Hyponatremia in the emergency department: an overview of diagnostic and therapeutic approach.

INTRODUCTION: Hyponatremia, defined as a serum sodium concentration <135 mmol/l, is a frequent electrolyte disorder in patients presenting to an emergency department (ED). In this context, appropriate diagnostic and therapeutic management is rarely performed and challenging due to complex pathophysiologic mechanisms and a variety of underlying diseases. OBJECTIVE: To implement a feasible pathway of central diagnostic and therapeutic steps in the setting of an ED. METHODS: We conducted a narrative review of the literature, considering current practice guidelines on diagnosis and treatment of hyponatremia. Underlying pathophysiologic mechanisms and management of adverse treatment effects are outlined. We also report four cases observed in our ED. RESULTS: Symptoms associated with hyponatremia may appear unspecific and range from mild cognitive deficits to seizures and coma. The severity of hyponatremia-induced neurological manifestation and the risk of poor outcome is mainly driven by the rapidity of serum sodium decrease. Therefore, emergency treatment of hyponatremia should be guided by symptom severity and the assumed onset of hyponatremia development, distinguishing acute (<48 hours) versus chronic hyponatremia (>48 hours). CONCLUSIONS: Especially in moderately or severely symptomatic patients presenting to an ED, the application of a standard management approach appears to be critical to improve overall outcome. Furthermore, an adequate work-up in the ED enables further diagnostic and therapeutic evaluation during hospitalization.

Fostering healthy aging through selective nutrition: A long-term comparison of two dietary patterns and their holistic impact on mineral status in middle-aged individuals-A randomized controlled intervention trial in Germany.

Aging is associated with a decline in physiological functions and an increased risk of age-related diseases, emphasizing the importance of identifying dietary strategies for healthy aging. Minerals play a crucial role in maintaining optimal health during aging, making them relevant targets for investigation. Therefore, we aimed to analyze the effect of different dietary pattern on mineral status in the elderly. We included 502 individuals aged 50-80 years in a 36-month randomized controlled trial (RCT) (NutriAct study). This article focuses on the results within the two-year intervention period. NutriAct is not a mineral-modulating-targeted intervention study, rather examining nutrition in the context of healthy aging in general. However, mineral status might be affected in an incidental manner. Participants were assigned to either NutriAct dietary pattern (proportionate intake of total energy consumption (%E) of 35-45 %E carbohydrates, 35-40 %E fats, and 15-25 %E protein) or the German Nutrition Society (DGE) dietary pattern (proportionate intake of total energy consumption (%E) of 55 %E carbohydrates, 30 %E fats, and 15 %E protein), differing in the composition of macronutrients. Data from 368 participants regarding dietary intake (energy, calcium, magnesium, iron, and zinc) and serum mineral concentrations of calcium, magnesium, iron, copper, zinc, selenium, iodine, and manganese, free zinc, and selenoprotein P were analyzed at baseline, as well as after 12 and 24 months to gain comprehensive insight into the characteristics of the mineral status. Additionally, inflammatory status - sensitive to changes in mineral status - was assessed by measurement of C-reactive protein and interleukin-6. At baseline, inadequate dietary mineral intake and low serum concentrations of zinc and selenium were observed in both dietary patterns. Throughout two years, serum zinc concentrations decreased, while an increase of serum selenium, manganese and magnesium concentrations was observable, likely influenced by both dietary interventions. No significant changes were observed for serum calcium, iron, copper, or iodine concentrations. In conclusion, long-term dietary interventions can influence serum mineral concentrations in a middle-aged population. Our findings provide valuable insights into the associations between dietary habits, mineral status, and disease, contributing to dietary strategies for healthy aging.

Improvement in Visceral Adipose Tissue and LDL Cholesterol by High PUFA Intake: 1-Year Results of the NutriAct Trial.

We assessed the effect of a dietary pattern rich in unsaturated fatty acids (UFA), protein and fibers, without emphasizing energy restriction, on visceral adipose tissue (VAT) and cardiometabolic risk profile. Within the 36-months randomized controlled NutriAct trial, we randomly assigned 502 participants (50-80 years) to an intervention or control group (IG, CG). The dietary pattern of the IG includes high intake of mono-/polyunsaturated fatty acids (MUFA/PUFA 15-20% E/10-15% E), predominantly plant protein (15-25% E) and fiber (≥30 g/day). The CG followed usual care with intake of 30% E fat, 55% E carbohydrates and 15% E protein. Here, we analyzed VAT in a subgroup of 300 participants via MRI at baseline and after 12 months, and performed further metabolic phenotyping. A small but comparable BMI reduction was seen in both groups (mean difference IG vs. CG: -0.216 kg/m2 [-0.477; 0.045], partial η2 = 0.009, p = 0.105). VAT significantly decreased in the IG but remained unchanged in the CG (mean difference IG vs. CG: -0.162 L [-0.314; -0.011], partial η2 = 0.015, p = 0.036). Change in VAT was mediated by an increase in PUFA intake (ß = -0.03, p = 0.005) and induced a decline in LDL cholesterol (ß = 0.11, p = 0.038). The NutriAct dietary pattern, particularly due to high PUFA content, effectively reduces VAT and cardiometabolic risk markers, independent of body weight loss.

Real-world experience with 11C-methionine positron emission tomography in the management of acromegaly.

BACKGROUND: L-[methyl-11C]-methionine-positron emission tomography (Met-PET) is a potentially important imaging adjunct in the diagnostic workup of pituitary adenomas, including somatotroph tumors. Met-PET can identify residual or occult disease and make definitive therapies accessible to a subgroup of patients who would otherwise require lifelong medical therapy. However, existing data on its use are still limited to small case series. Here, we report the largest single-center experience (n = 61) in acromegaly. METHODS: A total of 189 cases of acromegaly were referred to our national Met-PET service in the last 12 years. For this analysis, we have reviewed outcomes in those 61 patients managed exclusively by our multidisciplinary team (single center, single surgeon). Referral indications were as follows: indeterminate magnetic resonance imaging (MRI; n = 38, 62.3%), occult residual (n = 14, 23.0%), (radio-)surgical planning (n = 6, 9.8%), and occult de novo tumor (n = 3, 4.9%). RESULTS: A total of 33/61 patients (54.1%) underwent PET-guided surgery. Twenty-four of 33 patients (72.7%) achieved complete biochemical remission following (re-)surgery. Insulin-like growth factor 1 levels were reduced to <2 × upper limit of normal (ULN) in 6 of the remaining 9 cases, 3 of whom achieved levels of <1.1 × ULN compared with mean preoperative levels of 2.4 × ULN (SD 0.8) for n = 9. Only 3 patients developed single new hormonal deficits (gonadotropic/thyrotropic insufficiency). There were no neurovascular complications after surgery. CONCLUSION: In patients with persistent/recurrent acromegaly or occult tumors, Met-PET can facilitate further targeted intervention (surgery/radiosurgery). This led to complete remission in most cases (24/33) or significant improvement with comparatively low risk of complications. L-[methyl-11C]-methionine-positron emission tomography should therefore be considered in all patients who are potential candidates for further surgical intervention but present no clear target on MRI.

First effectiveness data of lenvatinib and pembrolizumab as first-line therapy in advanced anaplastic thyroid cancer: a retrospective cohort study.

BACKGROUND: Anaplastic thyroid cancer (ATC) is a rare and aggressive neoplasm. We still lack effective treatment options, so survival rates remain very low. Here, we aimed to evaluate the activity of the combination of lenvatinib and pembrolizumab as systemic first-line therapy in ATC. METHODS: In a retrospective analysis, we investigated the activity and tolerability of combined lenvatinib (starting dose 14 to 24 mg daily) and pembrolizumab (200 mg every three weeks) as first-line therapy in an institutional cohort of ATC patients. RESULTS: Five patients with metastatic ATC received lenvatinib and pembrolizumab as systemic first-line therapy. The median progression-free survival was 4.7 (range 0.8-5.9) months, and the median overall survival was 6.3 (range 0.8-not reached) months. At the first follow-up, one patient had partial response, three patients had stable disease, and one patient was formally not evaluable due to interference of assessment by concomitant acute infectious thyroiditis. This patient was then stable for more than one year and was still on therapy at the data cutoff without disease progression. Further analyses revealed deficient DNA mismatch repair, high CD8+ lymphocyte infiltration, and low macrophage infiltration in this patient. Of the other patients, two had progressive disease after adverse drug reactions and therapy de-escalation, and two died after the first staging. For all patients, the PD-L1 combined positive score ranged from 12 to 100%. CONCLUSIONS: The combination of lenvatinib and pembrolizumab was effective and moderately tolerated in treatment-naïve ATC patients with occasional long-lasting response. However, we could not confirm the exceptional responses for this combination therapy reported before in pretreated patients.

A Novel Variant in the WRN Gene Detected in a Case of Early-Onset Severe Insulin Resistance Displaying Some but Not All Hallmarks of Progeroid Werner Syndrome.

OBJECTIVE: Determining the cause of severe insulin resistance and early-onset diabetes in the case of a young woman in which a wide range of differential diagnoses did not apply. RESEARCH DESIGN AND METHODS: Diagnostic workup including medical history, physical examination, specialist consultations, imaging methods, laboratory assessment, and genetic testing carried out by next-generation panel sequencing. RESULTS: After ruling out several differential diagnoses, genetic testing revealed a previously unknown homozygous variant within the canonical splice site of intron 4 in the WRN gene classified as pathogenic. Thus, although not all cardinal clinical criteria according to existing guidelines had been met, the phenotype of our patient was attributed to Werner syndrome (WS), an autosomal-recessive inherited progeroid syndrome. CONCLUSIONS: WS, although rare, must be considered as a differential diagnosis in cases of severe insulin resistance. Moreover, recognized clinical criteria of WS may not lead to diagnosis in all cases.

An Overview of Different Vitamin D Compounds in the Setting of Adiposity.

A large body of research shows an association between higher body weight and low vitamin D status, as assessed using serum 25-hydroxyvitamin D concentrations. Vitamin D can be metabolised in adipose tissue and has been reported to influence gene expression and modulate inflammation and adipose tissue metabolism in vitro. However, the exact metabolism of vitamin D in adipose tissue is currently unknown. White adipose tissue expresses the vitamin D receptor and hydroxylase enzymes, substantially involved in vitamin D metabolism and efficacy. The distribution and concentrations of the generated vitamin D compounds in adipose tissue, however, are largely unknown. Closing this knowledge gap could help to understand whether the different vitamin D compounds have specific health effects in the setting of adiposity. This review summarises the current evidence for a role of vitamin D in adipose tissue and discusses options to accurately measure vitamin D compounds in adipose tissue using liquid chromatography tandem mass spectrometry (LC/MS-MS).

Analysis of acute COVID-19 including chronic morbidity: protocol for the deep phenotyping National Pandemic Cohort Network in Germany (NAPKON-HAP).

BACKGROUND: The severe acute respiratory syndrome corona virus 2 (SARS-CoV-2) pandemic causes a high burden of acute and long-term morbidity and mortality worldwide despite global efforts in containment, prophylaxis, and therapy. With unprecedented speed, the global scientific community has generated pivotal insights into the pathogen and the host response evoked by the infection. However, deeper characterization of the pathophysiology and pathology remains a high priority to reduce morbidity and mortality of coronavirus disease 2019 (COVID-19). METHODS: NAPKON-HAP is a multi-centered prospective observational study with a long-term follow-up phase of up to 36 months post-SARS-CoV-2 infection. It constitutes a central platform for harmonized data and biospecimen for interdisciplinary characterization of acute SARS-CoV-2 infection and long-term outcomes of diverging disease severities of hospitalized patients. RESULTS: Primary outcome measures include clinical scores and quality of life assessment captured during hospitalization and at outpatient follow-up visits to assess acute and chronic morbidity. Secondary measures include results of biomolecular and immunological investigations and assessment of organ-specific involvement during and post-COVID-19 infection. NAPKON-HAP constitutes a national platform to provide accessibility and usability of the comprehensive data and biospecimen collection to global research. CONCLUSION: NAPKON-HAP establishes a platform with standardized high-resolution data and biospecimen collection of hospitalized COVID-19 patients of different disease severities in Germany. With this study, we will add significant scientific insights and provide high-quality data to aid researchers to investigate COVID-19 pathophysiology, pathology, and chronic morbidity.

Endoscopic ultrasound-guided ethanol ablation versus surgical resection of insulinomas.

PURPOSE: Insulinoma is a rare tumor of the pancreas that can lead to hypoglycemia. To date, the standard therapy is surgical resection. After the first case report of successful endoscopic ultrasound-guided (EUS) ethanol injection 16 years ago, the need for establishing an alternative treatment method remains unchanged given the high morbidity rates of surgery and its unsuitability in some patients. MATERIALS AND METHODS: Here, we provide retrospective data from 33 insulinoma patients that were treated at our center between 2010 and 2021. Of these, 9 patients were treated with EUS-guided ethanol injection and 24 underwent pancreatic surgery. RESULTS: The ethanol group was older (ethanol: mean ± SE 67.8±11.2 years vs. surgery: 52.3±15.7, p=0.014) with a higher Charlson Comorbidity Index (3.0 (1.0;4.0) vs. 1.0 (0.0;2.0), p=0.008). The lowest glucose values were similar between groups before (ethanol: 2.09±0.17 mmol/l vs. surgery: 1.81±0.08, p=0.158) and after (4.95±0.74 vs. 5.41±0.28, p=0.581) the respective treatments. Complications occurred more frequently in the surgery group (11 % vs. 54 %, p=0.026). One patient after prior partial pancreatectomy died postoperatively. The hospitalization time was significantly shorter in the ethanol group (4.78±0.78 days vs. 19.88±4.07, p<0.001). CONCLUSION: EUS-guided ethanol injection can be similarly effective for the treatment of hyperinsulinemic hypoglycemia compared with pancreatic surgery but seems to be associated with less severe complications. This implies the need for prospective randomized trials in insulinoma patients with a low risk for malignancy.

Body mass, neuro-hormonal stress processing, and disease activity in lean to obese people with multiple sclerosis.

Overweight and obesity can worsen disease activity in multiple sclerosis (MS). Although psychobiological stress processing is increasingly recognized as important obesity factor that is tightly connected to proinflammatory metabolic hormones and cytokines, its role for MS obesity remains unexplored. Consequently, we investigated the interplay between body mass index (BMI), neural stress processing (functional connectivity, FC), and immuno-hormonal stress parameters (salivary cortisol and T cell glucocorticoid [GC] sensitivity) in 57 people with MS (six obese, 19 over-, 28 normal-, and four underweight; 37 females, 46.4 ± 10.6 years) using an Arterial-Spin-Labeling MRI task comprising a rest and stress stage, along with quantitative PCR. Our findings revealed significant positive connections between BMI and MS disease activity (i.e., higher BMI was accompanied by higher relapse rate). BMI was positively linked to right supramarginal gyrus and anterior insula FC during rest and negatively to right superior parietal lobule and cerebellum FC during stress. BMI showed associations with GC functioning, with higher BMI associated with lower CD8+ FKBP4 expression and higher CD8+ FKBP5 expression on T cells. Finally, the expression of CD8+ FKBP4 positively correlated with the FC of right supramarginal gyrus and left superior parietal lobule during rest. Overall, our study provides evidence that body mass is tied to neuro-hormonal stress processing in people with MS. The observed pattern of associations between BMI, neural networks, and GC functioning suggests partial overlap between neuro-hormonal and neural-body mass networks. Ultimately, the study underscores the clinical importance of understanding multi-system crosstalk in MS obesity.

Adipose retinol saturase is regulated by ß-adrenergic signaling and its deletion impairs lipolysis in adipocytes and acute cold tolerance in mice.

OBJECTIVE: Retinol saturase (RetSat) is an endoplasmic reticulum-localized oxidoreductase highly expressed in organs involved in lipid metabolism such as white (WAT) and brown adipose tissue (BAT). Cold exposure was shown to increase RETSAT protein in BAT but its relevance for non-shivering thermogenesis, a process with beneficial effects on metabolic health, is unknown. METHODS: We analyzed the regulation of RetSat expression in white and brown adipocytes and different murine adipose tissue depots upon ß-adrenergic stimulation and cold exposure. RetSat function during the differentiation and ß-adrenergic stimulation of brown adipocytes was dissected by loss-of-function experiments. Mice with BAT-specific deletion of RetSat were generated and exposed to cold. Gene expression in human WAT was analyzed and the effect of RetSat depletion on adipocyte lipolysis investigated. RESULTS: We show that cold exposure induces RetSat expression in both WAT and BAT of mice via ß-adrenergic signaling. In brown adipocytes, RetSat has minor effects on differentiation but is required for maximal thermogenic gene and protein expression upon ß-adrenergic stimulation and mitochondrial respiration. In mice, BAT-specific deletion of RetSat impaired acute but not long-term adaptation to cold exposure. RetSat expression in subcutaneous WAT of humans correlates with the expression of genes related to mitochondrial function. Mechanistically, we found that RetSat depletion impaired ß-agonist-induced lipolysis, a major regulator of thermogenic gene expression in adipocytes. CONCLUSIONS: Thus, RetSat expression is under ß-adrenergic control and determines thermogenic capacity of brown adipocytes and acute cold tolerance in mice. Modulating RetSat activity may allow for therapeutic interventions towards pathologies with inadequate metabolic activity.

Metastases to the pituitary gland: insights from the German pituitary tumor registry.

Metastatic involvement of the pituitary gland is a rare but clinically significant phenomenon, that often poses diagnostic and therapeutic challenges. The aim of this study was to provide a comprehensive analysis of the origin of pituitary metastases using data from the German Pituitary Tumor Registry, one of the globally largest collections of pituitary pathology specimens. Here, we report data from a retrospective analysis of patients with metastases to the pituitary registered between 1990 and 2022. Out of 17,896 pituitary cases in the registry during this period, a total of 96 metastases to the pituitary gland were identified, accounting for 0.5% of all pituitary tumors in the registry. The mean age of the patients was 64 years. Breast cancer was identified as the primary tumor in 25% of total cases (n = 24/96) and in 50% of female patients. The second most prevalent primary tumor was lung cancer (18.75%, n = 18/96), followed by renal cell carcinoma (14.58%, n = 14/96). In comparison to current meta-analyses, this cohort shows a higher prevalence of metastases originating from the kidney. Furthermore, in contrast to the existing literature, no case of primary thyroid tumor was identified. Our study highlights the importance of pituitary metastases as a differential diagnosis in patients presenting with pituitary tumors.

Protocol of the Berlin Long-term Observation of Vascular Events (BeLOVE): a prospective cohort study with deep phenotyping and long-term follow up of cardiovascular high-risk patients.

INTRODUCTION: The Berlin Long-term Observation of Vascular Events is a prospective cohort study that aims to improve prediction and disease-overarching mechanistic understanding of cardiovascular (CV) disease progression by comprehensively investigating a high-risk patient population with different organ manifestations. METHODS AND ANALYSIS: A total of 8000 adult patients will be recruited who have either suffered an acute CV event (CVE) requiring hospitalisation or who have not experienced a recent acute CVE but are at high CV risk. An initial study examination is performed during the acute treatment phase of the index CVE or after inclusion into the chronic high risk arm. Deep phenotyping is then performed after ~90 days and includes assessments of the patient's medical history, health status and behaviour, cardiovascular, nutritional, metabolic, and anthropometric parameters, and patient-related outcome measures. Biospecimens are collected for analyses including 'OMICs' technologies (e.g., genomics, metabolomics, proteomics). Subcohorts undergo MRI of the brain, heart, lung and kidney, as well as more comprehensive metabolic, neurological and CV examinations. All participants are followed up for up to 10 years to assess clinical outcomes, primarily major adverse CVEs and patient-reported (value-based) outcomes. State-of-the-art clinical research methods, as well as emerging techniques from systems medicine and artificial intelligence, will be used to identify associations between patient characteristics, longitudinal changes and outcomes. ETHICS AND DISSEMINATION: The study was approved by the Charité-Universitätsmedizin Berlin ethics committee (EA1/066/17). The results of the study will be disseminated through international peer-reviewed publications and congress presentations. STUDY REGISTRATION: First study phase: Approved WHO primary register: German Clinical Trials Register: https://drks.de/search/de/trial/DRKS00016852; WHO International Clinical Registry Platform: http://apps.who.int/trialsearch/Trial2.aspx?TrialID=DRKS00016852. Recruitment started on July 18, 2017.Second study phase: Approved WHO primary register: German Clinical Trials Register DRKS00023323, date of registration: November 4, 2020, URL: http://www.drks.de/ DRKS00023323. Recruitment started on January 1, 2021.

5-Aminovaleric acid betaine predicts impaired glucose metabolism and diabetes.

BACKGROUND: 5-Aminovaleric acid betaine (5-AVAB) has recently been identified as a diet and microbial-dependent factor inducing obesity and hepatic steatosis in mice fed a Western diet. Accumulating evidence suggests a role in metabolic dysfunction associated with obesity, diabetes, and fatty liver disease. However, whether 5-AVAB plays a role in human disease is unclear, and human data are sparse. METHODS: We measured circulating 5-AVAB serum levels in 143 individuals with overweight or obesity participating in a randomized intervention study (NCT00850629) investigating the long-term effect of a weight maintenance strategy after diet-induced weight reduction. RESULTS: Higher 5-AVAB serum levels correlate with worse estimates of obesity, glucose metabolism, and hepatic steatosis after weight loss. Furthermore, higher 5-AVAB levels after weight loss independently predict detrimental changes in glucose metabolism 18 months after the successful weight reduction. CONCLUSION: Our human data supports previous findings in rodents indicating a relevant, potentially disadvantageous function of 5-AVAB in the context of metabolic dysbalance.

Early-set POMC methylation variability is accompanied by increased risk for obesity and is addressable by MC4R agonist treatment.

Increasing evidence points toward epigenetic variants as a risk factor for developing obesity. We analyzed DNA methylation of the POMC (pro-opiomelanocortin) gene, which is pivotal for satiety regulation. We identified sex-specific and nongenetically determined POMC hypermethylation associated with a 1.4-fold (confidence interval, 1.03 to 2.04) increased individual risk of developing obesity. To investigate the early embryonic establishment of POMC methylation states, we established a human embryonic stem cell (hESC) model. Here, hESCs (WA01) were transferred into a naïve state, which was associated with a reduction of DNA methylation. Naïve hESCs were differentiated via a formative state into POMC-expressing hypothalamic neurons, which was accompanied by re-establishment of DNA methylation patterning. We observed that reduced POMC gene expression was associated with increased POMC methylation in POMC-expressing neurons. On the basis of these findings, we treated POMC-hypermethylated obese individuals (n = 5) with an MC4R agonist and observed a body weight reduction of 4.66 ± 2.16% (means ± SD) over a mean treatment duration of 38.4 ± 26.0 weeks. In summary, we identified an epigenetic obesity risk variant at the POMC gene fulfilling the criteria for a metastable epiallele established in early embryonic development that may be addressable by MC4R agonist treatment to reduce body weight.

Outcome of immunotherapy in adrenocortical carcinoma: a retrospective cohort study.

OBJECTIVE: Clinical trials with immune checkpoint inhibitors (ICI) in adrenocortical carcinoma (ACC) have yielded contradictory results. We aimed to evaluate treatment response and safety of ICI in ACC in a real-life setting. DESIGN: Retrospective cohort study of 54 patients with advanced ACC receiving ICI as compassionate use at 6 German reference centres between 2016 and 2022. METHODS: Objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and treatment-related adverse events (TRAE) were assessed. RESULTS: In 52 patients surviving at least 4 weeks after initiation of ICI, ORR was 13.5% (6-26) and DCR was 24% (16-41). PFS was 3.0 months (95% CI, 2.3-3.7). In all patients, median OS was 10.4 months (3.8-17). 17 TRAE occurred in 15 patients, which was associated with a longer PFS of 5.5 (1.9-9.2) vs 2.5 (2.0-3.0) months (HR 0.29, 95% CI, 0.13-0.66, P = 0.001) and OS of 28.2 (9.5-46.8) vs 7.0 (4.1-10.2) months (HR 0.34, 95% CI, 0.12-0.93). Positive tissue staining for programmed cell death ligand 1 (PD-L1) was associated with a longer PFS of 3.2 (2.6-3.8) vs 2.3 (1.6-3.0, P < 0.05) months. Adjusted for concomitant mitotane use, treatment with nivolumab was associated with lower risk of progression (HR 0.36, 0.15-0.90) and death (HR 0.20, 0.06-0.72) compared to pembrolizumab. CONCLUSIONS: In the real-life setting, we observe a response comparable to other second-line therapies and an acceptable safety profile in ACC patients receiving different ICI. The relevance of PD-L1 as a marker of response and the potentially more favourable outcome in nivolumab-treated patients require confirmation.

Hepatic Energy Metabolism under the Local Control of the Thyroid Hormone System.

The energy homeostasis of the organism is orchestrated by a complex interplay of energy substrate shuttling, breakdown, storage, and distribution. Many of these processes are interconnected via the liver. Thyroid hormones (TH) are well known to provide signals for the regulation of energy homeostasis through direct gene regulation via their nuclear receptors acting as transcription factors. In this comprehensive review, we summarize the effects of nutritional intervention like fasting and diets on the TH system. In parallel, we detail direct effects of TH in liver metabolic pathways with regards to glucose, lipid, and cholesterol metabolism. This overview on hepatic effects of TH provides the basis for understanding the complex regulatory network and its translational potential with regards to currently discussed treatment options of non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) involving TH mimetics.

Thrifty energy phenotype predicts weight regain in postmenopausal women with overweight or obesity and is related to FGFR1 signaling.

BACKGROUND&AIMS: Long term improvement of body weight and metabolism is highly requested in obesity. The specific impact of weight loss associated temporary negative energy balance or modified body composition on metabolism and weight regain is unclear. METHODS: We randomly assigned 80 post-menopausal women (BMI 33.9 (32.2-36.8)kg/m2) to an intervention (IG) or control group (CG). IG underwent a dietary three month-weight loss intervention followed by a four week-weight maintenance period without negative energy balance. The CG was instructed to keep their weight stable. Phenotyping was performed at baseline (M0), after weight loss (M3), the maintenance period (M4) and 24-month follow-up (M24). Co-primary outcomes were changes of insulin sensitivity (ISIClamp) and lean body mass (LBM). Energy metabolism and adipose gene expression were secondary endpoints. RESULTS: Between March 2012 and July 2015, 479 subjects were screened for eligibility. 80 subjects were randomly assigned to IG (n = 40) or CG (n = 40). The total number of dropouts was 18 (IG: n = 13, CG: n = 5). LBM and ISIClamp were stable in the CG between M0 and M3, but were changed in the IG at M3 (LBM: -1.4 (95%CI -2.2-(-0.6)) kg and ISIClamp: +0.020 (95%CI 0.012-0.028) mg·kg-1·min-1/(mU·l-1)) (p < 0.01 and p < 0.05 for IG vs. CG, respectively). Effects on LBM, ISIClamp, FM and BMI were preserved until M4. Lower resting energy expenditure per LBM (REELBM) at M3 and stronger difference of REELBM between M3 and M4 (ΔREELBM-M3M4), which indicates a thrifty phenotype, were positively associated with FM regain at M24 (p = 0.022 and p = 0.044, respectively). Gene set enrichment analysis revealed a relationship of this phenotype to weight loss-induced adaption of adipose FGFR1 signaling. CONCLUSION: Negative energy balance had no additional effect on insulin sensitivity. FGFR1 signaling might be involved in the adaption of energy expenditure to temporary negative energy balance, which indicates a thrifty phenotype susceptible to weight regain. TRIAL REGISTRATION: ClinicalTrials.gov number: NCT01105143, https://clinicaltrials.gov/ct2/show/NCT01105143, date of registration: April 16th, 2010.