William Cawthorn

University of Edinburgh, Centre for Cardiovascular Science, Faculty Member

University of Cambridge, Clinical Biochemistry, Alumnus

University of Michigan, Molecular and Integrative Physiology, Post-Doc

Followers

129

Following

Co-authors

Public Views

White adipose tissue (WAT) is a key regulator of metabolic homeostasis, both as a site for energy storage and as an endocrine organ. The past generation has seen extensive research into WAT biology, fuelled largely by the public health burden posed by obesity and associated diseases. As such, WAT formation and function is now relatively well understood. Adipocytes also exist in bone marrow, yet in contrast to WAT, our understanding of such bone marrow adipose tissue (MAT) is extremely limited. This ignorance is surprising: MAT accounts for up to 70% of bone marrow volume in healthy adult humans, which suggests that MAT has a role in normal human physiology. MAT further increases in conditions of altered bone formation or metabolic health. For example, increased MAT occurs in osteoporosis, suggesting that MAT might contribute to the bone fragility that defines this disease. Perhaps most bizarrely, MAT formation increases in starvation states, such as during caloric restriction (CR) in animals or in human patients with anorexia nervosa. This is in stark contrast to WAT, which is broken down during starvation to be used as fuel. CR has numerous health benefits, including increased lifespan, decreased risk of cancer and cardiovascular disease, and metabolic benefits such as enhanced fat breakdown and insulin sensitivity. MAT also increases in response to treatment with anti-diabetic drugs such as thiazolidinediones or fibroblast growth factor-21, which, like CR, enhance insulin sensitivity. These clinical observations raise the possibility that MAT directly promotes insulin sensitivity and metabolic health. However, whether MAT impacts metabolic homeostasis remains unknown. Such knowledge could reveal new approaches to treat metabolic diseases. Thus, there is a critical need to understand the functions of MAT.

My postdoctoral research revealed that, during CR, MAT is a key source of adiponectin, a hormone that helps to maintain insulin sensitivity and fat breakdown, and which is linked to decreased risk of obesity-associated cancers, cardiovascular disease and diabetes. My postdoctoral work further revealed that MAT expansion is required for skeletal muscle to adequately adapt to CR. This suggests that, as an endocrine organ, MAT can exert systemic effects in metabolically relevant peripheral tissues.

My current research will build on these findings by studying why MAT expands during CR, and investigating if MAT impacts metabolic health. Improving our knowledge of MAT formation and function might shed new light not only on normal human physiology, but also on diseases such as diabetes, osteoporosis, and cardiovascular disease. Such knowledge will be vital if we are to reduce the public health impact of these globally relevant health problems.
Supervisors: Brian Walker
Phone: 734-647-7721 (work)

less

InterestsView All (6)

Uploads

Papers by William Cawthorn

Decision letter: Bone marrow Adipoq-lineage progenitors are a major cellular source of M-CSF that dominates bone marrow macrophage development, osteoclastogenesis, and bone mass

OP4 Ubiquitin proteosome pathway; a novel therapeutic target in vascular calcification

Heart Journal - SCF, 2020

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

Author Reply to Peer Reviews of The effects of caloric restriction on adipose tissue and metabolic health are sex- and age-dependent

Bone Marrow Adipose Tissue

Elsevier eBooks, 2020

Abstract Bone marrow adipose tissue (BMAT) accounts for approximately 70% of total bone marrow (B... more Abstract Bone marrow adipose tissue (BMAT) accounts for approximately 70% of total bone marrow (BM) volume and over 10% of total adipose mass in lean, healthy humans. BMAT further increases with aging and in diverse clinical conditions, including osteoporosis, obesity, and with glucocorticoid treatment. The existence of bone marrow adipocytes (BMAds) has been noted for 150 years, yet their physiological roles and pathological implications have remained poorly understood. However, increasing research interest in BMAds is beginning to elucidate these functions, including their endocrine and metabolic properties and the impact of BMAds on skeletal remodeling, hematopoiesis, tumor progression and beyond.

Deletion of Hsd11b1 suppresses caloric-restriction-induced bone marrow adiposity in male mice

Journal of Endocrinology/Journal of endocrinology, May 1, 2024

Improving Research Culture and Integrity through Open Science

format_quotePressure to publish drives both research misconduct and compromised integrity, reflecting a dark side of scientific competitiveness.format_quote

Download

A novel deep learning method for large-scale analysis of bone marrow adiposity using UK Biobank Dixon MRI data

medRxiv (Cold Spring Harbor Laboratory), Dec 6, 2022

a new deep learning method for image segmentation. • Our method improves segmentation of small st... more a new deep learning method for image segmentation. • Our method improves segmentation of small structures from large volumetric data. • Using our method, we assess bone marrow fat fraction (BMFF) in UK Biobank MRI data. • This is the first use of deep learning for large-scale, multi-site BMFF analysis. • Our results highlight the potential of BMFF as a new clinical biomarker. .

format_quoteBMFF was highest in the femoral head, showing significant regional and sex differences: females had greater spinal BMFF, while males had higher femoral BMFF.format_quote

Download

Fat cell progenitors get singled out

Science, Apr 26, 2019

Distinct adipocyte progenitor cells may reveal therapeutic strategies for obesity 7 8 Fat tissue ... more Distinct adipocyte progenitor cells may reveal therapeutic strategies for obesity 7 8 Fat tissue is essential for the safe storage of excess calories and thereby plays a key role in metabolic health. 9 By storing lipid droplets, fat cells (adipocytes) protect organs from the damaging effects of ectopic lipid 10 accumulation (1). Understanding how to promote healthy fat expansion may therefore reveal treatments for 11 obesity and related diseases. Such expansion depends on the formation of new adipocytes from progenitor 12 cells within fat tissue (2). Distinct populations of adipocyte progenitor cells (APCs) have been identified, but 13 their interrelationships and relevance to physiological and pathological fat expansion have remained poorly 14 understood (3). On page 353 of this issue, Merrick et al. (4) identify three new classes of APCs that are 15 regulated with obesity, one of which resides in a potential new stem cell niche for tissue regeneration and 16 repair. 17 Deciphering APC biology is complicated by the heterogeneous nature of fat tissue. To isolate APCs from 18 the fat of mice, Merrick et al. used a method called fluorescence-activated cell sorting (FACS), which 19 separates fat cells based on the presence of specific cell-surface proteins. This cellular pool was further 20 resolved using single-cell RNA sequencing (scRNAseq), allowing cells to be grouped on the basis of 21 similarities in their gene expression. Most cells fell into one of three groups that had not been defined 22 previously: interstitial progenitor cells (IPCs), defined by expression of a protein called dipeptidyl peptidase-4 23 (DPP4); preadipocytes, marked by expression of intercellular adhesion molecule-1 (ICAM1); and group 3 24 cells, which expressed the protein CD142 (see the figure). Each group formed adipocytes in cell culture, thus 25 supporting their identification as APCs. 26 Different types of fat tissue, called depots, exist in distinct anatomical locations, with distinct cellular and 27 functional characteristics and pathological implications (2). Do APC classes differ between depots? Merrick 28 et al. found that visceral fat has fewer IPCs than subcutaneous fat, analogous to depot-dependent differences 29 reported elsewhere (5-9). It remains unclear whether these APCs exist in other depots, such as bone marrow 30 fat (10); however, they were also detected in brown fat, a depot that may help treat obesity. 31 To determine whether different APC classes interconvert in vivo, Merrick et al. obtained IPCs, 32 preadipocytes, and group 3 cells from newborn mice genetically engineered to express a red fluorescent 33 protein. This allowed the cells to be tracked after transplantation into normal newborn recipients. Doing so 34 revealed that IPCs acted as progenitors for both ICAM1+ and CD142+ cells, which themselves interconverted 35 in vivo but did not revert to IPCs. Each of these APC types also gave rise to adipocytes in vivo, further 36 demonstrating their role in fat development. The use of newborn mice is notable: Other studies focused on 37 adults only (5, 7, 9, 10), leaving the developmental relevance of the APCs studied unclear. By contrast, Merrick 38 et al. identified IPCs, preadipocytes, and group 3 cells in adults and newborns, observing similar proportions 56 identified with those of other studies, demonstrating how their IPCs, preadipocytes, and group 3 cells overlap 57 with other APC subtypes identified elsewhere (5, 7, 9). However, there is likely to be further heterogeneity 58 among these APC classes, and other distinct subtypes may also exist. It would be helpful for the field to reach 59 some consensus around the identities of such APC classes, the methods used to characterize them, and their 60 existence in humans. 61 Many reports indicate that APCs reside near blood vessels (2, 3), but Merrick et al. noted that IPCs were 62 found within the reticular interstitium, a fluid-filled network of collagen and elastin fibers that encases many 63 organs. By contrast, preadipocytes were observed beyond the reticular interstitium, adjacent to adipocytes. 64 Between the IPCs and preadipocytes were cells expressing both DPP4 and ICAM1, suggesting a transition 65 from IPCs to preadipocytes. The presence of IPCs within the reticular interstitium was assessed only for 66 subcutaneous fat of mice. Hence, it remains unclear if this represents a common site for IPCs among all fat 67 depots, or if it is analogous to the mesothelium as a source for visceral fat progenitors (6). Whether the reticular 68 interstitium plays a role in humans also remains to be determined. However, given that the reticular interstitium 69 exists in multiple human tissues (11),, an intriguing possibility is that it represents a new stem cell niche for fat 70 tissue and beyond. 71 Adipose formation and function are influenced by diverse physiological and pathological factors, including 72 genetics, age, sex, ethnicity, diet, and many clinical conditions. What is the relationship between these factors, 73 APC function, and the reticular interstitium? Moreover, some antidiabetic drugs can modulate APC dynamics 74 (12), and DPP4 is a target of other antidiabetic therapies (10). Whether such treatments can influence the 75 DPP4-expressing IPCs, or other APC subtypes, remains unknown. 76 A major challenge will be to determine the implications of altered APC function in health and disease. Doing 77 so holds great promise: By further unraveling the mysteries of APC biology, we may ultimately be able to 78 target these cells to improve human health.

Download

Induction of WNT11 by hypoxia and hypoxia-inducible factor-1α regulates cell proliferation, migration and invasion

Scientific Reports, Feb 10, 2016

Changes in cellular oxygen tension play important roles in physiological processes including deve... more Changes in cellular oxygen tension play important roles in physiological processes including development and pathological processes such as tumor promotion. The cellular adaptations to sustained hypoxia are mediated by hypoxia-inducible factors (HIFs) to regulate downstream target gene expression. With hypoxia, the stabilized HIF-α and aryl hydrocarbon receptor nuclear translocator (ARNT, also known as HIF-β) heterodimer bind to hypoxia response elements (HREs) and regulate expression of target genes. Here, we report that WNT11 is induced by hypoxia in many cell types, and that transcription of WNT11 is regulated primarily by HIF-1α. We observed induced WNT11 expression in the hypoxic area of allograft tumors. In addition, in mice bearing orthotopic malignant gliomas, inhibition with bevacizumab of vascular endothelial growth factor, which is an important stimulus for angiogenesis, increased nuclear HIF-1α and HIF-2α, and expression of WNT11. Gain-and loss-offunction approaches revealed that WNT11 stimulates proliferation, migration and invasion of cancerderived cells, and increases activity of matrix metalloproteinase (MMP)-2 and 9. Since tumor hypoxia has been proposed to increase tumor aggressiveness, these data suggest WNT11 as a possible target for cancer therapies, especially for tumors treated with antiangiogenic therapy. Increasing evidence suggests that changes in oxygen tension play important roles in physiological processes including development, and pathological processes such as tumor promotion 1-4. Cellular adaptations to sustained hypoxia are in part mediated by hypoxia-inducible factor (HIF). HIF is a heterodimeric transcription factor consisting of an oxygen-sensitive alpha subunit (HIF-1α or HIF-2α) and a constitutively expressed beta subunit, aryl hydrocarbon receptor nuclear translocator (ARNT, also known as HIF-1β) 2,3,5,6. In normoxia, HIF-1α and HIF-2α are rapidly hydroxylated, and degraded by the ubiquitin-proteasome pathway 2,3,5,6. In hypoxia, stabilized HIF-1α and HIF-2α bind to ARNT to regulate downstream target gene expression 1,2,5,6. HIF-1α and HIF-2α regulate distinct and partially overlapping sets of target genes 2,4,6. Since ARNT is not responsive to oxygen and is present in excess, HIF-1α and HIF-2α protein levels determine HIF transcriptional activity. Many genes are directly or indirectly regulated by HIFs, and HIF-mediated pathways are essential cellular responses to hypoxia such as metabolic adaptation, angiogenesis, erythropoiesis, and cell growth and differentiation 1-4,6,7. One well-established indirect mechanism for HIF-α to influence downstream cellular events is through regulation of WNT signaling proteins such as β-catenin 8,9 .

Download

TNF-α and adipocyte biology

FEBS Letters, Nov 26, 2007

Dyslipidemia and insulin resistance are commonly associated with catabolic or lipodystrophic cond... more Dyslipidemia and insulin resistance are commonly associated with catabolic or lipodystrophic conditions (such as cancer and sepsis) and with pathological states of nutritional overload (such as obesity-related type 2 diabetes). Two common features of these metabolic disorders are adipose tissue dysfunction and elevated levels of tumour necrosis factor-alpha (TNF-α). Herein, we review the multiple actions of this pro-inflammatory adipokine on adipose tissue biology. These include inhibition of carbohydrate metabolism, lipogenesis, adipogenesis and thermogenesis and stimulation of lipolysis. TNF-α can also impact the endocrine functions of adipose tissue. Taken together, TNF-α contributes to metabolic dysregulation by impairing both adipose tissue function and its ability to store excess fuel. The molecular mechanisms that underlie these actions are discussed.

Download

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

Frontiers in Medicine, Sep 6, 2018

Long non-coding RNAs (lncRNA) are emerging as new genetic/epigenetic regulators that can impact a... more 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. Genome-wide analysis reveals that SRA regulates hundreds of target genes in adipocytes and breast cancer cells and binds to thousands of genomic sites in human pluripotent stem cells. Recent studies indicate that SRA acts as a molecular scaffold and forms networks with numerous coregulators and chromatin-modifying regulators in both activating and repressive complexes. We discuss how modifications to SRA's unique stem-loop secondary structure are important for SRA function, and highlight the various SRA isoforms and mutations that have clinical implications. Finally, we discuss the future directions for better understanding the molecular mechanisms of SRA action and how this might lead to new diagnostic and therapeutic approaches.

format_quoteSRA enhances MyoD activity in muscle differentiation and promotes muscle development through coregulation with RNA helicases.format_quote

Download

Bone marrow adipose tissue

Annales D Endocrinologie, Oct 1, 2022

Bone Marrow Tumor Microenvironment of Obese Hodgkin Lymphoma Patients: implications of insulin axis

Background Excessive adiposity, or obesity, has been associated with cancer promotion, including ... more Background Excessive adiposity, or obesity, has been associated with cancer promotion, including an increased risk for developing Hodgkin Lymphoma (HL). However, the association between obesity and survival in HL can be somewhat paradoxical and may indeed influence prognosis. Examining the bone marrow (BM) cytokine profile in HL patients could provide insights into the mechanisms underlying the altered association between excess adiposity and HL. The BM is an important site for hematopoiesis and can be influenced by various factors, including disease processes and systemic metabolic changes associated with obesity. Methods From our cohort, we analyzed interstitial marrow fluid (IMF) from BM aspirates of 16 HL patients at diagnosis and 11 control subjects. Participants were then matched by sex, age, and Body mass index (BMI) for inclusion in our discovery protein array analysis (n = 8 HL and n = 8 donors). We validated our findings in the total sample by measuring adipokine-related m...

Download

Development of the Brief Open Research Survey (BORS) to measure awareness and uptake of Open Research practices

Objectives: Whilst the need for Open Research practices is well documented, there remains a lack ... more Objectives: Whilst the need for Open Research practices is well documented, there remains a lack of validated questionnaires to assess their prevalence. This study validated the Brief Open Research Survey (BORS) to measure Open Research awareness and uptake.Methods: The survey was developed in six steps: 1) a scoping exercise collated previous questionnaires on Open Research, 2) a brief (<5 minutes) questionnaire was developed, 3) peer-reviewed, 4) piloted, 5) revised, and 6) the final questionnaire was distributed across UK Reproducibility Network Local Networks.Results: Respondents (n = 1,274) reported being most aware of Open Access Publications (94.1%), Preprints (85.35%), and Open Data (83.4%) and least aware of Registered Reports (38.4%), Study Preregistration (50.8%) and Research Co-production (53.7%). They reported having mostly used Open Access Publications (77.8%), Preprints (56.5%) and Open Data (52.5%) and having least used Registered Reports (8.7%), Replication Studi...

Cawthorn Lab: Data for sex differences manuscript

Source data for figures included in our manuscript about age-dependent sex differences in the met... more Source data for figures included in our manuscript about age-dependent sex differences in the metabolic effects of caloric restriction (version date 12 January 2022). The abstract is as follows: "Caloric restriction (CR) is a nutritional intervention that reduces the risk of age-related diseases in numerous species, including humans. CR's metabolic effects, including decreased fat mass and improved insulin sensitivity, play an important role in its broader health benefits; however, many aspects of the CR response remain poorly understood. In particular, sex differences in metabolic function are increasingly well recognised, yet the extent and basis of sex differences in CR's health benefits have been largely ignored. Herein, we addressed this gap in knowledge. In young (3-month-old) male mice, 30% CR decreased fat mass and fasting blood glucose and improved glucose tolerance and insulin sensitivity; however, in young female mice these effects were blunted or absent. Ind...

Molecular mechanisms of anti-adipogenesis by tumour necrosis factor-alpha

A novel deep learning method for large-scale analysis of bone marrow adiposity using UK Biobank Dixon MRI data

ABSTRACTOBJECTIVESBone marrow adipose tissue (BMAT) represents >10% of total fat mass in healt... more ABSTRACTOBJECTIVESBone marrow adipose tissue (BMAT) represents >10% of total fat mass in healthy humans and further increases in diverse clinical conditions, but the impact of BMAT on human health and disease remains poorly understood. Magnetic resonance imaging (MRI) allows non-invasive measurement of the bone marrow fat fraction (BMFF), and human MRI studies have begun identifying associations between BMFF and skeletal or metabolic diseases. However, such studies have so far been limited to smaller cohorts: analysis of BMFF on a larger, population scale therefore has huge potential to reveal fundamental new knowledge of BMAT’s formation and pathophysiological functions. The UK Biobank (UKBB) is undertaking whole-body MRI of 100,000 participants, providing the ideal opportunity for such advances.MATERIALS AND METHODSHerein, we developed a deep learning pipeline for high-throughput BMFF analysis of these UKBB MRI data. Automatic bone marrow segmentation was achieved by designing ...

Download

Bone marrow adipose tissue as an endocrine organ: close to the bone?

Hormone Molecular Biology and Clinical Investigation, 2016

White"adipose"tissue"(WAT)"is"a"major"endocrine"organ,"secreting"a"diverse"range"of"hormones,"lip... more White"adipose"tissue"(WAT)"is"a"major"endocrine"organ,"secreting"a"diverse"range"of"hormones,"lipid" species,"cytokines"and"other"factors"to"exert"diverse"local"and"systemic"effects."These"secreted" products,"known"as"'adipokines',"contribute"extensively"to"WAT's"impact"on"physiology"and"disease." Adipocytes"also"exist"in"the"bone"marrow,"but"unlike"WAT,"study"of"this"bone"marrow"adipose"tissue" (MAT)"has"been"relatively"limited."We"recently"discovered"that"MAT"contributes"to"circulating" adiponectin,"an"adipokine"that"mediates"cardiometabolic"benefits."Moreover,"we"found"that"MAT" expansion"exerts"systemic"effects."Together,"these"observations"identify"MAT"as"an"endocrine"organ." Additional"studies"are"revealing"further"secretory"functions"of"MAT,"including"production"of"other" adipokines,"cytokines"and"lipids"that"exert"local"effects"within"bone."These"observations"suggest"that," like"WAT,"MAT"has"secretory"functions"with"diverse"potential"effects,"both"locally"and"systemically."A" major"limitation"is"that"these"findings"are"often"based"on"in!vitro!approaches"that"may"not"faithfully" recapitulate"the"characteristics"and"functions"of"bone"marrow"adipocytes"in!vivo.!This"underscores" the"need"to"develop"improved"methods"for"in!vivo!analysis"of"MAT"function,"including"more"robust" transgenic"models"for"MAT"targeting,"and"continued"development"of"techniques"for"non`invasive" analysis"of"MAT"quantity"and"quality"in"humans."Although"many"aspects"of"MAT"formation"and" function"remain"poorly"understood,"MAT"is"now"attracting"increasing"research"focus;"hence,"there"is" much"promise"for"further"advances"in"our"understanding"of"MAT"as"an"endocrine"organ,"and"how" MAT"impacts"human"health"and"disease." " "

Download

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

Journal of Bone and Mineral Research, Jan 16, 2020

Multiple myeloma is caused by abnormal plasma cells that accumulate in the bone marrow and intera... more 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. Using the C57BL/KaLwRij murine model of myeloma, bone marrow adiposity was found to be increased in early stage myeloma with BMAds localizing along the tumor-bone interface at later stages of disease. Myeloma cells were found to uptake BMAd-derived lipids in vitro and in vivo, although lipid uptake was not associated with the ability of BMAds to promote myeloma cell growth and survival. However, BMAd-derived factors were found to increase myeloma cell migration, viability, and the evasion of apoptosis. BMAds are a major source of adiponectin, which is known to be myeloma-suppressive. Myeloma cells were found to downregulate adiponectin specifically in a model of BMAds but not in white adipocytes. The ability of myeloma cells to downregulate adiponectin was dependent at least in part on TNF-α. Collectively our data support the link between increased bone marrow adiposity and myeloma progression. By demonstrating how TNF-α downregulates BMAd-derived adiponectin, we reveal a new mechanism by which myeloma cells alter the bone microenvironment to support disease progression.

Download

William Cawthorn

Uploads

Papers by William Cawthorn

Log In