High-carbohydrate and high-protein breakfasts similar to those Americans normally eat can cause substantial differences in the plasma tryptophan ratio and thus, probably, in brain tryptophan concentrations and serotonin synthesis. Such meals also change the plasma tyrosine ratio and may thereby modify catecholamine synthesis.
Stimulation of m1 and m3 muscarinic acetylcholine receptors, which are coupled to phosphoinositide hydrolysis and protein kinase C activation, has been shown to increase the release of soluble amyloid precursor protein derivatives (APPs). The effect is mimicked by phorbol esters, which directly activate protein kinase C. Using human embryonic kidney cells expressing individual muscarinic receptor subtypes, we found that stimulation of APPs release by the muscarinic agonist carbachol was only partially reduced by a specific inhibitor of protein kinase C (the bisindolylmaleimide GF 109203X), while the response to phorbol 12-myristate 13-acetate (PMA) was abolished. The increase in APPs release elicited by carbachol and PMA was accompanied by elevated tyrosine phosphorylation of several proteins and reduced by tyrosine kinase inhibitors; GF 109203X significantly reduced the stimulation of tyrosine phosphorylation by carbachol and PMA. Inhibition of protein tyrosine phosphatases by vanadyl hydroperoxide markedly increased cellular tyrosine phosphorylation and enhanced APPs release as effectively as PMA and carbachol. Direct phosphorylation of amyloid precursor protein on tyrosine residues following treatment with carbachol, PMA, or vanadyl hydroperoxide was not observed. The results implicate both tyrosine phosphorylation and protein kinase C-dependent mechanisms in the regulation of APPs release by G protein-coupled receptors, and suggest that carbachol and PMA increase APPs release from human embryonic kidney cells expressing m3 muscarinic receptors via partially divergent pathways that converge at a tyrosine phosphorylation-dependent step.
Anorexia nervosa (AN) is associated with very low levels of leptin, a cytokine secreted by adipose tissue and known to suppress appetite. Leptin may play a permissive role in onset of puberty and in resumption of gonadal function in conditions of undernutrition. The soluble leptin receptor (sOB-R) is the main leptin binding protein, and the ratio of serum leptin to sOB-R provides a measure of the free leptin index (FLI), which may be a more accurate determinant of leptin function. Determinants of sOB-R and FLI have not been examined in an adolescent population. We examined levels of sOB-R, leptin, and FLI, and body composition and hormonal determinants of these variables in 23 adolescent girls with AN and 21 healthy adolescent girls of comparable maturity prospectively over 1 yr. Measures of insulin resistance and adiponectin were also examined. We determined changes in levels of sOB-R, leptin, and FLI with weight recovery (defined as an increase in body mass index of>/=10%, n = 11), and with resumption of menstrual cycles (n = 13). Girls with AN had significantly higher levels of sOB-R (P = 0.0008) and significantly lower levels of leptin and FLI (P < 0.0001 for both) than healthy controls, and levels of FLI were reduced more than levels of leptin in girls with AN compared with controls. An inverse correlation was noted between levels of leptin and sOB-R for the group as a whole (r = -0.64, P < 0.0001) but not in girls with AN considered alone. The most important predictor of levels of sOB-R was cortisol in the group as a whole (r = 0.61, P < 0.0001) and in girls with AN considered alone (r = 0.66, P = 0.0008). Other independent predictors of sOB-R levels for the entire group were percent body fat (r = -0.44, P = 0.003) and levels of IGF-I (r = -0.37, P = 0.01). The most important predictors of leptin and FLI were body mass index and percent body fat. An inverse relationship was noted between measures of insulin resistance and sOB-R levels, whereas a positive association was noted between these measures and leptin and FLI. Adiponectin values did not differ in girls with AN compared with healthy controls and did not correlate with sOB-R, leptin, or FLI. Weight recovery resulted in significant decreases in levels of the sOB-R (24.7 +/- 1.7 to 17.6 +/- 1.2 U/ml, P = 0.004), and increases in levels of leptin (4.4 +/- 1.0 to 13.7 +/- 2.9 microg/liter, P = 0.02). Resumption of menstrual function, but not weight recovery alone, was associated with significant increases in FLI (0.19 +/- 0.04 to 0.50 +/- 0.09 microg/U x 10(-3), P = 0.02).We demonstrate an increase in levels of sOB-R and a decrease in the FLI in adolescent girls with AN, and also demonstrate that cortisol is the most important predictor of levels of sOB-R in this condition. Levels of leptin and FLI, conversely, are primarily predicted by body composition. Weight recovery is associated with a decrease in sOB-R and an increase in leptin. Resumption of menses is associated with significant increases in the FLI, suggesting that free leptin may be an important...
Anorexia nervosa (AN) is characterized by low weight and self-imposed caloric restriction and leads to severe bone loss. Although amenorrhea due to acquired GnRH deficiency is nearly universal in AN, a subset of patients maintains menses despite low weight. The mechanisms underlying continued GnRH secretion despite low weight in these patients and the impact of gonadal hormone secretion on bone mineral density (BMD) in such eumenorrheic, low-weight patients remain unknown. We hypothesized that 1) eumenorrheic women with AN would have higher body fat and levels of nutritionally dependent hormones, including leptin and IGF-I, than amenorrheic women with AN and comparable body mass index; and 2) BMD would be higher in these women. We also investigated whether the severity of eating disorder symptomatology differed between the groups. We studied 116 women: 1) 42 lowweight women who fulfilled all Diagnostic and Statistical Manual of Mental Disorders (fourth edition) diagnostic criteria for AN, except for amenorrhea; and 2) 74 women with AN and amenorrhea for at least 3 months. The two groups were similar in body mass index (17.1 ؎ 0.2 vs. 16.8 ؎ 0.2 kg/m 2 ), percent ideal body weight (78.2 ؎ 0.8% vs. 76.7 ؎ 0.8%), duration of eating disorder (70 ؎ 13 vs. 59 ؎ 9 months), age of menarche (13.2 ؎ 0.3 vs. 13.5 ؎ 0.2 yr), and exercise (4.5 ؎ 1.0 vs. 4.2 ؎ 0.5 h/wk). As expected, eumenorrheic patients had a higher mean estradiol level (186.6 ؎ 19.0 vs. 59.4 ؎ 2.5 nmol/ liter; P < 0.0001) than amenorrheic subjects. Mean percent body fat, total body fat mass, and truncal fat were higher in eumenorrheic than amenorrheic patients [20.9 ؎ 0.9% vs. 16.7 ؎ 0.6% (P ؍ 0.0001); 9.8 ؎ 0.5 vs. 7.8 ؎ 0.3 kg (P ؍ 0.0009); 3.4 ؎ 0.2 vs. 2.7 ؎ 0.1 kg (P ؍ 0.006)]. The mean leptin level was higher in the eumenorrheic compared with the amenorrheic group (3.7 ؎ 0.3 vs. 2.8 ؎ 0.2 ng/ml; P ؍ 0.04). Serum IGF-I levels were also higher in the eumenorrheic than in the amenorrheic group (41.8 ؎ 3.7 vs. 30.8 ؎ 2.3 nmol/liter; P ؍ 0.02). There were only minor differences in severity of eating disorder symptomatology, as measured by the Eating Disorders Inventory, and where differences were observed, eumenorrheic subjects manifested more severe symptomatology than amenorrheic subjects. Mean BMD at the posterior-anterior and lateral spine were low in both groups, but were higher in patients with eumenorrhea than in those with amenorrhea [posterioranterior spine T-score, ؊0.9 ؎ 0.1 vs. ؊1.9 ؎ 0.1 (P < 0.0001); lateral spine T-score, ؊1.2 ؎ 0.1 vs. ؊2.3 ؎ 0.2 (P < 0.0001)]. In contrast, preservation of menstrual function was not protective at the total hip (total hip T-score, ؊0.9 ؎ 0.1 vs. ؊1.1 ؎ 0.1; P ؍ 0.27), trochanter, or femoral neck. In summary, patients with eumenorrhea had more body fat and higher serum leptin levels than their amenorrheic counterparts of similar weight. Moreover, reduced bone density was observed in both groups, but was less severe at the spine, but not the hip, in women with undernutrition and preserved menstrua...
Anorexia nervosa (AN) is associated with high levels of GH and low levels of IGF-I suggestive of a nutritionally acquired lack of GH action or GH resistance. The suppression of GH levels after administration of inhibitors of GH secretion such as oral glucose is the definitive test to distinguish normal from pathological states of GH excess, such as acromegaly. However, suppression of GH by glucose has not been well characterized in states of adaptive GH excess, such as AN, especially in a younger adolescent population with relatively higher GH levels, compared with adults. In this study, we investigated GH suppression after a 100-g oral glucose load over a 1-h period in 19 adolescent girls with AN and 20 healthy controls of similar chronologic and bone age. We also compared nocturnal GH secretion characteristics by deconvolutional analysis in both groups to determine differences in secretory patterns between adolescents whose GH values suppressed vs. those whose values did not after oral glucose. Fasting levels of ghrelin, a GH secretagogue, and suppression of ghrelin with oral glucose were also determined to assess whether GH suppression or nonsuppression could be related to ghrelin values at respective time points. At 0 min (0') of the oral glucose tolerance test, girls with AN had significantly lower levels of glucose (P = 0.009) and higher levels of GH (P = 0.04) than controls. Nadir GH values were higher in AN than in controls (2.0 +/- 1.8 vs. 0.5 +/- 0.5 ng/ml, P = 0.001). Only 31.6% of girls with AN suppressed their GH values to 1 ng/ml or less vs. 85.0% of healthy adolescents (P = 0.0005). All healthy controls had nadir postglucose GH values of 2 ng/ml or less. Nadir GH concentrations during the oral glucose tolerance test correlated directly with all measures of GH secretion [basal (r = 0.37, P = 0.02), pulsatile (r = 0.56, P = 0.0002), and total (r = 0.57, P = 0.0002)]. Adolescent girls who did not suppress their GH values to 1 ng/ml or less had significantly higher levels of ghrelin at 0', 30', and 60' (P = 0.02, 0.004, and 0.008), significantly higher GH at 0' (P = 0.001), and higher nocturnal basal (P = 0.002), pulsatile (P = 0.05), and total GH secretion (P = 0.03) than those who did suppress below this level. Ghrelin values were higher in AN than in controls at each time point (P = 0.02, 0.0002, and 0.01 at 0', 30', and 60') but did not predict GH values at these time points. Adolescent girls with AN fail to adequately suppress their GH values after a 100-g oral glucose load. This lack of suppression may be related to the higher GH secretion seen in adolescents with this disorder. In contrast, all healthy adolescents suppress their GH values to 2 ng/ml or less but not 1 ng/ml or less after a glucose load. Although ghrelin values are higher in AN than in controls, we could not demonstrate a relationship between ghrelin and GH values. The inability of healthy girls to uniformly suppress GH levels to 1 ng/ml or less, a normal level defined for adults, may be related to higher GH secretion in the puber...
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