Investigating cell-cell interactions in human adipose tissue thermogenesis and dysregulation in obesity and type 2 diabetes

Background

Obesity is associated with multiple comorbidities such as type 2 diabetes, hypertension, dyslipidaemia and cardiovascular disease. This increasing prevalence of obesity globally, currently 30% in UK adults, has resulted in a massive economic impact, accounting for ~2.5% of GDP in affluent nations. Current pharmacotherapy for obesity, primarily incretin mimetics such as semaglutide or tirzepatide that act through suppression of appeitte, are not widely available on the NHS due to their cost, are far less effective in patients with type 2 diabetes, are not tolerated by >20% of patients, there are concerns over substantial muscle loss, and there is compensatory reduction in energy expenditure that lmiits efficacy. Strategies to enhance energy expenditure are less well studied in humans. Brown adipose tissue (BAT) is a thermogenic organ recently (re-)discovered in adult humans due to use of positron emission tomography/ computed tomography (PET/CT)¹. In rodents, increasing BAT activity can reduce body weight, but has more powerful effects on improving cardiometabolic risk factors. Similarly, adult humans with BAT have an improved cardiometabolic risk profile, interestingly including those with obesity, and repeated cold exposure improves cardiovascular risk factors although the reasons are unclear. We have shown that BAT function decreases with increasing age and weight², developed techniques to quantify BAT activity³, and identified novel regulators of human BAT function⁴. Importantly, even older patients with obesity retain prescursor cells that can form new thermogenic adipocytes. Most recently, we have recently undertaken single nucleus RNA sequencing in BAT from patients of various BMIs, and identified multiple different cell types that may contribute to thermogenic function. It is unclear how these different populations interact and how cells signal to enhance BAT proliferation and activation. 

Aims

This PhD aims to determine the cell-cell interactions in human BAT, how different immune cell types contribute to BAT function, and whether this is altered in obesity and obesity-associated type 2 diabetes. To investigate this, we will undertake spatial transcriptomics and proteomics on human BAT samples from patients undergoing elective neck surgery, encompassing people of different ages, sexes, BMIs, and those with and without type 2 diabetes using the CosMx platform. We aim to determine how thermogenic adipocytes and immune cells interact to optimize thermogenesis, and how this is altered in obesity and type 2 diabetes. The dataset generated by the student will be intergrated with our current single nucleus and bulk RNAseq datasets, in addition to other omics data to prioritise candidates for further investigation. The student will also develop a primary co-culture technique to investigate adipocyte-immune cell interactions and their effects on thermogenesis using techniques such as respiromety. Candidate pathways/ genes may be targeted pharmacologically and/or genetically in this cell model⁴. This project may inform us why different groups have altered BAT activity, and identify those that may benefit from therapeutic interventions to increase energy expenditure. 

Training Outcomes

This PhD will include training on spatial transcriptomics and proteomics, snRNAseq, human primary cell culture, respirometry, qPCR, Western blot, and genetic manipulation techniques such as siRNA knockdown. The student can also undertake image analysis of PET/CT scans.

References: 

1.         Kwok TC, Stimson RH. Human brown adipose tissue function: insights from current in vivo techniques. J Endocrinol 2023;259(1). DOI: 10.1530/JOE-23-0017.

2.         Kwok TC et al. UCP1 expression in human brown adipose tissue is inversely associated with cardiometabolic risk factors. Eur J Endocrinol 2024;191(1):106-115. DOI: 10.1093/ejendo/lvae074.

3.         Weir G et al. Substantial Metabolic Activity of Human Brown Adipose Tissue during Warm Conditions and Cold-Induced Lipolysis of Local Triglycerides. Cell Metab 2018;27(6):1348-1355. DOI: S1550-4131(18)30304-8 [pii];10.1016/j.cmet.2018.04.020 [doi].

4.         Suchacki KJ et al. The serotonin transporter sustains human brown adipose tissue thermogenesis. Nat Metab 2023;5(8):1319-1336. DOI: 10.1038/s42255-023-00839-2.