Estrogens play a major role in the modulation of energy balance through central and peripheral actions. Here, we demonstrate that central action of estradiol (E2) inhibits AMP-activated protein ...kinase (AMPK) through estrogen receptor alpha (ERα) selectively in the ventromedial nucleus of the hypothalamus (VMH), leading to activation of thermogenesis in brown adipose tissue (BAT) through the sympathetic nervous system (SNS) in a feeding-independent manner. Genetic activation of AMPK in the VMH prevented E2-induced increase in BAT-mediated thermogenesis and weight loss. Notably, fluctuations in E2 levels during estrous cycle also modulate this integrated physiological network. Together, these findings demonstrate that E2 regulation of the VMH AMPK-SNS-BAT axis is an important determinant of energy balance and suggest that dysregulation in this axis may account for the common changes in energy homeostasis and obesity linked to dysfunction of the female gonadal axis.
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•Central estradiol (E2) promotes negative energy balance•Central E2 increases thermogenic sympathetic nerve activity•Central E2 inhibits AMPK, specifically in the VMH, through ERα•The VMH AMPK-SNS-BAT axis mediates the central actions of E2 on energy balance
Estrogens play a major role in the regulation of body weight. Martínez de Morentin and colleagues show that estradiol (E2), acting through estrogen receptor alpha, selectively inhibits the energy sensor AMPK in the brain hypothalamic ventromedial nucleus, leading to activation of thermogenesis in brown adipose tissue.
Thyroid dysfunction and thyroid autoimmunity are prevalent among women of reproductive age and are associated with adverse pregnancy outcomes. Preconception or early pregnancy screening for thyroid ...dysfunction has been proposed but is not widely accepted. We conducted a systematic review of the literature on the clinical significance of thyroid dysfunction and thyroid autoimmunity before conception and in early pregnancy.
Relevant studies were identified by searching Medline, EMBASE and the Cochrane Controlled Trials Register.
From a total of 14 208 primary selected titles, 43 articles were included for the systematic review and 38 were appropriate for meta-analyses. No articles about hyperthyroidism were selected. Subclinical hypothyroidism in early pregnancy, compared with normal thyroid function, was associated with the occurrence of pre-eclampsia odds ratio (OR) 1.7, 95% confidence interval (CI) 1.1-2.6 and an increased risk of perinatal mortality (OR 2.7, 95% CI 1.6-4.7). In the meta-analyses, the presence of thyroid antibodies was associated with an increased risk of unexplained subfertility (OR 1.5, 95% CI 1.1-2.0), miscarriage (OR 3.73, 95% CI 1.8-7.6), recurrent miscarriage (OR 2.3, 95% CI 1.5-3.5), preterm birth (OR 1.9, 95% CI 1.1-3.5) and maternal post-partum thyroiditis (OR 11.5, 95% CI 5.6-24) when compared with the absence of thyroid antibodies.
Pregnant women with subclinical hypothyroidism or thyroid antibodies have an increased risk of complications, especially pre-eclampsia, perinatal mortality and (recurrent) miscarriage. Future research, within the setting of clinical trials, should focus on the potential health gain of identification, and effect of treatment, of thyroid disease on pregnancy outcome.
Exposure to light at night (LAN) is associated with insomnia in humans. Light provides the main input to the master clock in the hypothalamic suprachiasmatic nucleus (SCN) that coordinates the ...sleep-wake cycle. We aimed to develop a rodent model for the effects of LAN on sleep. Therefore, we exposed male Wistar rats to either a 12 h light (150-200lux):12 h dark (LD) schedule or a 12 h light (150-200 lux):12 h dim white light (5 lux) (LDim) schedule. LDim acutely decreased the amplitude of daily rhythms of REM and NREM sleep, with a further decrease over the following days. LDim diminished the rhythms of 1) the circadian 16-19 Hz frequency domain within the NREM sleep EEG, and 2) SCN clock gene expression. LDim also induced internal desynchronization in locomotor activity by introducing a free running rhythm with a period of ~25 h next to the entrained 24 h rhythm. LDim did not affect body weight or glucose tolerance. In conclusion, we introduce the first rodent model for disturbed circadian control of sleep due to LAN. We show that internal desynchronization is possible in a 24 h L:D cycle which suggests that a similar desynchronization may explain the association between LAN and human insomnia.
Abstract
Context
Pretreatment with α-adrenergic receptor blockers is recommended to prevent hemodynamic instability during resection of a pheochromocytoma or sympathetic paraganglioma (PPGL).
...Objective
To determine which type of α-adrenergic receptor blocker provides the best efficacy.
Design
Randomized controlled open-label trial (PRESCRIPT; ClinicalTrials.gov NCT01379898)
Setting
Multicenter study including 9 centers in The Netherlands.
Patients
134 patients with nonmetastatic PPGL.
Intervention
Phenoxybenzamine or doxazosin starting 2 to 3 weeks before surgery using a blood pressure targeted titration schedule. Intraoperative hemodynamic management was standardized.
Main Outcome Measures
Primary efficacy endpoint was the cumulative intraoperative time outside the blood pressure target range (ie, SBP >160 mmHg or MAP <60 mmHg) expressed as a percentage of total surgical procedure time. Secondary efficacy endpoint was the value on a hemodynamic instability score.
Results
Median cumulative time outside blood pressure targets was 11.1% (interquartile range IQR: 4.3–20.6 in the phenoxybenzamine group compared to 12.2% (5.3–20.2) in the doxazosin group (P = .75, r = 0.03). The hemodynamic instability score was 38.0 (28.8–58.0) and 50.0 (35.3–63.8) in the phenoxybenzamine and doxazosin group, respectively (P = .02, r = 0.20). The 30-day cardiovascular complication rate was 8.8% and 6.9% in the phenoxybenzamine and doxazosin group, respectively (P = .68). There was no mortality after 30 days.
Conclusions
The duration of blood pressure outside the target range during resection of a PPGL was not different after preoperative treatment with either phenoxybenzamine or doxazosin. Phenoxybenzamine was more effective in preventing intraoperative hemodynamic instability, but it could not be established whether this was associated with a better clinical outcome.
In pregnant women with Graves' disease, maternal thyrotropin receptor antibodies (TRAb) can cross the placenta and induce fetal or neonatal thyrotoxicosis. Symptoms of fetal thyrotoxicosis are ...tachycardia, intrauterine growth restriction, and intra-uterine death. Recommendations on an upper limit of TRAb concentrations below which intensive fetal monitoring can be safely omitted vary between different guidelines. The objective of this study was to define an evidence-based cutoff level for maternal TRAb necessitating additional fetal monitoring during pregnancy.
A literature search was performed to identify studies on pregnant women with Graves' disease and fetal and/or neonatal thyrotoxicosis. Only studies that reported TRAb were included.
From a total of 229 identified titles, 20 articles could be included in the analysis. A total of 53 cases of fetal and/or neonatal thyrotoxicosis were described. The lowest level of maternal TRAb leading to neonatal thyrotoxicosis was 4.4 U/L, which corresponds to 3.7 times the upper limit of normal. The level of evidence for this threshold is moderate to low.
In women with Graves' disease, intensive fetal monitoring is recommended when maternal TRAb concentrations are >3.7 times the upper limit of normal. This cutoff level should be interpreted with caution, since evidence is limited.
This review focuses on providing physicians with insights into the complex relationship between bone marrow adipose tissue (BMAT) and bone health, in the context of weight loss through caloric ...restriction or metabolic and bariatric surgery (MBS), in people living with obesity (PwO). We summarize the complex relationship between BMAT and bone health, provide an overview of noninvasive imaging techniques to quantify human BMAT, and discuss clinical studies measuring BMAT in PwO before and after weight loss. The relationship between BMAT and bone is subject to variations based on factors such as age, sex, menopausal status, skeletal sites, nutritional status, and metabolic conditions. The Bone Marrow Adiposity Society (BMAS) recommends standardizing imaging protocols to increase comparability across studies and sites, they have identified both water–fat imaging (WFI) and spectroscopy (1H-MRS) as accepted standards for in vivo quantification of BMAT. Clinical studies measuring BMAT in PwO are limited and have shown contradictory results. However, BMAT tends to be higher in patients with the highest visceral adiposity, and inverse associations between BMAT and bone mineral density (BMD) have been consistently found in PwO. Furthermore, BMAT levels tend to decrease after caloric restriction-induced weight loss. Although weight loss was associated with overall fat loss, a reduction in BMAT did not always follow the changes in fat volume in other tissues. The effects of MBS on BMAT are not consistent among the studies, which is at least partly related to the differences in the study population, skeletal site, and duration of the follow-up. Overall, gastric bypass appears to decrease BMAT, particularly in patients with diabetes and postmenopausal women, whereas sleeve gastrectomy appears to increase BMAT. More research is necessary to evaluate changes in BMAT and its connection to bone metabolism, either in PwO or in cases of weight loss through caloric restriction or MBS, to better understand the role of BMAT in this context and determine the local or systemic factors involved.
Hypothalamic effects of thyroid hormone Zhang, Zhi; Boelen, Anita; Bisschop, Peter H. ...
Molecular and cellular endocrinology,
12/2017, Letnik:
458
Journal Article
Recenzirano
Thyroid hormone (TH) is a key driver of metabolism in mammals. Plasma concentrations of TH are kept within a narrow range by negative feedback regulation in the hypothalamus-pituitary-thyroid (HPT) ...axis. Plasma TH concentrations are an important determinant of metabolic processes in liver and brown adipose tissue (BAT). In addition to endocrine effects of TH derived from the circulation, recent studies have demonstrated additional neural routes for intrahypothalamic thyroid hormone to regulate metabolism in liver and BAT via the sympathetic and parasympathetic branch of the autonomic nervous system (ANS). This review provides an overview of studies reporting metabolic effects of selective administration of T3 within hypothalamic nuclei including the paraventricular nucleus (PVN), the ventromedial nucleus (VMH), the arcuate nucleus (Arc), and the anterior hypothalamic area (AHA).
This overview of the literature suggests that intrahypothalamic T3 can have profound effects on hepatic glucose production and insulin sensitivity, energy expenditure in BAT, cardiovascular function and feeding behavior. As the experiments have been performed in experimental animals exclusively, and the timing and route of T3 administration may be an important determinant of effect size, the clinical relevance of these metabolic effects in the chronic setting remains to be established.
Differential effects of acute vs chronic intrahypothalamic T3 administration on energy metabolism. Arc: arcuate nucleus, BAT: brown adipose tissue, ICV: intracerebroventricular compartment, POA: preoptic area, PVN: paraventricular nucleus, REM: rapid eye movement sleep, VMH: ventromedial nucleus. Display omitted
•Thyroid hormone regulates metabolism both via the systemic circulation and via the autonomic nervous system.•T3 within the PVN controls glucose production and hepatic insulin sensitivity via sympathetic liver innervation.•T3 within the VMH induces sympathetic nervous system-mediated brown adipose tissue activation.•Timing and route of central T3 administration may determine metabolic effect size.
Aims/hypothesis
Animal studies have indicated that disturbed diurnal rhythms of clock gene expression in adipose tissue can induce obesity and type 2 diabetes. The importance of the circadian timing ...system for energy metabolism is well established, but little is known about the diurnal regulation of (clock) gene expression in obese individuals with type 2 diabetes. In this study we aimed to identify key disturbances in the diurnal rhythms of the white adipose tissue transcriptome in obese individuals with type 2 diabetes.
Methods
In a case–control design, we included six obese individuals with type 2 diabetes and six healthy, lean control individuals. All participants were provided with three identical meals per day for 3 days at zeitgeber time (ZT, with ZT 0:00 representing the time of lights on) 0:30, 6:00 and 11:30. Four sequential subcutaneous abdominal adipose tissue samples were obtained, on day 2 at ZT 15:30, and on day 3 at ZT 0:15, ZT 5:45 and ZT 11:15. Gene expression was measured using RNA sequencing.
Results
The core clock genes showed reduced amplitude oscillations in the individuals with type 2 diabetes compared with the healthy control individuals. Moreover, in individuals with type 2 diabetes, only 1.8% (303 genes) of 16,818 expressed genes showed significant diurnal rhythmicity, compared with 8.4% (1421 genes) in healthy control individuals. Enrichment analysis revealed a loss of rhythm in individuals with type 2 diabetes of canonical metabolic pathways involved in the regulation of lipolysis
.
Enrichment analysis of genes with an altered mesor in individuals with type 2 diabetes showed decreased activity of the translation initiating pathway ‘EIF2 signaling’. Individuals with type 2 diabetes showed a reduced diurnal rhythm in postprandial glucose concentrations.
Conclusions/interpretation
Diurnal clock and metabolic gene expression rhythms are decreased in subcutaneous adipose tissue of obese individuals with type 2 diabetes compared with lean control participants. Future investigation is needed to explore potential treatment targets as identified by our study, including clock enhancement and induction of EIF2 signalling.
Data availability
The raw sequencing data and supplementary files for rhythmic expression analysis and Ingenuity Pathway Analysis have been deposited in NCBI Gene Expression Omnibus (GEO series accession number GSE104674).
The Role of Estrone in Feminizing Hormone Treatment Tebbens, Marieke; Heijboer, Annemieke C; T'Sjoen, Guy ...
The journal of clinical endocrinology and metabolism,
01/2022, Letnik:
107, Številka:
2
Journal Article
Recenzirano
Odprti dostop
In trans women, hormone treatment induces feminization; however, the degree of feminization varies from person to person. A possible contributing factor could be estrone, a weak estrogen that ...interferes with the estrogen receptor.
We assessed whether estrone is involved in feminization induced by hormone treatment.
This prospective cohort study, with follow-up of 1 year, included 212 adult trans women at a gender identity clinic, who were starting gender-affirming hormone treatment between July 2017 and December 2019, median age 25 years. Change in fat percentage and breast development were assessed.
After 12 months of hormone treatment, estrone concentration was 187 pmol/L (95% CI, 153-220) in transdermal and 1516 pmol/L (95% CI, 1284-1748) in oral estradiol users. Fat percentage increased by 1.2% (interquartile range IQR, 0.3-4.8) in transdermal and 4.6% (IQR, 2.5-5.9) in oral estradiol users. This was not associated with estrone concentrations in transdermal (+4.4% (95% CI, -4.0 to 13) per 100 pmol/L increase in estrone concentration) nor in oral estradiol users (-0.7% 95% CI, -1.7 to 0.3). Breast volume increased by 69 mL (IQR, 58-134) in transdermal and 62 mL (IQR, 32-95) in oral estradiol users. This was not associated with estrone concentrations in transdermal (+14% 95% CI, -49 to 156 per 100 pmol/L increase in estrone concentration) nor oral estradiol users (+11% 95% CI -14 to 43).
Change in fat percentage and breast development in trans women were not associated with estrone concentrations nor with administration route. Therefore, measurement of estrone concentrations does not have a place in the monitoring of feminization in trans women.
Summary
Objective
TSH‐secreting pituitary adenomas (TSH‐omas) are a rare cause of thyrotoxicosis. First‐line therapy for these tumours is neurosurgery, although medical therapy with somatostatin ...analogues (SSAs) is increasingly used for this indication.
Design and patients
We retrospectively reviewed the data of patients with a TSH‐oma (n = 18, 67% males) followed between 1989 and 2011 (median follow‐up 7 years, range 1–21) in three academic medical centres in the Netherlands, focusing on the role of SSA treatment.
Measurements
Patient records were reviewed for clinical, biochemical, imaging, pathological and treatment characteristics.
Results
At initial evaluation, biochemical hyperthyroidism with non‐suppressed TSH concentrations was detected in 94% of the patients. The majority of patients (72%) had a macroadenoma with extrasellar extension. Fourteen patients underwent surgery, resulting in postoperative euthyroidism in six patients (43%). Recurrence of hyperthyroidism developed in three of them after 5, 24 and 32 months, respectively. Adjuvant radiotherapy (n = 2) did not induce remission. Three patients received SSA therapy exclusively, resulting in apparent cure in one of them. During long‐term follow‐up, 72% of all patients required medical therapy (mostly SSA treatment). Euthyroidism was achieved in all but one patient, who refused all treatments.
Conclusions
Our results demonstrate that patients with TSH‐omas, who often present with large macroadenomas with extrasellar extension, have an excellent response to SSA therapy. Because the results of surgery and radiotherapy are disappointing, primary medical therapy may be considered in virtually all patients, except in case of optic chiasm compression, especially in those harbouring large adenomas with parasellar extension.
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