OBJECTIVE: Leptin plays an important role in the regulation of reproduction. To explore the contribution of oestradiol to serum leptin levels in men, we measured the concentrations of serum leptin and insulin after inhibition of oestrogen biosynthesis by selective blockade of the aromatase enzyme. DESIGN: The study had a double-blind parallel group design. METHODS: The aromatase inhibitor, MPV 2213ad, was given to eight healthy male volunteers as a single dose of 100mg. Eight men received placebo. Serum leptin and insulin were determined from blood samples collected at 0800h, 1600h and 2000h both on the actual test day (day 0) and on the previous day (day -1), and from single blood samples taken in the morning of days 1, 2, 4 and 7. Changes in serum leptin were correlated with those seen in serum oestradiol, testosterone, LH, FSH, cortisol and aldosterone, which were determined earlier. RESULTS: After the aromatase inhibitor administration, mean serum oestradiol concentration was reduced by 74% from the baseline compared with a 19% reduction in the placebo group (P for difference <0.001), and returned to pre-treatment levels within four days. Despite marked changes in serum oestradiol and sustained elevations in serum testosterone, LH and FSH concentrations, serum leptin concentrations were similar in the group receiving the aromatase inhibitor and in the placebo group. We found a weak correlation between serum oestradiol and leptin, which could not be reproduced when the percentage changes in these variables were analysed. CONCLUSION: Marked short-term reduction in serum oestradiol concentration has no effect on serum leptin levels in young men.
Centrally administered leptin has been shown to increase insulin-stimulated glucose utilization and to favor the expression of uncoupling proteins (UCPs). To study if leptin also has direct peripherally mediated effects on these processes, this hormone (1 mg/day) or its vehicle was infused iv for 4 days to lean rats and insulin-stimulated glucose utilization in skeletal muscle and adipose tissue as well as the expression of UCP messenger RNAs (mRNAs) in brown adipose tissue were measured. Iv leptin administration resulted in decreases in food intake (31%), body weight gain, and plasma insulin levels (45%), in increases in overall (23%) as well as brown adipose tissue and muscle glucose utilization, and in decreases in white adipose tissue glucose uptake. Most of these changes were mimicked, in control rats, by giving them the same amount of food as that consumed by the leptin-infused group (pair-feeding). Iv leptin infusion also favored the expression of UCPs in brown adipose tissue, either by increasing their expression or preventing the fall occurring during the pair-feeding regimen. Relative UCP expression levels were 100, 104, and 33 for UCP1, 100, 191, and 125 for UCP2 and 100, 107, and 29 for UCP3 in ad libitum fed control rats, in leptin-treated rats and in pair-fed control rats, respectively. These results suggest that the overall effect of leptin on glucose utilization and on the expression of UCPs may be mediated through central mechanism.
OBJECTIVE:To validate five previously identified CSF biomarkers for FTLD-TDP, and to report a novel, robust, stand-alone CSF biomarker for FTLD-TDP.BACKGROUND: There is currently no reliable way to predict the underlying FTLD pathology while the patients are still living, and an ante-mortem biomarker for one of the main FTLD subtypes (FTLD-TDP or FTLD-Tau) can significantly enhance the pathology-based FTLD diagnosis and clinical trials for FTLD-TDP and FTLD-Tau.DESIGN/METHODS: Two independent cohorts of patients with frontotemporal dementia (FTD) were recruited independently from Emory University (Atlanta, GA) and University of Pennsylvania (Penn; Philadelphia, PA) to undergo CSF analysis.These include patients with high likelihood FTLD-TDP (FTD patients with amyotrophic lateral sclerosis or FTD patients with mutations in PGRN or C9ORF72) and patients with high likelihood FTLD-Tau (FTD patients with progressive supranuclear palsy or FTD patients with mutations in MAPT).Levels of five CSF previously identified proteins were measured, along with levels of total Tau (t-Tau) and Tau phosphorylated at threonine 181 (p-Tau 181 ).RESULTS: 29 Emory patients and 40 Penn patients participated in the study, including 43 patients with high likelihood FTLD-TDP and 26 patients with high likelihood FTLD-Tau.Using the Emory cohort, we validated the group level differences in CSF eotaxin-3, Fas, and IL-23 (p , 0.01) previously identified using the Penn cohort.We also identified the ratio of p-Tau 181 to t-Tau (p/t-Tau ratio) to be significantly lower in Emory FTLD-TDP cases compared to Emory FTLD-Tau and AD cases.Using the Penn cohort as a validation set, p/t-Tau ratio alone is sufficient to identify FTLD-TDP with 88% sensitivity and 73% specificity.CONCLUSIONS: CSF biomarkers have the potential of accurately identifying FTLD-TDP, and further development of this and other FTLD-TDP biomarkers will significantly accelerate the ante-mortem prediction of FTLD-TDP pathology and design of substrate-specific FTLD clinical trials.
Abstract Background: Availability of the α 2C -adrenoceptor (α 2C -AR) positron emission tomography (PET) tracer, [ 11 C]ORM-13070, and the α 2C -AR antagonist ORM-12741 allows probing of the roles of this G-protein coupled receptor subtype in brain function, both in healthy humans and in patients with various brain disorders. This translational study employed [ 11 C]ORM-13070 autoradiography and PET to determine α 2C -AR occupancy by ORM-12741 in rat and human brain, respectively. Results: ORM-12741 has high affinity (K i : 0.08 nM) and potent antagonist activity (K b : 0.04 nM) as well as selectivity (K i estimates for the human α 2A -AR and α 2B -AR were 8.3 nM and 0.8 nM, respectively) for the human α 2C -AR subtype. [ 11 C]ORM-13070 had highest uptake in the basal ganglia of rat and human brain. Pretreatment with ORM-12741 inhibited [ 11 C]ORM-13070 binding in rat striatum in a time- and dose-dependent manner at 10 and 50 µg/kg (s.c.) with an EC 50 estimate of 1.42 ng/mL in rat plasma, corresponding to protein-free drug concentration of 0.23 nM. In the living human brain, time- and dose-related α 2C -AR occupancy was detected with EC 50 estimates of 24 ng/mL and 31 ng/mL for the caudate nucleus and putamen, respectively, corresponding to protein-free concentrations in plasma of 0.07 nM and 0.1 nM. Modelling-based maximum α 2C -AR occupancy estimates were 63 % and 52 % in the caudate nucleus and the putamen, respectively. Conclusions: ORM-12741 is a selective α 2C -AR antagonist which penetrates the rat and human brain to occupy α 2C -ARs in a manner consistent with its receptor pharmacology. Trial registration number and date of registration: ClinicalTrial.cov NCT00829907. Registered 11 December 2008. https://clinicaltrials.gov/.
The effect of chronic treatment with metformin (320 mg/kg/day) on plasma glucose and insulin as well as liver glycogen synthase activity and hepatic glycogen content was studied in obese hyperinsulinemic Zucker rats. Metformin significantly reduced both plasma glucose (by 10%) and insulin levels (by 39%) at fasting but had no effect on hepatic glycogen content or on the basal activity of liver glycogen synthase.
We have shown previously that continuous (6 days) intracerebroventricular (ICV) leptin infusion in normal rats resulted in decreases in food intake and body weight. A reduction of food intake imposed on control rats (pair-feeding), aimed at mimicking leptin-induced hyperphagia, produced a marked decrease in the expression of muscle uncoupling protein-3 (UCP-3), whereas ICV infusion of leptin prevented such a decrease in UCP-3. To investigate an involvement of thyroid hormones in this effect of leptin, plasma levels of these hormones were determined in ICV leptin-infused, ICV vehicle-infused ad libitum fed or pair-fed controls. ICV leptin infusion and pair-feeding resulted in decreased plasma thyroid-stimulating hormone (TSH) and T4 levels relative to ad libitum fed controls. ICV leptin infusion maintained plasma levels of T3, but the levels were decreased by pair-feeding. The activity of the enzyme (hepatic 5'-monodeiodinase) responsible for T4/T3 conversion was measured. In the leptin-infused group, the activity of 5'-monodeiodinase was maintained at the values measured in ad libitum fed rats; in pair-fed rats, activity was reduced. Thus, conversion of T4 to T3 is decreased by pair-feeding, whereas such is not the case during leptin infusion. To further substantiate an involvement of thyroid hormones in the effect of leptin on muscle UCP-3 expression, hypothyroid rats were ICV infused with leptin or vehicle. It was observed that in hypothyroid rats, ICV leptin was unable to maintain muscle UCP-3 expression at values measured in ad libitum fed controls. These results suggest that central leptin stimulates T3 production via an activation of T4 to T3 conversion, and that this stimulation could be responsible for the effect of leptin on muscle UCP-3 expression. Thyroid hormones could thus be important mediators of the effect of leptin on energy expenditure.
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