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EASTBIO - Single-cell and population-level approaches to establish the impact of bone marrow adipocytes on normal human health


Project Description

Bone marrow adipose tissue (BMAT) is a major feature of normal human anatomy, accounting for over 10% of total fat mass in healthy humans. Strikingly, BMAT further accumulates in conditions of leanness and caloric restriction (CR) (1). Thus, BMAT expansion may represent an evolutionary mechanism that promotes survival during periods of starvation, and that contributes to the health benefits of leanness and CR. However, BMAT’s biological functions remain poorly understood, in part because of the difficulty in isolating and characterising bone marrow adipocytes (BMAds).

The lead supervisor, Dr William Cawthorn, is an expert in BMAT. He previously revealed that, during CR, BMAT is a major source of adiponectin, an anti-inflammatory hormone implicated with improved cardio-metabolic health (reviewed in (1)). This identifies BMAT as an endocrine organ that, via adiponectin, might exert systemic effects. However, it also raises a fundamental question: why does adiponectin increase during CR? Indeed, adiponectin research has focussed largely on obesity and diabetes, leaving its role in normal human biology poorly understood (1). Notably, adiponectin is the most abundant hormone in the blood; hence, the fact that it increases further in conditions of energy deficit suggests important roles in this evolutionarily relevant context.

To address these potential roles of BMAT and adiponectin, Dr Cawthorn’s group has pursued CR studies in adiponectin knockout mice. These unpublished studies have shown, unexpectedly, that CR’s metabolic benefits are enhanced in the absence of adiponectin and that this is associated with increased glucose uptake within the BM. The latter is consistent with the Cawthorn lab’s recent identification of BMAT as a site of high glucose uptake (2). Together, these observations suggest that BMAds influence systemic responses in conditions of leanness, both via metabolic mechanisms and through unexpected functions of adiponectin. However, several critical questions remain:

1. Why does adiponectin knockout enhance the metabolic benefits of CR?
2. How does CR influence the properties of BMAds? How do these properties compare to those of adipocytes from other adipose depots, both in mice and in humans?
3. Does adiponectin directly influence the relationship between leanness and human health?

This PhD project uses interdisciplinary, data-driven approaches to address these critical questions.

For question 1, the student will utilise in-depth metabolic phenotyping to determine how adiponectin knockout influences insulin sensitivity and glucose disposal during CR. For question 2, the student will use single-nucleus RNA sequencing (snRNAseq) to characterise the BMAd transcriptome, not only from the knockout and CR mouse models but also from human surgical patients. Adipocytes from white adipose tissue will be similarly characterised. Adipocytes are too fragile to be sorted and analysed by single-cell RNAseq, and therefore using snRNAseq holds immense promise for revealing the fundamental properties of these cells. Finally, question 3 will be addressed via Mendelian Randomisation studies in the UK Biobank, which will test if variation in circulating adiponectin plays a causal role in the link between leanness, metabolic function and other physiological effects.



Funding Notes

Download application and reference forms via: View Website

Applications: Completed application form along with your supporting documents should be sent to

References: Please send the reference request form to two referees. Completed forms for this project should be returned to [email protected],ac.uk ny the closing date: 5th January 2020.

It is your responsibility to ensure that references are provided by the specified deadline.

References



1. E. L. Scheller, et al., Adipocyte 5, (2016).
2. K. J. Suchacki, et al., bioRxiv (2019).


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