of the sex. However, in vivo pulsatile GH secretion decreased in adult but not adolescent Ghsr-/- females, while in males, GHS-R1a deletion was associated with reduction in pulsatile GH secretion during adolescence exclusively. In males, linear growth did not correlate with pulsatile GH secretion, but rather with ApEn, a measure that reflects irregularity of the rhythmic secretion. Fat mass, plasma leptin concentrations, or ambulatory activity did not predict differences in GH secretion. Discussion/Conclusion: These results point to a sex-dependent dimorphic effect of GHS-R1a signaling to modulate pulsatile GH secretion and meal pattern in mice with different compensatory mechanisms occurring in the hypothalamus of adult males and females after GHS-R1a deletion. Altogether, we show that GHS-R1a signaling plays a more critical role in the regulation of pulsatile GH secretion during adolescence in males and adulthood in females. Show less
The thesis contains a large study in which eight male hypocretin deficient narcolepsy with cataplexy patients and eight matched controls were enrolled. Blood was sampled before and on the 5th day... Show moreThe thesis contains a large study in which eight male hypocretin deficient narcolepsy with cataplexy patients and eight matched controls were enrolled. Blood was sampled before and on the 5th day of SXB administration. SXB was taken 2 times 3g per night for 5 consecutive nights. Both groups underwent 24-h blood sampling and many hormones (prolactin, Growth hormone, melatonin, ghrelin, leptin) were measured and compared before and during SXB treatment. A study using the golden standard on insuline sensitivity is decribed to compare insuline sensitivity between patients and controls, and between patients, before and during satisfactory SXB treatment. ANother study describes body and skintemperature differences between narcolepsy patients and controls. Another chapter describes a rarely described, common feature in narcolepsy, in which patients mistake the memory of a dream for a real experience. In another chapter describes that date of birth is not a risk factor for narcolepsy. Show less
STUDY OBJECTIVES:Narcolepsy is caused by a selective loss of hypocretin neurons and is associated with obesity. Ghrelin and leptin interact with hypocretin neurons to influence energy homeostasis.... Show moreSTUDY OBJECTIVES:Narcolepsy is caused by a selective loss of hypocretin neurons and is associated with obesity. Ghrelin and leptin interact with hypocretin neurons to influence energy homeostasis. Here, we evaluated whether human hypocretin deficiency, or the narcolepsy therapeutic agent sodium oxybate, alter the levels of these hormones. METHODS:Eight male, medication free, hypocretin deficient, narcolepsy with cataplexy patients, and 8 healthy controls matched for age, sex, body mass index (BMI), waisttohip ratio, and body fat percentage were assessed. Blood samples of total ghrelin and leptin were collected over 24 hours at 60 and 20-min intervals, respectively, during 2 study occasions: baseline, and during the last night of 5 consecutive nights of sodium oxybate administration (2 × 3.0 g/night). RESULTS:At baseline, mean 24-h total ghrelin (936 ± 142 vs. 949 ± 175 pg/mL, p = 0.873) and leptin (115 ± 5.0 vs. 79.0 ± 32 mg/L, p = 0.18) levels were not different between hypocretin deficient narcolepsy patients and controls. Furthermore, sodium oxybate did not significantly affect the plasma concentration of either one of these hormones. CONCLUSIONS:The increased BMI of narcolepsy patients is unlikely to be mediated by hypocretin deficiency-mediated alterations in total ghrelin or leptin levels. Thus, the effects of these hormones on hypocretin neurons may be mainly unidirectional. Although sodium oxybate may influence body weight, the underlying mechanism is unlikely to involve changes in total ghrelin or leptin secretion. Show less
The general aim of the studies described in this thesis is the effect evaluation of a family-based multidisciplinary cognitive behavioral treatment on several domains related to childhood obesity... Show moreThe general aim of the studies described in this thesis is the effect evaluation of a family-based multidisciplinary cognitive behavioral treatment on several domains related to childhood obesity compared to standard care. The main findings from these studies are a modest long-term reduction of both total and abdominal adiposity accompanied by improved physical fitness, while unchanged adiposity in the untreated controls led to decreased physical fitness and deteriorating insulin sensitivity. In addition, we found significantly impaired health related quality of life in the obese children compared to their normal weight peers. We showed that our multidisciplinary lifestyle treatment improved health related quality of life of the obese children after 1 year. We observed a significantly increased postprandial ghrelin response after the multidisciplinary treatment, but no effect on inflammatory markers, nor on gut hormones PYY and GLP-1. Finally, we propose an alternative for the definition of the metabolic syndrome in children, since the usefulness of its current dichotomous form is questionable. We show that a multivariate prediction model based on the individual components of the metabolic syndrome expressed as standard deviation scores (SDS) has a good predictive value regarding increased HOMA-IR SDS. Show less
