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

BACKGROUNDAdipocytes were long considered inert components of the bone marrow niche, but mouse and human models suggest bone marrow adipose tissue (BMAT) is dynamic and responsive to hormonal and nutrient cues.METHODSIn this study of healthy volunteers, we investigated how BMAT responds to acute nutrient changes, including analyses of endocrine determinants and paracrine factors from marrow aspirates. Study participants underwent a 10-day high-calorie protocol, followed by a 10-day fast.RESULTSWe demonstrate (a) vertebral BMAT increased significantly during high-calorie feeding and fasting, suggesting BMAT may have different functions in states of caloric excess compared with caloric deprivation; (b) ghrelin, which decreased in response to high-calorie feeding and fasting, was inversely associated with changes in BMAT; and (c) in response to high-calorie feeding, resistin levels in the marrow sera, but not the circulation, rose significantly. In addition, TNF-α expression in marrow adipocytes increased with high-calorie feeding and decreased upon fasting.CONCLUSIONHigh-calorie feeding, but not fasting, induces an immune response in bone marrow similar to what has been reported in peripheral adipose tissue. Understanding the immunomodulatory regulators in the marrow may provide further insight into the homeostatic function of this unique adipose tissue depot.FUNDINGNIH grant R24 DK084970, Harvard Catalyst/The Harvard Clinical and Translational Science Center (National Center for Advancing Translational Sciences, NIH, award UL 1TR002541), and NIH grants P30 DK040561 and U19 AG060917S1.

Modulation of neural fMRI responses to visual food cues by overeating and fasting interventions: A preliminary study.

Neural processing of visual food stimuli is perturbated at extremes of weight. Human fMRI studies investigating diet effects on neural processing of food cues could aid in understanding altered brain activation in conditions of under- and overnutrition. In this preliminary study, we examined brain activity changes in response to 10 days of high-calorie-diet (HCD), followed by 10 days of fasting, hypothesizing that HCD would decrease activation in homeostatic and reward regions, while fasting would increase activation in homeostatic/reward regions and decrease activation of self-control regions. Seven adults completed fMRI scanning during a food-cue paradigm (high- and low-calorie food images and nonfood objects), pre- and post-10-day HCD. Six adults completed fMRI scanning pre- and post-10-day fasting. BOLD response changes for contrasts of interest pre- versus post-intervention in regions of interest were examined (peak-level significance set at p(FWE)<0.05). BMI increased by 6.8% and decreased by 8.1% following HCD and fasting, respectively. Following HCD, BOLD response in the hypothalamus (homeostatic control), was attenuated at trend level in response to high- versus low-calorie foods. Following fasting, BOLD response to food versus objects in inhibitory-control areas (dorsolateral prefrontal cortex) was reduced, whereas the activation of homeostatic (hypothalamus), gustatory, and reward brain areas (anterior insula and orbitofrontal cortex) increased. Overfeeding and fasting for 10 days modulate brain activity in response to food stimuli, suggesting that in healthy adults, changes in energy balance affect saliency and reward value of food cues. Future studies are required to understand this interaction in states of unhealthy weight.

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 1 H-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.

Transdermal Estrogen in Women With Anorexia Nervosa: An Exploratory Pilot Study.

Anorexia nervosa (AN) is a psychiatric disorder characterized by self-induced starvation, low body weight, and elevated levels of bone marrow adipose tissue (BMAT). BMAT is negatively associated with BMD in AN and more than 85% of women with AN have low bone mass and an increased risk of fracture. Although a majority of women with AN are amenorrheic, which is associated with low BMD, oral contraceptive pills, containing supraphysiologic doses of estrogen, are not effective in increasing bone mass. We performed a 6-month, open-label study of transdermal estradiol (0.045 mg/day) + levonorgestrel (0.015 mg/day) in 11 women with AN (mean age ± SEM: 37.2 ± 2.3 years) to investigate the effects of transdermal, physiologic doses of estrogen on BMD and BMAT in women with AN. We measured change in BMD by DXA, change in BMAT at the spine/hip by 1H-magnetic resonance spectroscopy, and change in C-terminal collagen cross-links (CTX), P1NP, osteocalcin, IGF-1, and sclerostin after 3 and 6 months of transdermal estrogen. Lumbar spine (2.0% ± 0.8%; p = 0.033) and lateral spine (3.2% ± 1.1%; p = 0.015) BMD increased after 6 months of transdermal estrogen. Lumbar spine BMAT decreased significantly after 3 months (-13.9 ± 6.0%; p = 0.046). Increases in lateral spine BMD were associated with decreases in CTX (p = 0.047). In conclusion, short-term treatment with transdermal, physiologic estrogen increases spine BMD in women with AN. Future studies are needed to assess the long-term efficacy of this treatment. © 2019 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.

Changes in marrow adipose tissue with short-term changes in weight in premenopausal women with anorexia nervosa.

OBJECTIVE: In anorexia nervosa, a psychiatric disease characterized by self-induced starvation and a model of chronic undernutrition, levels of subcutaneous (SAT) and visceral (VAT) adipose tissue are low, whereas marrow adipose tissue (MAT) levels are elevated compared to normal-weight women. The reason for this paradoxical elevation of an adipose tissue depot in starvation is not known. We sought to understand changes in MAT in response to subacute changes in weight and to compare these changes with those of other fat depots and body composition parameters. DESIGN AND METHODS: We conducted a 12-month longitudinal study including 46 premenopausal women (n = 26 with anorexia nervosa and n = 20 normal-weight controls) with a mean (s.e.m.) age of 28.2 ± 0.8 years. We measured MAT, SAT, VAT and bone mineral density (BMD) at baseline and after 12 months. RESULTS: At baseline, SAT (P < 0.0001), VAT (P < 0.02) and BMD of the spine and hip (P ≤ 0.0002) were significantly lower and vertebral and metaphyseal MAT (P ≤ 0.001) significantly higher in anorexia nervosa compared to controls. Weight gain over 12 months was associated with increases not only in SAT and VAT, but also epiphyseal MAT (P < 0.03). Changes in epiphyseal MAT were positively associated with changes in BMD (P < 0.03). CONCLUSIONS: In contrast to the steady state, in which MAT levels are higher in anorexia nervosa and MAT and BMD are inversely associated, short-term weight gain is associated with increases in both MAT and BMD. These longitudinal data demonstrate the dynamic nature of this fat depot and provide further evidence of its possible role in mineral metabolism.