Inflammation and impaired adipogenesis in human white adipose tissue

University dissertation from Stockholm : Karolinska Institutet, Dept of Medicine, Huddinge

Abstract: This thesis aimed to study inflammation and adipogenesis capacity in human subcutaneous white adipose tissue with respect to the development of obesity and associated comorbidities, including insulin resistance. Study I showed that the transcription factor, MAFB, was associated with increased adiposity and involved in regulation of TNFα-mediated inflammatory response, yet did not seem to directly influence adipogenesis or metabolism in human adipocytes. MAFB expression was upregulated during adipogenesis, and knocking down MAFB mRNA led to reduced TNFα-mediated inflammation. However, MAFB was highly expressed in white adipose tissue (WAT) macrophages, which most likely explains its association with BMI and metabolic syndrome. Study II identified increased fat cell size as a hallmark of non-obese type 2 diabetic individuals. This hypertrophic status was associated with insulin resistance, inflammation and adipose tissue lipolysis indicating fat cell size to be a marker of pathogenesis. Relative amount of pro-inflammatory macrophages (M1/M2 ratio) correlated positively with fat cell size, lipolysis and TNFα secretion. In addition, early and late adipogenesis markers correlated negatively with fat cell size, suggesting impaired production of new fat cells in WAT hypertrophy. Study III revealed that human adipocyte progenitors from subcutaneous WAT of healthy individuals consist of a single homogenous cell population. Furthermore, multiple macrophage subtypes were identified. We could not exclude that adipose progenitor subtypes might exist. However, any subtypes were not detectable by the methods employed in this study. Both findings are significant and warrant further investigation. To conclude the finding in this thesis, we defined a role for MAFB in adipose tissue inflammation, which can possibly serve as a biomarker of insulin resistance and inflammation in WAT. Fat cell size seemed to be the best predictor for insulin resistance in non-obese individuals and this appeared likely connected to impaired adipogenic capacity of WAT. However, a search for different progenitor populations bearing varied abilities to become fat cells through the use of a single-cell RNA sequencing technique was not successful as only one major population of progenitors in healthy WAT was found. This demonstrated a need for further studies in larger cohorts of individuals characterized by different metabolic statuses.

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