| Subclinical hypothyroidism, a condition characterized by elevated thyroid stimulating hormone (TSH) levels, is a risk factor for cardiovascular disease (CVD). Adipose tissue contributes significantly to the circulating levels of interleukin-6 (IL-6), an atherogenic and pro-inflammatory cytokine. Adipose cells express TSH receptors and are responsive to TSH. The overall hypothesis of my Ph.D. project is that TSH acts on adipose cells to stimulate the release of IL-6.;I first showed that in 3T3-Ll cells, TSH induces IL-6 release from differentiated adipocytes, but not from precursor cells (preadipocytes). Differentiated 3T3-Ll adipocytes increased IL-6 release in response to TSH via activation of the cAMP-dependent protein kinase (PKA) pathway. Following analysis of the TSH effect on 3T3-Ll adipose cell line, I proceeded to examine the effect of TSH on human primary adipose cells.;For the abdominal subcutaneous depot, I found that preadipocytes did not release IL-6 in response to TSH, but their differentiated adipocytes counterparts were TSH-responsive. In contrast, for the omental depot, I showed that neither preadipocytes nor the differentiated adipocytes increased IL-6 release in response to TSH.;Signaling studies on the human abdominal subcutaneous differentiated adipocytes revealed that TSH activates the nuclear factor kappa-B pathway to induce IL-6 release. Furthermore, PKA activation by TSH does not result in increased NF-kappaB signaling.;In this thesis, I studied TSH-induced IL-6 release and the related signaling mechanisms using the mouse 3T3-Ll adipose cell line. I also evaluated human primary adipose cells, and examined the influence of stage of differentiation and fat depot localization on the effect of TSH on IL-6 release.;To demonstrate that TSH could act in an extra-thyroidal fashion in vivo, I analyzed serum IL-6levels in thyroidectomized patients with a past history of thyroid cancer undergoing recombinant human (rh)TSH administration. Injection with rhTSH increased IL-6 serum levels, supporting the notion that TSH has extra-thyroidal actions in vivo.;In summary, this thesis demonstrates that TSH is capable of regulating inflammatory responses on adipose cells and of elevating IL-6, a biomarker of inflammation, in the circulation of thyroidectomized patients. |
