Deep learning and genome-wide association meta-analyses of bone marrow adiposity in the UK Biobank.

Bone marrow adipose tissue is a distinct adipose subtype comprising more than 10% of fat mass in healthy humans. However, the functions and pathophysiological correlates of this tissue are unclear, and its genetic determinants remain unknown. Here, we use deep learning to measure bone marrow adiposity in the femoral head, total hip, femoral diaphysis, and spine from MRI scans of approximately 47,000 UK Biobank participants, including over 41,000 white and over 6300 non-white participants.

Deletion of Hsd11b1 suppresses caloric restriction-induced bone marrow adiposity in male but not female mice.

Bone marrow adipose tissue (BMAT) comprises >10% of total adipose mass in healthy humans. It increases in diverse conditions, including ageing, obesity, osteoporosis, glucocorticoid therapy, and notably, during caloric restriction (CR). BMAT potentially influences skeletal, metabolic, and immune functions, but the mechanisms of BMAT expansion remain poorly understood.

The effects of caloric restriction on adipose tissue and metabolic health are sex- and age-dependent.

Caloric restriction (CR) reduces the risk of age-related diseases in numerous species, including humans. CR's metabolic effects, including decreased adiposity and improved insulin sensitivity, are important for its broader health benefits; however, the extent and basis of sex differences in CR's health benefits are unknown. We found that 30% CR in young (3-month-old) male mice decreased fat mass and improved glucose tolerance and insulin sensitivity, whereas these effects were blunted or absent in young females.

Turning the spotlight on bone marrow adipocytes in haematological malignancy and non-malignant conditions.

Whilst bone marrow adipocytes (BMAd) have long been appreciated by clinical haemato-pathologists, it is only relatively recently, in the face of emerging data, that the adipocytic niche has come under the watchful eye of biologists. There is now mounting evidence to suggest that BMAds are not just a simple structural entity of bone marrow microenvironments but a bona fide driver of physio- and pathophysiological processes relevant to multiple aspects of health and disease. Whilst the truly multifaceted nature of BMAds has only just begun to emerge, paradigms have shifted already for normal, malignant and non-malignant haemopoiesis incorporating a view of adipocyte regulation.

Guidelines for Biobanking of Bone Marrow Adipose Tissue and Related Cell Types: Report of the Biobanking Working Group of the International Bone Marrow Adiposity Society.

Over the last two decades, increased interest of scientists to study bone marrow adiposity (BMA) in relation to bone and adipose tissue physiology has expanded the number of publications using different sources of bone marrow adipose tissue (BMAT). However, each source of BMAT has its limitations in the number of downstream analyses for which it can be used. Based on this increased scientific demand, the International Bone Marrow Adiposity Society (BMAS) established a Biobanking Working Group to identify the challenges of biobanking for human BMA-related samples and to develop guidelines to advance establishment of biobanks for BMA research.

Adipocytes disrupt the translational programme of acute lymphoblastic leukaemia to favour tumour survival and persistence.

The specific niche adaptations that facilitate primary disease and Acute Lymphoblastic Leukaemia (ALL) survival after induction chemotherapy remain unclear. Here, we show that Bone Marrow (BM) adipocytes dynamically evolve during ALL pathogenesis and therapy, transitioning from cellular depletion in the primary leukaemia niche to a fully reconstituted state upon remission induction. Functionally, adipocyte niches elicit a fate switch in ALL cells towards slow-proliferation and cellular quiescence, highlighting the critical contribution of the adipocyte dynamic to disease establishment and chemotherapy resistance.

Ablation of Results in Transient Bone Hypomineralization.

Biomineralization is a fundamental process key to the development of the skeleton. The phosphatase orphan phosphatase 1 (PHOSPHO1), which likely functions within extracellular matrix vesicles, has emerged as a critical regulator of biomineralization. However, the biochemical pathways that generate intravesicular PHOSPHO1 substrates are currently unknown.

PHOSPHO1 is a skeletal regulator of insulin resistance and obesity.

Background: The classical functions of the skeleton encompass locomotion, protection and mineral homeostasis. However, cell-specific gene deletions in the mouse and human genetic studies have identified the skeleton as a key endocrine regulator of metabolism. The bone-specific phosphatase, Phosphatase, Orphan 1 (PHOSPHO1), which is indispensable for bone mineralisation, has been recently implicated in the regulation of energy metabolism in humans, but its role in systemic metabolism remains unclear.

Bone marrow adipose tissue is a unique adipose subtype with distinct roles in glucose homeostasis.

Bone marrow adipose tissue (BMAT) comprises >10% of total adipose mass, yet unlike white or brown adipose tissues (WAT or BAT) its metabolic functions remain unclear. Herein, we address this critical gap in knowledge. Our transcriptomic analyses revealed that BMAT is distinct from WAT and BAT, with altered glucose metabolism and decreased insulin responsiveness.

Standardised Nomenclature, Abbreviations, and Units for the Study of Bone Marrow Adiposity: Report of the Nomenclature Working Group of the International Bone Marrow Adiposity Society.

Research into bone marrow adiposity (BMA) has expanded greatly since the late 1990s, leading to development of new methods for the study of bone marrow adipocytes. Simultaneously, research fields interested in BMA have diversified substantially. This increasing interest is revealing fundamental new knowledge of BMA; however, it has also led to a highly variable nomenclature that makes it difficult to interpret and compare results from different studies.

Myeloma Cells Down-Regulate Adiponectin in Bone Marrow Adipocytes Via TNF-Alpha.

Multiple myeloma is caused by abnormal plasma cells that accumulate in the bone marrow and interact with resident cells of the bone microenvironment to drive disease progression and development of an osteolytic bone disease. Bone marrow adipocytes (BMAds) are emerging as having important endocrine functions that can support myeloma cell growth and survival. However, how BMAds respond to infiltrating tumor cells remains poorly understood.

Bone marrow adipose tissue does not express UCP1 during development or adrenergic-induced remodeling.

Adipocytes within the skeleton are collectively termed bone marrow adipose tissue (BMAT). BMAT contributes to peripheral and local metabolism, however, its capacity for cell-autonomous expression of uncoupling protein 1 (UCP1), a biomarker of beige and brown adipogenesis, remains unclear. To overcome this, Ucp1-Cre was used to drive diphtheria toxin expression in cells expressing UCP1 (Ucp1).

A comparison of the bone and growth phenotype of , and murine models with the C57BL/10 wild-type mouse.

The muscular dystrophy X-linked () mouse is commonly used as a mouse model of Duchenne muscular dystrophy (DMD). Its phenotype is, however, mild, and other mouse models have been explored. The mouse carries a human-like mutation in the gene and has a severe muscle phenotype, but its growth and bone development are unknown.

New Insights Into the Long Non-coding RNA SRA: Physiological Functions and Mechanisms of Action.

Long non-coding RNAs (lncRNA) are emerging as new genetic/epigenetic regulators that can impact almost all physiological functions. Here, we focus on the long non-coding steroid receptor RNA activator (SRA), including new insights into its effects on gene expression, the cell cycle, and differentiation; how these relate to physiology and disease; and the mechanisms underlying these effects. We discuss how SRA acts as an RNA coactivator in nuclear receptor signaling; its effects on steroidogenesis, adipogenesis, and myocyte differentiation; the impact on breast and prostate cancer tumorigenesis; and, finally, its ability to modulate hepatic steatosis through several signaling pathways.

Molecular Interaction of Bone Marrow Adipose Tissue with Energy Metabolism.

Purpose Of Review: The last decade has seen a resurgence in the study of bone marrow adipose tissue (BMAT) across diverse fields such as metabolism, haematopoiesis, skeletal biology and cancer. Herein, we review the most recent developments of BMAT research in both humans and rodents, including the distinct nature of BMAT; the autocrine, paracrine and endocrine interactions between BMAT and various tissues, both in physiological and pathological scenarios; how these interactions might impact energy metabolism; and the most recent technological advances to quantify BMAT.

Recent Findings: Though still dwarfed by research into white and brown adipose tissues, BMAT is now recognised as endocrine organ and is attracting increasing attention from biomedical researchers around the globe.

Adipose specific disruption of seipin causes early-onset generalised lipodystrophy and altered fuel utilisation without severe metabolic disease.

Objective: Mutations to the BSCL2 gene disrupt the protein seipin and cause the most severe form of congenital generalised lipodystrophy (CGL). Affected individuals exhibit a near complete loss of white adipose tissue (WAT) and suffer from metabolic disease. Seipin is critical for adipocyte development in culture and mice with germline disruption to Bscl2 recapitulate the effects of BSCL2 disruption in humans.

Bone marrow adipocytes resist lipolysis and remodeling in response to β-adrenergic stimulation.

Bone marrow adipose tissue (BMAT) is preserved or increased in states of caloric restriction. Similarly, we found that BMAT in the tail vertebrae, but not the red marrow in the tibia, resists loss of neutral lipid with acute, 48-hour fasting in rats. The mechanisms underlying this phenomenon and its seemingly distinct regulation from peripheral white adipose tissue (WAT) remain unknown.

Genetic inhibition of PPARγ S112 phosphorylation reduces bone formation and stimulates marrow adipogenesis.

A common feature of many skeletal diseases is the accumulation of marrow fat. A reciprocal relationship exists between osteogenesis and adipogenesis in bone marrow that is mediated by the relative activity of PPARγ and RUNX2 transcription factors. The ERK/MAPK pathway is an important inducer of MSC differentiation to osteoblasts and an inhibitor of adipogenesis that functions by phosphorylating RUNX2 and PPARγ.

Skeletal energy homeostasis: a paradigm of endocrine discovery.

Throughout the last decade, significant developments in cellular, molecular and mouse models have revealed major endocrine functions of the skeleton. More recent studies have evolved the interplay between bone-specific hormones, the skeleton, marrow adipose tissue, muscle and the brain. This review focuses on literature from the last decade, addressing the endocrine regulation of global energy metabolism via the skeleton.

Increased Circulating Adiponectin in Response to Thiazolidinediones: Investigating the Role of Bone Marrow Adipose Tissue.

Background: Bone marrow adipose tissue (MAT) contributes to increased circulating adiponectin, an insulin-sensitizing hormone, during caloric restriction (CR), but whether this occurs in other contexts remains unknown. The antidiabetic thiazolidinediones (TZDs) also promote MAT expansion and hyperadiponectinemia, even without increasing adiponectin expression in white adipose tissue (WAT).

Objectives: To test the hypothesis that MAT expansion contributes to TZD-associated hyperadiponectinemia, we investigated the effects of rosiglitazone, a prototypical TZD, in wild-type (WT) or -Wnt10b mice.

Inside out: Bone marrow adipose tissue as a source of circulating adiponectin.

The adipocyte-derived hormone adiponectin mediates beneficial cardiometabolic effects, and hypoadiponectinemia is a biomarker for increased metabolic and cardiovascular risk. Indeed, circulating adiponectin decreases in obesity and insulin-resistance, likely because of impaired production from white adipose tissue (WAT). Conversely, lean states such as caloric restriction (CR) are characterized by hyperadiponectinemia, even without increased adiponectin production from WAT.