Deficiency of Retinaldehyde Dehydrogenase 1 Induces BMP2 and Increases Bone Mass In Vivo

The effects of retinoids, the structural derivatives of vitamin A (retinol), on post-natal peak bone density acquisition and skeletal remodeling are complex and compartment specific. Emerging data indicates that retinoids, such as all trans retinoic acid (ATRA) and its precursor all trans retinaldehyde (Rald), exhibit distinct and divergent transcriptional effects in metabolism. Despite these observations, the role of enzymes that control retinoid metabolism in bone remains undefined. In this study, we examined the skeletal phenotype of mice deficient in retinaldehyde dehydrogenase 1 (Aldh1a1), the enzyme responsible for converting Rald to ATRA in adult animals. Bone densitometry and micro-computed tomography (µCT) demonstrated that Aldh1a1-deficient (Aldh1a1−/−) female mice had higher trabecular and cortical bone mass compared to age and sex-matched control C57Bl/6 wild type (WT) mice at multiple time points. Histomorphometry confirmed increased cortical bone thickness and demonstrated significantly higher bone marrow adiposity in Aldh1a1−/− mice. In serum assays, Aldh1a1−/− mice also had higher serum IGF-1 levels. In vitro, primary Aldh1a1−/− mesenchymal stem cells (MSCs) expressed significantly higher levels of bone morphogenetic protein 2 (BMP2) and demonstrated enhanced osteoblastogenesis and adipogenesis versus WT MSCs. BMP2 was also expressed at higher levels in the femurs and tibias of Aldh1a1−/− mice with accompanying induction of BMP2-regulated responses, including expression of Runx2 and alkaline phosphatase, and Smad phosphorylation. In vitro, Rald, which accumulates in Aldh1a1−/− mice, potently induced BMP2 in WT MSCs in a retinoic acid receptor (RAR)-dependent manner, suggesting that Rald is involved in the BMP2 increases seen in Aldh1a1 deficiency in vivo. Collectively, these data implicate Aldh1a1 as a novel determinant of cortical bone density and marrow adiposity in the skeleton in vivo through modulation of BMP signaling

A direct tissue-grafting approach to increasing endogenous brown fat

There is widespread evidence that increasing functional mass of brown adipose tissue (BAT) via browning of white adipose tissue (WAT) could potentially counter obesity and diabetes. However, most current approaches focus on administration of pharmacological compounds which expose patients to highly undesirable side effects. Here, we describe a simple and direct tissue-grafting approach to increase BAT mass through ex vivo browning of subcutaneous WAT, followed by re-implantation into the host; this cell-therapy approach could potentially act synergistically with existing pharmacological approaches. With this process, entitled “exBAT”, we identified conditions, in both mouse and human tissue, that convert whole fragments of WAT to BAT via a single step and without unwanted off-target pharmacological effects. We show that ex vivo, exBAT exhibited UCP1 immunostaining, lipid droplet formation, and mitochondrial metabolic activity consistent with native BAT. In mice, exBAT exhibited a highly durable phenotype for at least 8 weeks. Overall, these results enable a simple and scalable tissue-grafting strategy, rather than pharmacological approaches, for increasing endogenous BAT and studying its effect on host weight and metabolism

The ReCoDe addiction research consortium:Losing and regaining control over drug intake-Findings and future perspectives

Substance use disorders (SUDs) are seen as a continuum ranging from goal-directed and hedonic drug use to loss of control over drug intake with aversive consequences for mental and physical health and social functioning. The main goals of our interdisciplinary German collaborative research centre on Losing and Regaining Control over Drug Intake (ReCoDe) are (i) to study triggers (drug cues, stressors, drug priming) and modifying factors (age, gender, physical activity, cognitive functions, childhood adversity, social factors, such as loneliness and social contact/interaction) that longitudinally modulate the trajectories of losing and regaining control over drug consumption under real-life conditions. (ii) To study underlying behavioural, cognitive and neurobiological mechanisms of disease trajectories and drug-related behaviours and (iii) to provide non-invasive mechanism-based interventions. These goals are achieved by: (A) using innovative mHealth (mobile health) tools to longitudinally monitor the effects of triggers and modifying factors on drug consumption patterns in real life in a cohort of 900 patients with alcohol use disorder. This approach will be complemented by animal models of addiction with 24/7 automated behavioural monitoring across an entire disease trajectory; i.e. from a naïve state to a drug-taking state to an addiction or resilience-like state. (B) The identification and, if applicable, computational modelling of key molecular, neurobiological and psychological mechanisms (e.g., reduced cognitive flexibility) mediating the effects of such triggers and modifying factors on disease trajectories. (C) Developing and testing non-invasive interventions (e.g., Just-In-Time-Adaptive-Interventions (JITAIs), various non-invasive brain stimulations (NIBS), individualized physical activity) that specifically target the underlying mechanisms for regaining control over drug intake. Here, we will report on the most important results of the first funding period and outline our future research strategy.</p

The significance of beige and brown fat in humans

Promotion of brown adipose tissue (BAT) activity or browning of white adipose tissue has shown great potential as anti-obesity strategy in numerous preclinical models. The discovery of active BAT in humans and the recent advances in the understanding of human BAT biology and function have significantly propelled this field of research. Pharmacological stimulation of energy expenditure to counteract obesity has always been an intriguing therapeutic concept; with the identification of the specific molecular pathways of brown fat function, this idea has now become as realistic as ever. Two distinct strategies are currently being pursued; one is the activation of bone fide BAT, the other is the induction of BAT-like cells or beige adipocytes within white fat depots, a process called browning. Recent evidence suggests that both phenomena can occur in humans. Cold-induced promotion of BAT activity is strongly associated with enhanced thermogenesis and energy expenditure in humans and has beneficial effects on fat mass and glucose metabolism. Despite these encouraging results, a number of issues deserve additional attention including the distinct characteristics of human vs rodent BAT, the heterogeneity of human BAT depots or the identification of the adipocyte precursors that can give rise to thermogenic cells in human adipose tissue. In addition, many pharmaceutical compounds are being tested for their ability to promote a thermogenic program in human adipocytes. This review summarizes the current knowledge about the various cellular and molecular aspects of human BAT as well as the relevance for energy metabolism including its therapeutic potential for obesity.(VLID)485167

Transfusion / Glycated hemoglobin concentrations of packed red blood cells minimally increase during storage under standard blood banking conditions

BACKGROUND Few and inconsistent data exist describing the effect of storage duration on glycated hemoglobin (HbA1c) concentrations of red blood cells (RBCs), impeding interpretation of HbA1c values in transfused diabetic patients. Hence the aim of this study was to evaluate to what extent HbA1c concentrations of RBCs change during the maximum allowed storage period of 42 days. STUDY DESIGN AND METHODS Blood was drawn from 16 volunteers, leukofiltered, and stored under standard blood banking conditions. HbA1c concentrations of RBCs were measured on Days 1 and 42 of storage using three different validated devices (ionexchange highperformance liquid chromatography Method A1 and A2, turbidimetric immunoassay Method B). RESULTS Mean HbA1c concentrations of RBCs on Day 1 were 5.3 0.3% (Method A1), 5.4 0.4% (Method A2), and 5.1 0.4% (Method B). HbA1c concentrations increased to 5.6 0.3% (A1, p < 0.0001), 5.7 0.3% (A2, p = 0.004), and 5.5 0.4% (B, p < 0.0001) on Day 42, respectively, corresponding to a 1.06fold increase across all methods. Glucose concentrations in the storage solution of RBCs decreased from 495 27 to 225 55 mg/dL (p < 0.0001), confirming that stored RBCs were metabolically active. CONCLUSION These results suggest a significant, albeit minor, and most likely clinically insignificant increase in HbA1c concentrations during storage of RBCs for 42 days.(VLID)341760

Circulating Betatrophin Is Strongly Increased in Pregnancy and Gestational Diabetes Mellitus.

Betatrophin has recently been introduced as a novel hormone and promotor of beta cell proliferation and improved glucose tolerance in mouse models of insulin resistance. In obese and diabetic humans altered levels were reported and a role in pathophysiology of metabolic diseases was therefore hypothesized. However its release and regulation in women with gestational diabetes mellitus (GDM), as well as its associations with markers of obesity, glucose and lipid metabolism during pregnancy still remain unclear.Circulating betatrophin was quantified in 21 women with GDM and 19 pregnant body mass index-matched women with normal glucose tolerance (NGT) as well as 10 healthy age-matched non-pregnant women by enzyme-linked immunosorbent assay. Additionally we performed radioimmunassay (RIA) to confirm the results.Betatrophin concentrations measured by ELISA were significantly higher in GDM than in NGT (29.3±4.4 ng/ml vs. 18.1±8.7 ng/ml, p<0.001) which was confirmed by RIA. Betatrophin did not correlate with BMI or insulin resistance but showed a weak association with leptin levels in pregnancy and negative relationship with fasting C-peptide levels in all women. Moreover it correlated significantly with lipid parameters including triglycerides and total cholesterol in pregnancy, as well as estrogen, progesteron and birth weight.Circulating betatrophin concentrations are dramatically increased in pregnancy and are significantly higher in GDM versus pregnant NGT. In the light of the previously reported role in lipid metabolism, betatrophin may represent a novel endocrine regulator of lipid alterations in pregnancy. However additional studies are needed to elucidate whether hormonal factors, such as estrogen, control the production of betatrophin and if targeting betatrophin could hold promise in the fight against metabolic disease

Mining Exceptional Mediation Models

Lemmerich F, Kiefer C, Langenberg B, Cacho Aboukhalil J, Mayer A. Mining Exceptional Mediation Models. In: Helic D, Leitner G, Stettinger M, Felfernig A, Raś ZW, eds. Foundations of Intelligent Systems. 25th International Symposium, ISMIS 2020, Graz, Austria, September 23–25, 2020, Proceedings. Lecture Notes in Computer Science. Vol 12117. Cham: Springer ; 2020: 318-328

Retinaldehyde dehydrogenase 1 deficiency inhibits PPARγ-mediated bone loss and marrow adiposity.

PPARγ, a ligand-activated nuclear receptor, regulates fundamental aspects of bone homeostasis and skeletal remodeling. PPARγ-activating anti-diabetic thiazolidinediones in clinical use promote marrow adiposity, bone loss, and skeletal fractures. As such, delineating novel regulatory pathways that modulate the action of PPARγ, and its obligate heterodimeric partner RXR, may have important implications for our understanding and treatment of disorders of low bone mineral density. We present data here establishing retinaldehyde dehydrogenase 1 (Aldh1a1) and its substrate retinaldehyde (Rald) as novel determinants of PPARγ-RXR actions in the skeleton. When compared to wild type (WT) controls, retinaldehyde dehydrogenase-deficient (Aldh1a1(-/-)) mice were protected against bone loss and marrow adiposity induced by either the thiazolidinedione rosiglitazone or a high fat diet, both of which potently activate the PPARγ-RXR complex. Consistent with these results, Rald, which accumulates in vivo in Aldh1a1(-/-) mice, protects against rosiglitazone-mediated inhibition of osteoblastogenesis in vitro. In addition, Rald potently inhibits in vitro adipogenesis and osteoclastogenesis in WT mesenchymal stem cells (MSCs) and hematopoietic stem cells (HSCs) respectively. Primary Aldh1a1(-/-) HSCs also demonstrate impaired osteoclastogenesis in vitro compared to WT controls. Collectively, these findings identify Rald and retinoid metabolism through Aldh1a1 as important novel modulators of PPARγ-RXR transactivation in the marrow niche