The role of thyroid stimulating hormone receptor and novel candidate genes FAM13a and POM121c in adipocyte dysfunction

Sammanfattning: This thesis aimed to investigate the role of thyroid stimulating hormone receptors (TSHRs) in adipose tissue (AT) and their role in AT dysfunction and obesity-related metabolic complications. Furthermore, we aimed to functionally evaluate novel candidate genes associated with insulin resistance, a marker of dysfunctional adipose tissue. Study I report that in a cohort of Swedish children with obesity, thyroid stimulating hormone was associated with the degree of obesity and metabolic risk markers such as fasting serum insulin levels and blood lipids. In Study II, the TSHR in AT was functionally evaluated by investigating the effect of partially removing TSHRs from the adipocytes on body weight and body temperature, in animals on both normal and high-fat diets. Mice with reduced TSHR-expression gained weight at a faster rate than corresponding wild-type mice. Several genes central to adipogenesis and adipocyte function were down-regulated, in both white AT (WAT) and brown AT (BAT) in TSHR knockout mice. Study III. From a genome-wide association study (GWAS) meta-analysis which identified SNPs for fasting insulin, we identified FAM13A and POM121C as novel candidate genes for obesity-related insulin resistance. Using expression quantitative trait (eQTL) analysis of SNPs associated with fasting insulin, we identified candidate genes for disease. Functional analysis of the candidate genes using siRNA knockdown in human mesenchymal stem cells revealed them to be important for lipolysis and adipogenesis and they might therefore be involved in the genetic control of insulin sensitivity. Study IV, report that expression of the TSHR in human WAT is affected by weight change. We also report that TSHR-expression in WAT is associated with the expression of genes central to adipocyte functions such as lipolysis and insulin sensitivity. The results revealed that, independent of BMI, individuals with higher TSHR expression had a lower basal lipolysis rate and higher hormone stimulated lipolysis, suggesting that TSHRs in human WAT are involved in the regulation of adipocyte metabolism. In summary, a reduction of TSHR led to dysfunctional AT regarding the regulation of adipocyte metabolism and adipogenesis. Our findings implicate that TSHRs have a regulatory role in both WAT and BAT, and thus having a role in the regulation of whole-body energy homeostasis. Furthermore, we identified two novel genes with potential regulatory roles in adipocyte lipolysis and adipogenesis, and might thereby be involved in the genetic control of systemic insulin sensitivity.