Adipocyte plasticity in health and disease

<jats:p>&lt;p dir="ltr"&gt;Adipose tissue is the central energy reservoir of the human body, containing the vast majority of stored calories. Its main functional cell type is the adipocyte, characterised by one or more lipid droplets filled with energy-dense triacylglycerol. Because adipocytes must both store and release lipids according to physiological needs, they play a crucial role in maintaining energy homeostasis and communicate extensively with other metabolic organs such as the brain, muscle, and liver.&lt;br&gt;&lt;br&gt;Adipocytes exist in two major forms located in distinct depots: energy-storing and -releasing white adipocytes in white adipose tissue, and thermogenic brown or beige adipocytes in brown adipose tissue. Although these cell types have characteristic differences, considerable interconversion can occur depending on metabolic demand. Adipocytes are highly plastic: white adipocytes can expand and shrink by several orders of magnitude over their lifespan, and under thermogenic activation, adipocytes remodel their lipid droplets from a unilocular to a multilocular architecture to increase the surface area required for fuel mobilisation. Organelles such as mitochondria also vary dramatically in abundance depending on cellular state and adipocyte subtype.&lt;br&gt;&lt;br&gt;Adipose tissue itself is equally dynamic, and changes in its architecture directly reflect underlying shifts in adipocyte populations. In obesity, adipocytes enlarge and increase in number, thermogenic adipocytes become scarce, vascular density decreases, and low-grade inflammation and fibrosis emerge. In contrast, thermogenic activation reduces adipocyte size and increases vascularisation and innervation. Adipose tissue status strongly correlates with metabolic health: greater thermogenic capacity is protective against metabolic syndrome, while hypertrophic and dysfunctional adipose tissue contributes to insulin resistance and is associated with conditions such as type 2 diabetes, cardiovascular disease, and altered cancer risk and prognosis.&lt;br&gt;&lt;br&gt;Given the central metabolic importance of adipose tissue and its relevance to human health, this thesis focuses on how adipocyte populations change in health, disease, and ageing. It examines the prevalence and function of human brown fat, compares single-cell sequencing strategies for adipocytes, and investigates how adiposity, insulinaemia, and senescence influence white adipocytes in subcutaneous and visceral depots.&lt;br&gt;&lt;br&gt;Using stereology in a cohort of 65 individuals, we sampled seven putative brown fat depots in humans. By staining for uncoupling protein 1 (UCP1), the key thermogenic protein, we quantified adipocyte subtypes according to morphology and thermogenic potential. Regression models incorporating BMI, age, temperature, and sex demonstrated that the incidence and abundance of thermogenic adipocytes decline with age and adiposity. Monte Carlo simulations of whole-body energy expenditure suggested that human brown fat can contribute meaningfully to energy metabolism. Analysis of tissue from an individual who died following prolonged hypothermia indicated that human brown fat is capable of far greater thermogenic activation than previously assumed. Using agent-based modelling, we further showed that active thermogenic adipocytes can reduce lipid stores in neighbouring white adipocytes—a finding confirmed by spatial analyses demonstrating smaller white adipocytes adjacent to thermogenic cells. These results indicate that brown fat can influence tissue architecture locally.&lt;br&gt;&lt;br&gt;Changes associated with adiposity were also observed in white adipocytes studied in this thesis. Through single-cell sequencing, single-cell immunocytochemistry, and complementary molecular analyses of &lt;/p&gt;&lt;p dir="ltr"&gt;subcutaneous and visceral adipocytes, we demonstrated that these cells can re-enter the cell cycle, synthesise DNA, and undergo cellular senescence, with insulin acting as a key driver of these processes. Subcutaneous adipocytes, but not visceral adipocytes, were capable of becoming senescent. Using beta-binomial regression, we identified shifts in three metabolically distinct adipocyte populations—first in response to adiposity, and subsequently to insulinaemia. The most strongly affected adipocytes displayed hallmarks of senescence and hypertrophy, features associated with inflammation and metabolic decline. By integrating single-cell sequencing with bulk proteomics, we disentangled the contributions of hypertrophy and senescence, showing that metabolic dysfunction is primarily driven by hypertrophy, while inflammation is more closely linked to cellular senescence.&lt;br&gt;&lt;br&gt;In conclusion, this thesis characterises the remarkable plasticity of both white and thermogenic adipocytes. In doing so, it advances our understanding of adipose tissue biology and identifies plausible avenues for therapeutic development. The local effects of thermogenic adipocytes may help reduce adipocyte size and thereby improve metabolic health, while identifying senescence as a driver of adipocyte inflammation highlights senescent cells as promising targets for emerging senolytic therapies. Together, these findings suggest two mechanisms that could expand current anti-obesity strategies.&lt;/p&gt;&lt;p dir="ltr"&gt;&lt;br&gt;&lt;/p&gt;&lt;p dir="ltr"&gt;&lt;br&gt;&lt;/p&gt;</jats:p>