The Functional Cellular Identity and Interconversion of Human White, Beige, and Brown Adipocytes

Abstract

Since the mid-20th century, the prevalence of obesity has seen an unprecedented growth, with nearly 40 % of the population now qualifying as overweight, and almost 15 % as obese. Due to its systemic nature, obesity represents a significant healthcare concern, and can lead to the development of a large number of comorbidities, including cardiovascular disease, type 2 diabetes, dementia, and cancer, and puts significant stress on healthcare systems worldwide. Despite the widespread prevalence of obesity, treatment options remain limited, with existing approaches often either ineffective in the long term, or highly invasive. With the recent discovery of brown adipose tissue activity in human adults, adipocyte thermogenesis has received significant interest due to its therapeutic potential for reversing obesity, or in assisting orthogonal treatment approaches. However, while metabolic changes in the form of increased energy expenditure in adipocytes form the core of this therapeutic potential, little is known about the metabolic differences between white and brown adipocytes, as well as the thermogenic beige adipocytes arising within white adipose tissue upon stimulation, and this knowledge gap remains a significant road block for the development of pharmacological treatment options. To address this gap, we here use an integrated multiomic, quantitative exometabolomic, and 13C-assisted metabolic modelling approach to quantify metabolic differences between human white and brown adipocytes isolated from the same donor. To this extent, we present a novel workflow for the inference of metabolic reaction expression states from combined transcriptomic and proteomic data. Our results highlight the elevated catabolism of brown adipocytes, and point towards differential pathway utilization and substrate preferences of white and brown adipocytes. Further, our results suggest that alanine excretion may act as a browning-responsive nitrogen excretion route in adipocytes, similar to the Cahill cycle in muscle cells. To assess the interconversion of white to beige adipocytes, we benchmark a number of small molecules, peptides, and metabolites that have been reported to induce their interconversion in the past (so-called browning agents). Through a combination of gene expression profiling, quantitative microscopy, bioenergetic profiling, metabolic/lipidomic profiling, and quantitative exometabolomics, we identify significant diversity in the response of human white adipocytes to browning agents, suggesting that a more detailed definition of browning might be required. By combining browning agents, we further explore potential interactions between treatments, revealing a complex interaction landscape with a large number of independent effects, potentially allowing for considerable control over adipocyte metabolism.