Identification of novel factors regulating human adipocyte function and their link to metabolic health

The white adipose tissue (WAT) regulates energy homeostasis by storing and releasing energy in the form of fat as well as functioning as an endocrine organ secreting a myriad of different peptides. The heterogeneous WAT consists of various cell types including the lipid-storing cells termed adipocytes. The energy-storing capacity of WAT is challenged by the rapid worldwide changes in diet and physical activity. This thesis aimed to identify novel factors regulating adipocyte function and to assess their impact on metabolic health.

The transcription factor Early B Cell Factor 1 (EBF1) has previously been shown to regulate WAT morphology (adipocyte size and number). Low expression/activity is associated with WAT hypertrophy (few but large adipocytes), a metabolically detrimental phenotype. Study I aimed to determine if the expression and activity of EBF1 associated with metabolic risk markers. Results suggested that EBF1 expression and activity associated with parameters of the metabolic syndrome. Adipocytes in WAT is continuously renewed however, the turnover is irreversibly increased when a person gains weight. In fact, fat cell number is increased during weight gain and kept constant after weight loss. Study II aimed to identify the factor/s contributing to the maintenance of the high adipocyte number. Prospective analyses in clinical cohorts identified a set of growth factors that were highly expressed in obese compared to never-obese and were kept high after weight loss. Among these, transforming growth factor beta 3 (TGFB3) induced immature adipocyte proliferation. The WAT was studied in a mouse model expressing half of the gene expression and the results displayed a reduced proliferative capacity of immature adipocytes, hypertrophic WAT and glucose intolerance.

The hypertrophic WAT is characterized by changes in several biological processes including inflammation. The chronic low grade inflammation in obesity is one of the processes believed to cause insulin resistance and type 2 diabetes mellitus. Study III focused on identifying upstream regulators of adipocyte inflammation. This led to the identification of SLC19A1, a gene encoding a cell membrane bound folate transporter. Folate is metabolized by the one-carbon-cycle, an important pathway for DNA-methylation. We linked the inflammatory effects of reduced SLC19A1 expression to increased global DNA-methylation. In particular, methylation of a glucocorticoid receptor binding site in the promotor of the pro-inflammatory gene CCL2 regulated its expression.

Altogether, this work contributes to the characterization of a dysfunctional WAT. Furthermore, the clinical relevance of the reported regulators of WAT function was evaluated. This knowledge confirms an emerging theory, that an important link between obesity and metabolic disease is limited WAT expansion. Therapies resolving WAT expansion exists and this knowledge could contribute in making these more effective. However, whether such therapies should replace interventions targeting behavior (nutrition and physical activity) warrants ethical appraisal and discussion.

List of scientific papers

I. Petrus P, Mejhert N, Gao H, Bäckdahl J, Arner E, Arner P, Rydén M. Low early B-cell factor 1 (EBF1) activity in human subcutaneous adipose tissue is linked to a pernicious metabolic profile. Diabetes Metab. 2015 Dec;41(6):509-12.
https://doi.org/10.1016/j.diabet.2015.02.004

II. Petrus P, Mejhert N, Corrales P, Lecoutre S, Li Q, Maldonado E, Kulyté A, Lopez Y, Campbell M, Acosta JR, Laurencikiene J, Douagi I, Gao H, Martínez-Álvarez C, Hedén P, Spalding KL, Vidal-Puig A, Medina-Gomez G, Arner P, Rydén M. Transforming Growth Factor-β3 Regulates Adipocyte Number in Subcutaneous White Adipose Tissue. Cell Reports. 2018 Oct.
https://doi.org/10.1016/j.celrep.2018.09.069

III. Petrus P, Bialesova L, Checa A, Kerr A, Naz S, Bäckdahl J, Gracia A, Toft S, Dahlman-Wright K, Hedén P, Dahlman I, Wheelock CE, Arner P, Mejhert N, Gao H, Rydén M. Adipocyte Expression of SLC19A1 Links DNA Hypermethylation to Adipose Tissue Inflammation and Insulin Resistance. J Clin Endocrinol Metab. 2018 Feb 1.
https://doi.org/10.1210/jc.2017-01382