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/.
OBJECTIVE: Leptin is the hormonal product of the ob gene. It is expressed in adipocytes and participates in the regulation of food intake and metabolism. Since leptin also seems to signal metabolic information to the reproductive system, we studied the association between reproductive hormones and plasma leptin in normal-weight young women. DESIGN: Eight young women with normal menstrual cycles (body mass index (BMI) 21.2 +/- 1.6 kg/m2) and eight young women using hormonal contraception (BMI 21.4 +/- 1.1 kg/m2) were studied. Furthermore, six women with normal menstrual cycles and no hormonal therapy (BMI 20.7 +/- 1.2 kg/m2) were studied around the time of the anticipated ovulation. METHODS: Serum leptin, estradiol, progesterone and luteinizing hormone (LH) concentrations were measured with radioimmunoassays. RESULTS: Serum leptin concentrations were similar at the beginning of the cycle, at the time of the anticipated ovulation and at the end of the menstrual cycle (10.2 +/- 7.1, 10.7 +/- 7.0 and 11.8 +/- 6.9 microg/l respectively). There was an association between leptin and LH concentrations (r= 0.37, P< 0.01) when values recorded during different time points during the cycle were plotted with each other. There was no change in serum leptin in samples taken at different times of the cyclic treatment with an oral contraceptive. There was no significant difference in mean serum leptin concentrations between women using oral contraceptives and women with no hormonal therapy. CONCLUSIONS: There is a link between serum leptin and LH concentrations during the menstrual cycle. Variations in circulating estrogen and/or progesterone concentrations have no major influence on circulating leptin in young female subjects.
The role of gonadotropins, androgens, and insulin in the regulation of circulating leptin levels is obscure. In order to clarify the relationships of these parameters we studied serum leptin levels in 19 healthy control subjects and in 35 hyperandrogenic and hyperinsulinemic patients with polycystic ovary syndrome (PCOS).
Abstract: ICI D7114 is a selective β 3 ‐agonist which stimulates brown adipose tissue thermogenesis. In the present study the effects of 18 days treatment with ICI D7114 (2 mg/kg/day orally) on macronutrient selection and brown adipose tissue thermogenesis were investigated in Sprague‐Dawley rats. The rats were maintained on a free‐feeding self‐selection paradigm with three pure macronutrient diets of carbohydrate, fat and protein. Treatment with ICI D7114 did not change the macronutrient selection or total calories consumed by the rats. To monitore the thermogenic activation of brown adipose tissue the binding of [ 3 H]GDP to brown adipose tissue mitochondria was measured. The treatment with ICI D7114 increased the binding of GDP both when expressed as total binding per lobe (P<0.001) and per mg of protein (P<0.01). It is concluded that ICI D7114, used in doses affecting brown adipose tissue thermogenesis, does not change the macronutrient selection or total energy intake in Sprague‐Dawley rats.
Among other actions ,leptin has been suggested to increase energy expenditure and to modulate the menstrual cycle. In fact ,the main effect of leptin seems to be modulating the sympathetic nervous system and gonadotropin-releasing hormone pulsatility. We investigated whether changes in the plasma steroid concentrations during the estrous cycle and after ovariectomy and steroid replacement can modulate plasma leptin levels ,adipose tissue leptin mRNA expression ,and some of the candidates for mediating energy expenditure (uncoupling proteins (UCP) 1 ,2 ,and 3 mRNA) in white and brown adipose tissue. Rats in estrous cycle or ovariectomized rats with or without estradiol or progesterone replacement therapy for 18 days were studied. Plasma leptin ,insulin ,estradiol and progesterone were measured with radio-immunoassays. Leptin mRNA expression was measured in subcutaneous ,periovarian and mesenteric white adipose tissue and in interscapular brown adipose tissue. Expression of UCP 1 ,2 ,and 3 mRNA in periovarian white and brown adipose tissue was analyzed. Plasma leptin levels were significantly decreased in the estrous (1.1 ± 0.4 ng/ml) compared with the pro-estrous (1.7 ± 0.4 ng/ml ,F = 3.0 ,p = 0.046) phase of cycle. UCP1 mRNA levels in brown adipose tissue were more elevated during pro-estrus than during metestrus (F = 3.17 ,p = 0.039). Gene expressions of leptin ,UCP2 or UCP3 mRNA did not change significantly during the cycle. In ovariectomized rats ,estradiol and/or progesterone treatment had no effect on plasma leptin levels. Gene expression analysis of leptin and UCP1 ,2 and 3 in adipose tissue was not affected by steroid replacement. In conclusion ,the estrous cycle appears to have a minor effect on modulation of leptin and uncoupling proteins. Only plasma leptin levels and expression of UCP1 mRNA are modestly elevated during the estrous cycle in the rat. Since estrogen and/or progesterone substitution in ovariectomized rats does not affect circulating leptin concentration or expression of leptin and UCPs in adipose tissue ,it is unlikely that steroids play a major role in their regulation.
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