Red and White Blood Cell Counts Are Associated With Bone Marrow Adipose Tissue, Bone Mineral Density, and Bone Microarchitecture in Premenopausal Women

Bone marrow adipose tissue (BMAT) resides within the bone marrow microenvironment where its function remains poorly understood. BMAT is elevated in anorexia nervosa, a disease model of chronic starvation, despite depletion of other fat depots. In addition to BMAT, the marrow microenvironment also consists of osteoblast and hematopoietic progenitors. BMAT is inversely associated with bone mineral density (BMD) in multiple populations including women with anorexia nervosa, and regulates hematopoiesis in animal models. We hypothesized that BMAT would be associated with circulating populations of hematopoietic cells (red and white blood cells) in humans and performed a post hoc analysis of two studies—a cross‐sectional study and a longitudinal study—to investigate this hypothesis. We studied 89 premenopausal women cross‐sectionally (median age [interquartile range], 27 [24.5, 31.7] years), including 35 with anorexia nervosa. We investigated associations between red blood cell (RBC) and white blood cell (WBC) counts and BMAT assessed by 1H‐magnetic resonance spectroscopy, BMD assessed by DXA, and bone microarchitecture assessed by HR‐pQCT. In addition, we analyzed longitudinal data in six premenopausal women with anorexia nervosa treated with transdermal estrogen for 6 months and measured changes in BMAT and blood cell counts during treatment. Cross‐sectionally, BMAT was inversely associated with WBC and RBC counts. In contrast, BMD and parameters of bone microarchitecture were positively associated with WBC and RBC. In women with anorexia nervosa treated with transdermal estrogen for 6 months, decreases in BMAT were significantly associated with increases in both RBC and hematocrit (rho = −0.83, p = 0.04 for both). In conclusion, we show that BMAT is inversely associated with WBC and RBC in premenopausal women, and there is a potential association between longitudinal changes in BMAT and changes in RBC. These associations warrant further study and may provide further insight into the role and function of this understudied adipose depot. © 2020 American Society for Bone and Mineral Research.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/155991/1/jbmr3986.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/155991/2/jbmr3986_am.pd

Irisin Levels Are Lower in Young Amenorrheic Athletes Compared with Eumenorrheic Athletes and Non-Athletes and Are Associated with Bone Density and Strength Estimates

Irisin and FGF21 are novel hormones implicated in the “browning” of white fat, thermogenesis, and energy homeostasis. However, there are no data regarding these hormones in amenorrheic athletes (AA) (a chronic energy deficit state) compared with eumenorrheic athletes (EA) and non-athletes. We hypothesized that irisin and FGF21 would be low in AA, an adaptive response to low energy stores. Furthermore, because (i) brown fat has positive effects on bone, and (ii) irisin and FGF21 may directly impact bone, we hypothesized that bone density, structure and strength would be positively associated with these hormones in athletes and non-athletes. To test our hypotheses, we studied 85 females, 14–21 years [38 AA, 24 EA and 23 non-athletes (NA)]. Fasting serum irisin and FGF21 were measured. Body composition and bone density were assessed using dual energy X-ray absorptiometry, bone microarchitecture using high resolution peripheral quantitative CT, strength estimates using finite element analysis, resting energy expenditure (REE) using indirect calorimetry and time spent exercising/week by history. Subjects did not differ for pubertal stage. Fat mass was lowest in AA. AA had lower irisin and FGF21 than EA and NA, even after controlling for fat and lean mass. Across subjects, irisin was positively associated with REE and bone density Z-scores, volumetric bone mineral density (total and trabecular), stiffness and failure load. FGF21 was negatively associated with hours/week of exercise and cortical porosity, and positively with fat mass and cortical volumetric bone density. Associations of irisin (but not FGF21) with bone parameters persisted after controlling for potential confounders. In conclusion, irisin and FGF21 are low in AA, and irisin (but not FGF21) is independently associated with bone density and strength in athletes

Il tensore energia-impulso per un fluido perfetto in relatività ristretta e generale

Con questo lavoro si vuole discutere la connessione esistente tra l' equazione di continuità e l'equazione del moto di un fluido perfetto in Relatività Ristretta e Generale. Dapprima forniremo una breve introduzione sulle basi della Relatività Ristretta , introducendo il tensore energia-impulso ed analizzando in maniera specifica tale tensore per un fluido perfetto, ricavandone le equazioni del moto. Forniremo un secondo esempio di tensore Energia-Impulso per la materia incoerente. Conclusa questa argomentazione ci concentreremo sulla Relatività Generale, analizzandone i principi che sono alla base e privilegiando tra questi il Principio di Covarianza Generale come linea guida per le argomentazioni logiche. In maniera analoga a quanto fatto per la Relatività Ristretta riprenderemo la discussione per il tensore energia-impulso per un fluido perfetto dal punto di vista della Relatività Generale , soffermandoci nel caso di equilibrio idrostatico. Sempre nel contesto della Relatività Generale verrà in ultima analisi discusso il concetto di fluido incoerente e moto geodetico. L'ultimo capitolo è dedicato ad una appendice matematica nel quale vengono ricordati alcuni risultati dell'analisi tensoriali utili nel seguire i calcoli effettuati

Pituitary society guidance: pituitary disease management and patient care recommendations during the COVID-19 pandemic—an international perspective

Abstract: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the viral strain that has caused the coronavirus disease 2019 (COVID-19) pandemic, has presented healthcare systems around the world with an unprecedented challenge. In locations with significant rates of viral transmission, social distancing measures and enforced ‘lockdowns’ are the new ‘norm’ as governments try to prevent healthcare services from being overwhelmed. However, with these measures have come important challenges for the delivery of existing services for other diseases and conditions. The clinical care of patients with pituitary disorders typically involves a multidisciplinary team, working in concert to deliver timely, often complex, disease investigation and management, including pituitary surgery. COVID-19 has brought about major disruption to such services, limiting access to care and opportunities for testing (both laboratory and radiological), and dramatically reducing the ability to safely undertake transsphenoidal surgery. In the absence of clinical trials to guide management of patients with pituitary disease during the COVID-19 pandemic, herein the Professional Education Committee of the Pituitary Society proposes guidance for continued safe management and care of this population

Pituitary Society Delphi Survey: An international perspective on endocrine management of patients undergoing transsphenoidal surgery for pituitary adenomas.

PURPOSE: In adults and children, transsphenoidal surgery (TSS) represents the cornerstone of management for most large or functioning sellar lesions with the exception of prolactinomas. Endocrine evaluation and management are an essential part of perioperative care. However, the details of endocrine assessment and care are not universally agreed upon. METHODS: To build consensus on the endocrine evaluation and management of adults undergoing TSS, a Delphi process was used. Thirty-five statements were developed by the Pituitary Society's Education Committee. Fifty-five pituitary endocrinologists, all members of the Pituitary Society, were invited to participate in two Delphi rounds and rate their extent of agreement with statements pertaining to perioperative endocrine evaluation and management, using a Likert-type scale. Anonymized data on the proportion of panelists' agreeing with each item were summarized. A list of items that achieved consensus, based on predefined criteria, was tabulated. RESULTS: Strong consensus (≥ 80% of panelists rating their agreement as 6-7 on a scale from 1 to 7) was achieved for 68.6% (24/35) items. If less strict agreement criteria were applied (ratings 5-7 on the Likert-type scale), consensus was achieved for 88% (31/35) items. CONCLUSIONS: We achieved consensus on a large majority of items pertaining to perioperative endocrine evaluation and management using a Delphi process. This provides an international real-world clinical perspective from an expert group and facilitates a framework for future guideline development. Some of the items for which consensus was not reached, including the assessment of immediate postoperative remission in acromegaly or Cushing's disease, represent areas where further research is needed

Fibroblast Growth Factor-21 May Mediate Growth Hormone Resistance in Anorexia Nervosa

Context: Anorexia nervosa (AN), a state of chronic nutritional deprivation, is characterized by GH resistance with elevated GH levels and decreased levels of IGF-I. Fibroblast growth factor (FGF)-21, a hormone produced in the liver and adipocytes, is induced in the liver by fasting and peroxisome proliferator-activated receptor-α agonists. In a transgenic mouse model, FGF-21 reduces IGF-I levels by inhibiting signal transducer and activator of transcription-5, a mediator of the intracellular effects of GH

The dynamics of human bone marrow adipose tissue in response to feeding and fasting

The administration of a high fat content diet (HFD) is an accelerating factor for metabolic syndrome, impaired glucose tolerance, and early type 2 diabetes. The present study aims to assess the impact of a high fat diet or acute weight gain on human marrow adipose tissue. Adipose tissues secrete numerous active substances termed adipokines, including adiponectin, leptin, resistin, interleukin-6 (IL-6), etc. Adipokines physiologically regulate development, metabolism, eating behavior, fat storage, insulin sensitivity, hemostasis, blood pressure, immunity, and inflammation. Our objective is to determine the effect of HFD on adipokines from marrow adipose tissue, as well as, the effect of HFD on resistin, TNF?, RCAN2 and SEMA3E/PLXND1 gene expression. Marrow serum, peripheral blood serum as well as marrow adipocytes from healthy adult human who underwent either 10 days of fasting or 10 days of HFD, were collected according to published protocols. To analyze the expression of resistin, IL-6, TNF? and adiponectin in human serum from marrow and peripheral blood, we used DuoSet ELISA kit (R&D systems) respectively. To analyze the gene expression of resistin, TNF?, RCAN2 and SEMA3E/PLXND1 on marrow adipocytes, qRT-PCR were performed. All primers were synthesized by Integrated DNA Technologies (Coralville, IA). Results were normalized to GAPDH and all samples were run in duplicate. Our results show that in paired aspirates, resistin increased markedly with a HFD, but not with fasting, and not in the circulation, without significant changes on adiponectin neither IL-6 levels. Resistin is a cytokine produced in WAT (adipocytes in rodents, macrophages in human) and is thought to mediate type 2 diabetes mellitus (T2DM) and cardiovascular disease and to mark macrophage activation and TLR4 signaling. In our previous studies with mouse models, PLXND1 is highly expressed on marrow stromal cells and has been linked to adiposity and type 2 diabetes. Also, inhibition of the SEMA3E(ligand)/PLXND1(receptor) axis markedly reduced adipose tissue inflammation and improved systemic insulin resistance in mouse model. PLXND1 also was one of the most highly expressed genes in a MSCs from a mouse with high marrow adiposity and consistent with our findings noted in human volunteers. RCAN2, one of the three main regulators of calcineurin, is located 43.7 Mb on mouse chromosome 17 and in a QTL study of marrow fat from DO strains, that region gave the highest LOD score. Our data show that expression of SEMA3E/PLXND1, RCAN2 and TNF? were increased on marrow adipocytes from the HFD volunteers. Also we identified up-regulation of the macrophage gene marker, EMR-1 (homologous to F4/80 in mice), suggestive of an inflammatory response in the marrow of normal volunteers on a HFD but not fasting. The bone microenviroment can be modulated by various factors including aging, obesity, and inflammation. Stress signal could be modulated by SEMA3E/PLXND1 axis as a chemoattractant for macrophages, provoking adipose tissue inflammation, and also by RCAN2, through calcineurin activity, which is indispensable for osteoclast differentiation, creating less bone resorption and impaired normal bone homeostasis. Further analysis are needed to understanding the immune response in the context of marrow adiposity in humans and mouse models

The effect of short-term high-caloric feeding and fasting on bone microarchitecture

BACKGROUND: States of chronic overnutrition and undernutrition are both associated with impaired bone health and increased fracture risk but there are no data on bone microarchitecture following short-term controlled nutritional challenges. OBJECTIVE: The purpose of our study was to evaluate the impact of short-term high-caloric feeding and fasting on bone microarchitecture. We hypothesized that both high-caloric feeding and fasting would have negative effects on microarchitecture. MATERIALS AND METHODS: We recruited 23 adult healthy subjects (13 males, 10 females, mean age 33.2 ± 1.4 years, mean BMI 26.0 ± 1.5 kg/m). Subjects underwent an in-patient 10-day high-caloric visit (caloric intake with goal to achieve 7% weight gain), after which they went home to resume a normal diet for 13-18 days (stabilization period), and were then readmitted for a 10-day in-patient fasting stay (no caloric intake). All subjects underwent HRpQCT (XtremeCT, Scanco Medical AG, Brüttisellen, Switzerland) of the distal tibia and distal radius after each visit to assess volumetric bone mineral density (vBMD), trabecular and cortical microarchitecture, and strength estimates. The Wilcoxon signed rank test was used to perform within group comparisons. RESULTS: During the high-caloric period, there was a mean increase in weight by 6.3 + 1.7% (p \u3c 0.0001). There were no significant changes in bone parameters in the distal tibia or distal radius (p \u3e 0.05). During the stabilization period there was a significant reduction in weight by -2.7 + 1.9% (p \u3c 0.0001) but no change in bone parameters (p \u3e 0.05). During the fasting period there was a further reduction in weight by -8.8 + 1.2% (p \u3c 0.0001). In the distal tibia, there was a significant increase in total and cortical vBMD, trabecular and cortical parameters as well as strength estimates (p \u3c 0.05). In the distal radius there was an increase in total and trabecular vBMD (p \u3c 0.05), while there were no changes in other microarchitecture parameters or strengths estimates. CONCLUSION: Short-term fasting after high-caloric feeding improves vBMD, bone microarchitecture and strength estimates of the distal tibia, while short-term high-caloric feeding does not change vBMD or microarchitecture. These results suggest that short-term fasting after high-caloric feeding in healthy individuals improves bone health and that these changes can be detected using HRpQCT in-vivo

Marrow fat composition in anorexia nervosa.

PURPOSE: Women with anorexia nervosa (AN) have increased marrow fat despite severe depletion of body fat. Recent studies have suggested that marrow fat composition may serve as a biomarker for bone quality. The purpose of our study was to investigate marrow fat composition of the femur using proton MR spectroscopy ((1)H MRS), and the relationship between measures of marrow fat composition and BMD and body composition in women with AN and normal-weight controls. MATERIALS AND METHODS: 14 women with AN (29.5±1.9years) and 12 age-matched normal-weight controls underwent (1)H MRS to determine total marrow fat content and marrow fat composition of the femoral diaphysis and soleus intramyocellular lipids und unsaturated muscle lipids. MRI was performed to quantify abdominal fat, thigh fat and muscle areas. Lumbar spine BMD, fat and lean mass were assessed by DXA. RESULTS: Subjects with AN had higher marrow fat content (p0.05) compared to normal-weight controls. There was an inverse association between marrow methylene protons, an estimate of fatty acid (FA) saturated bonds, and lumbar spine BMD (r=-0.52, p=0.008) independent of %ideal body weight (%IBW). Olefinic protons at 5.3ppm, an estimate of FA unsaturated bonds, were inversely associated with body fat depots, independent of %IBW, and positively associated with soleus unsaturation (p≤0.05). CONCLUSION: Women with AN have higher total femoral marrow fat but similar composition compared to normal-weight controls. The degree of marrow FA saturation correlates inversely with BMD, suggesting that saturated lipids may have negative effects on BMD. The degree of marrow FA unsaturation correlates positively with soleus unsaturation, suggesting that marrow fat composition may be influenced by the same factors as ectopic lipid composition in muscle