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EASTBIO - Why do females resist the metabolic benefits of caloric restriction? Investigating the role of adiponectin


College of Medicine and Veterinary Medicine

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Dr W Cawthorn , Dr L Kang No more applications being accepted Competition Funded PhD Project (Students Worldwide)

About the Project

Adiponectin is the most abundant hormone in our blood and has been studied extensively since its discovery 25 years ago. It is produced by fat-storing cells, called adipocytes, and can exert beneficial metabolic, cardiovascular and anti-inflammatory effects. These include enhancing insulin sensitivity, decreasing atherosclerosis and suppressing apoptosis (1).
Despite being produced from adipose tissue, circulating adiponectin decreases in obesity and increases in lean states, including during caloric restriction (CR). This striking finding, dubbed ‘The Adiponectin Paradox’ was solved through research from the lead supervisor Dr William Cawthorn. His studies revealed that, during CR, increased adiponectin is derived from adipocytes present within the bone marrow (2). However, a key question remains unanswered: what is the role of adiponectin during CR? Many effects of CR represent evolutionary adaptations that improve survival during periods of food scarcity; such adaptations thereby represent fundamental aspects of normal human biology.
Moreover, CR has therapeutic benefits, such as improving metabolic health and decreasing the risk of chronic diseases. Elucidating the roles of adiponectin during CR may thereby reveal fundamental aspects of human biology while also identifying new therapeutic approaches to promote healthy ageing.

To determine these roles of adiponectin, Dr Cawthorn’s group has studied CR in wild-type (WT) and adiponectin-deficient (KO) mice. This has revealed two unexpected findings. Firstly, there are striking sex differences, with females of each genotype resisting fat loss and improved glucose homeostasis during CR. Secondly, in both sexes, adiponectin deficiency enhances, rather than impairs, CR’s metabolic benefits. Together, these observations demonstrate that adiponectin has unexpected functions in conditions of leanness that contribute to sex differences in metabolic health. However, several critical questions remain:
1. Why do females resist CR-induced improvements in glucose tolerance? Does this relate to effects on insulin production, insulin sensitivity, or other mechanisms?
2. How does adiponectin deficiency influence these sex-dependent effects of CR?
3. Does females’ resistance to fat loss relate to sex differences in adipocyte function? How do CR and adiponectin impact on these adipocyte characteristics?
This PhD project uses advanced data-driven approaches to address these critical questions.
For questions 1-2, you will utilise in-depth metabolic phenotyping, including hyperinsulinaemic-euglycaemic clamps, to determine how biological sex and adiponectin knockout influence insulin sensitivity and glucose disposal during CR. This will be done with expert guidance from Dr Li Kang, a global leader in these advanced metabolic techniques. For question 3, you will use single-nucleus RNA sequencing (snRNAseq) to characterise the adipocyte transcriptome, not only from the KO and CR mouse models, but also from human samples available in the Edinburgh Adipose Tissue Biobank. Adipocytes are too fragile to be sorted for single-cell RNAseq, and therefore snRNAseq holds immense promise for revealing their properties on a single-cell level. Together, these studies will help to elucidate the physiological role of adiponectin and the mechanisms underlying sex differences in biological function, thereby revealing new knowledge fundamental to human biology.

Funding Notes

This 4 year PhD project is part of a competition funded by EASTBIO BBSRC Doctoral Training Partnership http://www.eastscotbiodtp.ac.uk/how-apply-0. This opportunity is open to UK and International students and provides funding to cover stipend and UK level tuition (Please state if your institution will provide funding to cover the difference in fees). Please refer to UKRI website and Annex B of the UKRI Training Grant Terms and Conditions for full eligibility criteria.

References

1. Straub and Scherer, Nat Metab 1:334–339 (2019).
2. Cawthorn et al, Cell Metab 20(2):368-375 (2014).
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