Background: Acyl-ghrelin is a 28-amino acid peptide released from the stomach. Ghrelin O-acyl transferase (GOAT) attaches an 8-carbon medium chain fatty acid (MCFA) (octanoate) to serine(3) of ghrelin. This acylation is necessary for ghrelin's activity. Animal data suggest that MCFAs provide substrate for GOAT and increase of nutritional octanoate increases acyl-ghrelin. Objectives: To address the question of the source of substrate for acylation, we studied whether the decline in ghrelin acylation during fasting is associated with a decline in circulating MCFAs. Methods: Eight healthy young men (ages 18-28, BMI range 20.6 - 26.2 kg/m(2)) had blood drawn every 10 min for acyl- and desacyl-ghrelin and every hour for free fatty acids (FFAs) during the last 24 h of a 61.5 h fast and during a fed day. FFAs were measured by a highly sensitive LC/MS method. Acyl- and desacyl-ghrelin were measured in an in-house assay, the results have been published previously. Ghrelin acylation was assessed by the ratio acyl- to total ghrelin Results: With the exception of MCFAs C8 and C10, all other FFAs, the MCFAs (C6, C12) and the long chain FAs (LCFA, C14-C18) significantly increased with fasting (P<0.05). There was no significant association between the fold change in ghrelin acylation and circulating FFAs. Conclusions: These results suggest that changes in circulating MCFAs are not linked to the decline in ghrelin acylation during fasting and support the hypothesis that acylation of ghrelin depends at least partially on the availability of gastro-luminal MCFAs or the regulation of GOAT activity.
Ghrelin is a 28-amino acid peptide released from the stomach. Ghrelin is found in the circulation in two forms: acyl- and desacyl-ghrelin. Acyl- and desacyl-ghrelin concentrations increase at night, when cortisol concentrations are low. Acute ghrelin administration increases ACTH and cortisol concentrations and a feedback loop between the ghrelin and ACTH-cortisol axis has been postulated. A previous study showed that exogenously induced hypercortisolism for 5 days decreased plasma ghrelin concentrations.
Ghrelin, which is a stomach-derived hormone, increases with fasting and energy restriction and may influence eating behaviors through brain hedonic reward-cognitive systems. Therefore, changes in plasma ghrelin might mediate counter-regulatory responses to a negative energy balance through changes in food hedonics.OBJECTIVE: We investigated whether ghrelin administration (exogenous hyperghrelinemia) mimics effects of fasting (endogenous hyperghrelinemia) on the hedonic response and activation of brain-reward systems to food.DESIGN: In a crossover design, 22 healthy, nonobese adults (17 men) underwent a functional magnetic resonance imaging (fMRI) food-picture evaluation task after a 16-h overnight fast (Fasted-Saline) or after eating breakfast 95 min before scanning (730 kcal, 14% protein, 31% fat, and 55% carbohydrate) and receiving a saline (Fed-Saline) or acyl ghrelin (Fed-Ghrelin) subcutaneous injection before scanning. One male subject was excluded from the fMRI analysis because of excess head motion, which left 21 subjects with brain-activation data.RESULTS: Compared with the Fed-Saline visit, both ghrelin administration to fed subjects (Fed-Ghrelin) and fasting (Fasted-Saline) significantly increased the appeal of high-energy foods and associated orbitofrontal cortex activation. Both fasting and ghrelin administration also increased hippocampus activation to high-energy- and low-energy-food pictures. These similar effects of endogenous and exogenous hyperghrelinemia were not explicable by consistent changes in glucose, insulin, peptide YY, and glucagon-like peptide-1. Neither ghrelin administration nor fasting had any significant effect on nucleus accumbens, caudate, anterior insula, or amygdala activation during the food-evaluation task or on auditory, motor, or visual cortex activation during a control task.CONCLUSIONS: Ghrelin administration and fasting have similar acute stimulatory effects on hedonic responses and the activation of corticolimbic reward-cognitive systems during food evaluations. Similar effects of recurrent or chronic hyperghrelinemia on an anticipatory food reward may contribute to the negative impact of skipping breakfast on dietary habits and body weight and the long-term failure of energy restriction for weight loss.
Bariatric surgery improves glucose homeostasis and alters gut hormones partly independent of weight loss. Leptin plays a role in these processes; levels are decreased following bariatric surgery, creating a relative leptin insufficiency. We previously showed that leptin administration in a weight-reduced state after Roux-en-Y gastric bypass (RYGB) caused no further weight loss. Here, we discuss the impact of leptin administration on gut hormones, glucostasis, and appetite. Weight stable women after RYGB were randomized to receive placebo or recombinant human metreleptin (0.05?mg/kg twice daily). At weeks 0 and 16, a liquid meal challenge was performed. Glucose, insulin, C-peptide, GLP-1, PYY, glucagon, and ghrelin (total, acyl, and desacyl) were measured fasting and postprandially. Appetite was assessed using a visual analog scale. Mean post-op period was 53 ± 2.3 months; mean BMI was 34.6 ± 0.2?kg/m(2). At 16 weeks, there was no significant change in weight within or between groups. Fasting PYY was significantly different between groups and the leptin group had lower sweets craving at week 16 than the placebo group (P < 0.05). No other differences were observed. Leptin replacement does not alter gut hormones or glucostasis but may diminish sweet cravings compared to placebo in this population of post-RYGB women.
Background:Acyl-ghrelin is thought to have both orexigenic effects and to stimulate growth hormone (GH) release. A possible cause of the anorexia of aging is an age-dependent decrease in circulating acyl-ghrelin levels.Objectives:The purpose of the study was to compare acyl-ghrelin and GH concentrations between healthy old and young adults and to examine the relationship of acyl-ghrelin and GH secretion in both age groups.Methods:Six healthy older adults (ages 62-74, BMI range 20.9 - 29 kg/m(2)) and eight healthy young men (ages 18-28, BMI range 20.6 - 26.2 kg/m(2)) had frequent blood samples drawn for hormone measurements every 10 min for 24 hr. Ghrelin was measured in an in-house two-site sandwich ELISA specific for full-length acyl-ghrelin. GH was measured in a sensitive assay (Immulite 2000) and GH peaks were determined by deconvolution analysis. The acyl-ghrelin/GH association was estimated from correlations between amplitudes of individual GH secretory events and the average acyl-ghrelin concentration in the 60-min interval preceding each GH burst.Results:24-h mean (± SEM) GH (0.48 ± 0.14 vs. 2.2 ± 0.3 ? g/L, p<0.005) and acyl-ghrelin (14.7 ± 2.3 vs. 27.8 ± 3.9 pg/mL, p<0.05) levels were significantly lower in older adults compared to young. 24-h cortisol concentrations were higher in the old than the young (15.1 ± 1.0 vs. 10.6 ± 0.9 ? g/dL, respectively), p<0.01. The ghrelin/GH association was more than 3-fold lower in the older group compared to the young adults (0.16 ± 0.12 vs. 0.69 ± 0.04), p<0.001.Conclusions:These results provide further evidence of an age-dependent decline in circulating acyl-ghrelin levels, which might play a role both in the decline of GH and in the anorexia of aging. Our data also suggest that with normal aging, endogenous acyl-ghrelin levels are less tightly linked to GH regulation.
There are no effective therapies for malnutrition in CKD/ESRD patients. This study hypothesized that ghrelin, an endogenous orexigenic hormone, would correlate with renal function and might suggest therapeutic interventions for CKD/ESRD malnutrition.
The G protein-coupled receptor 83 (Gpr83) is widely expressed in brain regions regulating energy metabolism. Here we report that hypothalamic expression of Gpr83 is regulated in response to nutrient availability and is decreased in obese mice compared with lean mice. In the arcuate nucleus, Gpr83 colocalizes with the ghrelin receptor (Ghsr1a) and the agouti-related protein. In vitro analyses show heterodimerization of Gpr83 with Ghsr1a diminishes activation of Ghsr1a by acyl-ghrelin. The orexigenic and adipogenic effect of ghrelin is accordingly potentiated in Gpr83-deficient mice. Interestingly, Gpr83 knock-out mice have normal body weight and glucose tolerance when fed a regular chow diet, but are protected from obesity and glucose intolerance when challenged with a high-fat diet, despite hyperphagia and increased hypothalamic expression of agouti-related protein, Npy, Hcrt and Ghsr1a. Together, our data suggest that Gpr83 modulates ghrelin action but also indicate that Gpr83 regulates systemic metabolism through other ghrelin-independent pathways.
Ghrelin stimulates GH secretion and regulates energy and glucose metabolism. The two circulating isoforms, acyl (AG) and des-acyl (DAG) ghrelin, have distinct metabolic effects and are under active investigation for their therapeutic potentials. However, there is only limited data on the pharmacokinetics of AG and DAG.
In humans, growth hormone (GH) is secreted from the anterior pituitary in a pulsatile pattern. The traditional view is that this secretory pattern is driven by two counter regulatory neurohormones, GHRH and somatostatin. Ghrelin, the natural ligand for the growth hormone (GH)-secretagogue receptor (GHS-R), is produced in the stomach. Ghrelin is the strongest GH secretagogue known to date, but the role of endogenous ghrelin in the regulation of circulating GH levels remains controversial. The following review examines the evidence suggesting that endogenous ghrelin may be a key regulator of GH peak amplitude and discusses studies of diseases with altered GH levels, where it is found that in these states GH and ghrelin levels change in a similar way.
Ghrelin, the natural ligand for the growth hormone (GH)-secretagogue receptor (GHS-R), is produced predominantly in the stomach. It is present in the circulation in two major forms, an acylated and an unacylated form, both of which have reported activities. Some of the best understood actions of acylated ghrelin administration are its orexigenic effects, and the stimulation of GH secretion. Ghrelin also seems to play a role in glucose homeostasis, lipid metabolism and immune function. Based on its orexigenic and metabolic effects, ghrelin and ghrelin mimetics have potential benefit in antagonizing protein breakdown and weight loss in catabolic conditions such as cancer cachexia, renal, cardiac and pulmonary disease, and age-related frailty. Ghrelin also has potentially useful positive effects on cardiac function and gastric motility. Ghrelin antagonists may be of benefit to increase insulin sensitivity and potentiate weight loss. The following chapter presents some background on ghrelin and ghrelin assays and discusses some of the potential therapeutic approaches for the use of ghrelin, ghrelin mimetic compounds and ghrelin antagonists in clinical disease.
Ghrelin is the endogenous agonist for the growth hormone secretagogue receptor (GHS-R). Intravenous administration of ghrelin induces insulin resistance and hyperglycemia and increases the levels of free fatty acids (FFA).
The typically indolent behavior of pituitary tumors is juxtaposed with high rates of tumor cell invasion into adjacent dural structures, and occasional aggressive behavior. Although clinically significant invasion and malignant transformation remain uncommon, there are limited treatment options available for the management of these aggressive tumors. Recently, case reports have described efficacy of temozolomide for the treatment of aggressive pituitary tumors.
Classical actions of insulin involve increased glucose uptake from the bloodstream and its metabolism in peripheral tissues, the most important and relevant effects for human health. However, nonoxidative and oxidative glucose disposal by activation of glycogen synthase (GS) and mitochondrial pyruvate dehydrogenase (PDH) remain incompletely explained by current models for insulin action. Since the discovery of insulin receptor Tyr kinase activity about 25 years ago, the dominant paradigm for intracellular signaling by insulin invokes protein phosphorylation downstream of the receptor and its primary Tyr phosphorylated substrates-the insulin receptor substrate family of proteins. This scheme accounts for most, but not all, intracellular actions of insulin. Essentially forgotten is the previous literature and continuing work on second messengers generated in cells in response to insulin. Treatment and even prevention of diabetes and metabolic syndrome will benefit from a more complete elucidation of cellular-signaling events activated by insulin, to include the actions of second messengers such as glycan molecules that contain D-chiro-inositol (DCI). The metabolism of DCI is associated with insulin sensitivity and resistance, supporting the concept that second messengers have a role in responses to and resistance to insulin.
Ghrelin, an endogenous ligand for the GH secretagogue receptor, is an orexigenic peptide hormone produced primarily by the stomach. Recent studies suggest significant differences in the specificity of currently available ghrelin assays.
The orexigenic hormone ghrelin is secreted from the stomach and has been implicated in the regulation of energy and glucose homeostasis. We hypothesized that ghrelin, like other gastrointestinal (GI) hormones, is present in intestinal lymph, and sampling this compartment would provide advantages for studying ghrelin secretion in rodents. Blood and lymph were sampled from catheters in the jugular vein and mesenteric lymph duct before and after intraduodenal (ID) administration of isocaloric Ensure, dextrin, or Liposyn meals or an equal volume of saline in conscious Sprague-Dawley rats. Total ghrelin levels were measured using an established radioimmunoassay. Acyl and des-acyl ghrelin were measured using two-site ELISA. Fasting ghrelin levels in lymph were significantly higher than in plasma (means +/- SE: 3,307.9 +/- 272.9 vs. 2,127.1 +/- 115.0 pg/ml, P = 0.004). Postingestive acyl and des-acyl ghrelin levels were also significantly higher, whereas the ratio of acyl:des-acyl ghrelin was similar in lymph and plasma (0.91 +/- 0.28 vs. 1.20 +/- 0.36, P = 0.76). The principle enzymes responsible for deacylation of ghrelin were lower in lymph than in plasma. Following ID Ensure, maximum ghrelin suppression occurred at 2 h in lymph compared with at 1 h in plasma. The return of suppressed ghrelin levels to baseline was also delayed in lymph. Similarly, dextrin also induced significant suppression of ghrelin (two-way ANOVA: P = 0.02), whereas Liposyn did not (P = 0.32). On the basis of these findings, it appears that intestinal lymph, which includes drainage from the interstitium of the GI mucosa, is enriched in ghrelin. Despite reduced deacylating activity in lymph, there is not a disproportionate amount of acyl ghrelin in this pool. The postprandial dynamics of ghrelin are slower in lymph than plasma, but the magnitude of change is greater. Assessing ghrelin levels in the lymph may be advantageous for studying its secretion and concentrations in the gastric mucosa.
Recent studies in rodent models suggest that liver X receptors (LXRs) may play an important role in the maintenance of glucose homeostasis and islet function. To date, however, no studies have comprehensively examined the role of LXRs in human islet biology. Human islets were isolated from non-diabetic donors and incubated in the presence or absence of two synthetic LXR agonists, TO-901317 and GW3965, under conditions of low and high glucose. LXR agonist treatment enhanced both basal and stimulated insulin secretion, which corresponded to an increase in the expression of genes involved in anaplerosis and reverse cholesterol transport. Furthermore, enzyme activity of pyruvate carboxylase, a key regulator of pyruvate cycling and anaplerotic flux, was also increased. Whereas LXR agonist treatment up-regulated known downstream targets involved in lipogenesis, we observed no increase in the accumulation of intra-islet triglyceride at the dose of agonist used in our study. Moreover, LXR activation increased expression of the genes encoding hormone-sensitive lipase and adipose triglyceride lipase, two enzymes involved in lipolysis and glycerolipid/free fatty acid cycling. Chronically, insulin gene expression was increased after treatment with TO-901317, and this was accompanied by increased Pdx-1 nuclear protein levels and enhanced Pdx-1 binding to the insulin promoter. In conclusion, our data suggest that LXR agonists have a direct effect on the islet to augment insulin secretion and expression, actions that should be considered either as therapeutic or unintended side effects, as these agents are developed for clinical use.
Experimental studies in GH-deficient patients and in healthy subjects receiving somatostatin-infusion suggest that GH is an important regulator of substrate metabolism during fasting. These models may not adequately reflect the selective effects of GH, and GH receptor (GHR) blockade offers a new model to define the metabolic role of GH.
We have previously demonstrated that spontaneous (physiological) GH secretion was entirely normal in cranially irradiated patients who had normal individual peak GH responses to the insulin tolerance test (ITT) but reduced maximal somatotroph reserve as indicated by substantially reduced group GH responses to the GHRH + arginine stimulation test (AST). The normality of spontaneous GH secretion was attributed to a compensatory increase in hypothalamic stimulatory input within a partially damaged hypothalamic-pituitary (h-p) axis. It is unknown, however, if such compensatory stimulation can also maintain normality of GH secretion in those who fail the ITT but pass the GHRH + AST. STUDY SUBJECTS AND DESIGN: We studied 24-h spontaneous GH secretion by 20-min sampling both in the fed state (n = 11) and in the last 24 h of a 33-h fast (n = 9) in adult cancer survivors with subnormal peak GH responses to the ITT but either normal or relatively less attenuated peak GH responses to the GHRH + AST. The study was conducted 8.3 +/- 1.8 (range 2-23) years after cranial irradiation for nonpituitary brain tumours (n = 9) or leukaemia/lymphoma (n = 2) in comparison with 30 normal controls (fasting, 14).
The aim of the study was to compare the regulation of ghrelin, leptin, and adiponectin by insulin and glucose during the second and third trimesters of pregnancy in women with diabetes. We studied 9 pregnant women with diabetes. All women were treated with insulin and omitted the morning dose on the day of the test. After collection of baseline fasting samples, we performed 3 successive glucose clamps: 2 euglycemic clamps (glucose, 5 mmol/L; insulin infusion at 20 and 40 mU m(-2) min(-1)) and 1 hyperglycemic clamp (glucose, 10 mmol/L; insulin infusion at 40 mU m(-2) min(-1)). We determined concentrations of acyl and desacyl ghrelin (using a double-antibody sandwich assay that recognizes the full-length molecule), leptin, and adiponectin. Fasting desacyl ghrelin concentrations decreased, whereas insulin and leptin concentrations increased, between the second and third trimesters of pregnancy (P < or = .011). During the clamp studies, desacyl ghrelin concentrations decreased by 33% (second trimester, P = .004) and 27% (third trimester, P = .09) with increasing glucose and insulin concentrations, whereas acyl ghrelin, leptin, and adiponectin concentrations were unaffected. Glucose and insulin regulate desacyl ghrelin concentrations in pregnant women with diabetes. Impaired desacyl ghrelin regulation may affect energy metabolism in pregnant women with poorly controlled diabetes.
The expected increase in the aging population will have a significant impact on society and the health system in the coming years and decades. Enhancing healthspan, "healthy aging", and thus extending the time that the elderly are able to function independently is a significant task and is imperative. Age-dependent changes such as weight loss, sarcopenia and anorexia, which contribute to the development of frailty in the elderly are discussed. The role of the age-dependent decrease in growth hormone secretion in this process and the potential benefits and risks of hormonal interventions to delay, prevent or reverse frailty in the elderly are reviewed.
Despite the fact that growth hormone (GH) has not been approved for antiaging purposes, its use for this indication is widespread and increasing. The Growth Hormone Research Society (GRS) convened an international workshop to critically review and debate the available evidence related to the use of GH in the older adults and the relationship between the GH/insulin-like growth factor I (IGF-I) axis and the aging process. This statement presents the conclusions reached and gives recommendations for future studies in this research field regarding the use of GH and growth hormone secretagogues (GHS) for promoting health span. The participants concluded that, until future clinical research in this area is conducted, in particular carefully designed, long-term studies, using validated outcome parameters, the clinical use of GH or GHS in older adults, alone or in combination with testosterone, cannot be recommended. In addition, future basic studies in model systems, to continue to unravel GH/IGF-I effects related to human life span and health span, were advocated.
GH plays an important role in lipid metabolism as a partitioning hormone. PPARdelta regulates lipid oxidation in skeletal muscle and is activated by several physiological ligands including fatty acids. To investigate whether GH has an effect on the regulation of transcription of PPARdelta and other genes involved in energy metabolism in skeletal muscle, mRNA levels were studied by real-time RT-PCR in lit/lit mice (isolated GH deficiency) and lit/+ mice controls (normal GH levels). Mice received either a single bolus (120 ng/g) of rat GH or vehicle, and skeletal muscle was collected 4h later. PPARdelta mRNA was increased in vehicle-treated lit/lit mice compared to vehicle-treated lit/+ mice (1.67 fold, P<0.05). lit/lit mice treated with GH showed a further increase in PPARdelta mRNA levels (2.83 fold vs. vehicle-treated lit/+ mice, P<0.001). mRNA levels of Foxo1 were increased in vehicle-treated lit/lit mice compared to vehicle-treated lit/+ mice (1.74 fold, P<0.05). lit/lit mice treated with GH showed a further increase in Foxo1 mRNA levels (6.30 fold vs. vehicle-treated lit/+ mice, P<0.001). mRNA levels of acyl CoA-oxidase showed a trend to be higher in vehicle-treated lit/lit mice compared to vehicle-treated lit/+ mice. This reached statistical significance in GH-treated lit/lit mice compared to vehicle-treated lit/+ mice (2.11 fold, P<0.05). In summary, mRNA levels of PPARdelta and Foxo1 were increased in skeletal muscle of GH-deficient mice, and further acutely increased by GH administration. These results suggest that GH plays a relevant role in the lipid catabolism in skeletal muscle.
Acylated (octanoylated) ghrelin stimulates food intake and growth hormone secretion and is deacylated into desacyl ghrelin by butyrylcholinesterase. Acylated and desacyl ghrelin both promote adipogenesis. Ghrelin concentrations decrease with hyperglycemia and hyperinsulinism. We hypothesized that 1) acylated ghrelin increases during pregnancy, contributing positively to energy balance, but is lower in women with gestational diabetes and 2) butyrylcholinesterase activity is inversely correlated with acylated ghrelin concentrations. In a first group of subjects, using two-site sandwich ghrelin assays that specifically detect full-length forms, we investigated women with and without gestational diabetes (n = 14/group) during pregnancy and after delivery. We examined whether changes in ghrelin during a test meal were correlated with changes in pituitary growth hormone [assessed through calculation of the area under the curve (AUC) during the test meal]. In postpartum subjects, the percent of total ghrelin that is acylated was four to five times higher than previously observed using single antibody assays. During pregnancy, acylated ghrelin concentrations (mean +/- SE) were lower compared with the postpartum period throughout the meal (AUC 1.2 +/- 0.2 vs. 10.2 +/- 1.9 ng.ml(-1).90 min(-1), P < 0.001). In the postpartum, acylated ghrelin and growth hormone were positively correlated (r = 0.50, P = 0.007). Desacyl (but not acylated) ghrelin was increased in subjects with gestational diabetes during and after pregnancy (AUC 15.4 +/- 1.9 vs. 8.6 +/- 1.2 ng.ml(-1).90 min(-1), P = 0.005). In a second group of subjects (n = 13), acylated ghrelin was similarly suppressed during pregnancy. Circulating octanoate concentrations (3.1 +/- 0.5 vs. 4.5 +/- 0.6 microg/ml, P = 0.029) and cholinesterase activity (705 +/- 33 vs. 1,013 +/- 56 U/ml, P < 0.001) were lower during pregnancy compared with the postpartum period. In conclusion, acylated ghrelin markedly decreases during pregnancy, likely because of a decrease in the acylation process. Desacyl ghrelin increases in gestational diabetes, possibly reflecting resistance to the inhibitory effect of insulin on ghrelin secretion.
This work presents a new approach to the analysis of aperiodic pulsatile heteroscedastic time-series data, specifically hormone pulsatility. We have utilized growth hormone (GH) concentration time-series data as an example for the utilization of this new algorithm. While many previously published approaches used for the analysis of GH pulsatility are both subjective and cumbersome to use, AutoDecon is a nonsubjective, standardized, and completely automated algorithm. We have employed computer simulations to evaluate the true-positive, the false-positive, the false-negative, and the sensitivity percentages of several of the routinely employed algorithms when applied to GH concentration time-series data. Based on these simulations, it was concluded that this new algorithm provides a substantial improvement over the previous methods. This novel method has many direct applications in addition to hormone pulsatility, for example, to time-domain fluorescence lifetime measurements, as the mathematical forms that describe these experimental systems are both convolution integrals.
Use of highly active antiretroviral therapy in patients infected with HIV can lead to lipodystrophy, a condition characterized by changes in body-fat distribution. In addition, infected individuals often exhibit relative growth hormone (GH) deficiency. Treatment with supraphysiological levels of GH improves body composition in these patients, but is associated with adverse effects. In this Practice Point commentary, we discuss an 18-month, randomized, double-blind, placebo-controlled study of low-dose GH therapy in 56 HIV-positive adults with lipodystrophy and relative GH deficiency. Lo et al. found that administration of low-dose GH (mean 0.33 mg daily) led to improvements in body composition (e.g. visceral adipose-tissue area), diastolic blood pressure and triglyceride levels. Furthermore, this treatment regimen was not associated with an increased incidence of adverse events compared with placebo. Here, we discuss the implications of the findings of Lo et al., and describe additional strategies that might be used to treat lipodystrophy in HIV-positive individuals.
Alzheimers disease (AD) is a progressive dementia that correlates highly with synapse loss. This loss appears due to the synaptic accumulation of toxic A? oligomers (ADDLs), which damages synapse structure and function. Although it has been reported that oligomer binding and toxicity can be prevented by stimulation of neuronal insulin signaling with PPAR? agonists, these agonists have problematic side effects. We therefore investigated the therapeutic potential of chiro-inositols, insulin-sensitizing compounds safe for human consumption. Chiro-inositols have been studied extensively for treatment of diseases associated with peripheral insulin resistance, but their insulin mimetic function in memory-relevant central nervous system (CNS) cells is unknown. Here we demonstrate that mature cultures of hippocampal neurons respond to d-chiro-inositol (DCI), pinitol (3-O-methyl DCI), and the inositol glycan INS-2 (pinitol ?-1-4 galactosamine) with increased phosphorylation in key upstream components in the insulin-signaling pathway (insulin receptor, insulin receptor substrate-1, and Akt). Consistent with insulin stimulation, DCI treatment promotes rapid withdrawal of dendritic insulin receptors. With respect to neuroprotection, DCI greatly enhances the ability of insulin to prevent ADDL-induced synapse damage (EC(50) of 90 nM). The mechanism comprises inhibition of oligomer binding at synapses and requires insulin/IGF signaling. DCI showed no effects on A? oligomerization. We propose that inositol glycans and DCI, a compound already established as safe for human consumption, have potential as AD therapeutics by protecting CNS synapses against A? oligomers through their insulin mimetic activity.
Reductions in levels of the hunger-stimulating hormone ghrelin have been proposed to mediate part of the effects of vertical sleeve gastrectomy (VSG) and Roux-en-Y gastric bypass surgeries for obesity. We studied circulating levels of acyl and desacyl ghrelin in rats after these surgeries. We found that blood levels of ghrelin were reduced after VSG, but not after Roux-en-Y gastric bypass, based on enzyme-linked immunosorbent assay and mass-spectrometry analyses. We compared the effects of VSG in ghrelin-deficient mice and wild-type mice on food intake, body weight, dietary fat preference, and glucose tolerance. We found that VSG produced comparable outcomes in each strain. Reduced ghrelin signaling therefore does not appear to be required for these effects of VSG.
Growth hormone (GH) is present in human lymphocytes and the relative concentration of GH mRNA in circulating cells is reportedly increased in patients with acromegaly. No quantitative assay has been described to measure GH in circulating cells.
Reducing caloric intake, while maintaining adequate nutrition, promotes longevity in diverse organisms, possibly by preserving stem and progenitor cell function. Yilmaz and colleagues (2012) now show that caloric restriction alters intestinal stem cell proliferation and differentiation, and elucidate a mechanism for how the mammalian stem cell niche responds to environmental inputs.
Ghrelin acylation by ghrelin O-acyltransferase (GOAT) has recently been reported to be essential for the prevention of hypoglycemia during prolonged negative energy balance. Using a unique set of four different genetic loss-of-function models for the GOAT/ghrelin/growth hormone secretagogue receptor (GHSR) system, we thoroughly tested the hypothesis that lack-of-ghrelin activation or signaling would lead to hypoglycemia during caloric deprivation.
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