Inflammasome activation as a link between obesity and thyroid disorders: Implications for an integrated clinical management

Abstract

Obesity is strongly associated with chronic low-grade inflammation. Obese patients have an increased risk to develop thyroid autoimmunity and to became hypothyroid, suggesting a pathogenetic link between obesity, inflammation and autoimmunity. Moreover, type 2 diabetes and dyslipidemia, also characterized by low-grade inflammation, were recently associated with more aggressive forms of Graves’ ophthalmopathy. The association between obesity and autoimmune thyroid disorders may also go in the opposite direction, as treating autoimmune hyper and hypothyroidism can lead to weight gain. In addition, restoration of euthyroidism by L-T4 replacement therapy is more challenging in obese athyreotic patients, as it is difficult to maintain thyrotropin stimulation hormone (TSH) values within the normal range. Intriguingly, pro-inflammatory cytokines decrease in obese patients after bariatric surgery along with TSH levels. Moreover, the risk of thyroid cancer is increased in patients with thyroid autoimmune disorders, and is also related to the degree of obesity and inflammation. Molecular studies have shown a relationship between the low-grade inflammation of obesity and the activity of intracellular multiprotein complexes typical of immune cells (inflammasomes). We will now highlight some clinical implications of inflammasome activation in the relationship between obesity and thyroid disease.

Obesity and recurrent miscarriage: The interconnections between adipose tissue and the immune system

“…Systemic inflammation induced by obesity combined with insulin resistance are responsible for increased production of reactive oxygen radical species (ROS) that activate the inflammasome complex in different tissues. [43][44][45] D'Ippolito et al observed that the endometrium of women with a history of RM has a higher expression of inflammasome NALP-3 and ASC protein, an increased activation of caspase-1, and increased levels of IL-1β and IL-18 compared to control. 46 Obesity and an unhealthy diet can induce changes in the gut microbiome with an impact on the innate immune system, such as an increase in the Th1/Th17 response and a reduction in Treg lymphocytes.…”

“…Obesity is recognized as a chronic low‐grade inflammatory disease, being responsible for triggering an imbalance of the immune response in the adipose tissue and systemically. Systemic inflammation induced by obesity combined with insulin resistance are responsible for increased production of reactive oxygen radical species (ROS) that activate the inflammasome complex in different tissues 43–45 . D'Ippolito et al.…”

Thyroid Eye Disease and Its Association With Diabetes Mellitus: A Major Review

“…The concept of orbital inflammation connects delicate mechanisms of the disease spectrum where at one end lies the autoimmune reaction typically associated with GD or HT and at the other newer concept of inflammasome activation along with a cohort of metabolic factors. 32,33 The pathogenesis of TED involves hereditary factors, environmental factors, thyroid-stimulating hormone receptor (TSHR) antibodies, and type 1 insulin-like growth factor receptors (IGF-1R). 32 Smoking is a common underlying environmental factor in TED pathogenesis.…”

“…Thyroxine hormone also increases catecholamines that stimulate hepatic gluconeogenesis, with active lipolysis and increased levels of free fatty acids. 33 The marked hepatic glucose release is responsible for IR, hyperinsulinemia, and low glucose tolerance. 42 IR causes hyperinsulinemia, which causes decreased availability of IGF binding proteins, increasing the bioavailability of IGF1.…”

“…In addition, TSH and IGF-1R receptors are overexpressed in preadipocytes and fibroblasts of orbit. 33…”