Endocrine Abstracts

Recent advances in drug discovery and development allowed the identification of THRβ-selective thyromimetic TG68 as a powerful lipid lowering and anti-amyloid agent. To expand our knowledge on the therapeutic potential of this novel thyromimetic, we investigated its anti-inflammatory effects in in vitro human models of neuroinflammation. Subsequently, we performed in vivo studies on high fat diet (HFD) obese/insulin resistant mice, a well-established model of obesity/neuroinflammation, to investigate the effects of TG68 on behavior, bodyweight (BW), energetic metabolism, and neuroinflammation. Pre-treatment of human microglia cells (HMC3) with TG68 (0.1, 1, and 10μM), followed by inflammatory stimulation with LPS (10μg/ml)/ TNF□- (50 ng/ml) for 24 h, resulted in a significant (P < 0.05) decrease of pro-inflammatory IL-6, and a significant increase of anti-inflammatory IL-10. It is well known that β-amyloid oligomers can activate microglia to secrete proinflammatory factors. In our experimental settings, exposure of HMC3 cells to 10 μM Aβ25-35 for 24h led to a significant (P < 0.05) increase of TNF-α and IL-6 release. In Aβ-treated cells, the pre-treatment with 10μM TG68 for 24h reduced TNF-α and IL-6 and increased IL-10 levels. Taken together, these findings suggest the potential of TG68 to prevent neuroinflammation and Aβ-induced neurotoxicity. Next, we demonstrated that in HFD-mice (CD-1 male mice; HFD C1090-60; 10 weeks), treatment with TG68 (10 mg/kg/day; 2 weeks; in drinking water) significantly (P = 0.02) reduced anxiety-like behavior in stretch-attend posture (SAP) tests, while producing a 12% BW loss and a significant (P < 0.05) decrease in blood glucose and lipids levels. Due to the observed significant differences in circulating metabolic markers, we performed qPCR on serum, adipose tissue, and hypothalamus, to assess whether TG68 administration could counteract the changes in gene expression of metabolic and inflammatory markers induced by HFD. Our analysis revealed that TG68 limited HFD-induced decrease of SIRT6, PPARγ, and ADIPOQ expression in adipose tissue, while inducing a decrease of leptin and APOD expression. An increased expression of GLUT1 and GLUT5 was also observed at the hypothalamic level. Systemic inflammation, with elevated serum levels of TNFα- and IL6 was highlighted in obese mice, associated with decreased hypothalamic expression of BDNF. Notably, chronic administration of TG68 induced a significant reduction of TNFα- and IL6 serum levels, and a significant increase of BDNF expression, further supporting its neuroprotective role. Overall, these data indicate that TG68 may represent a promising multitarget agent for the treatment of interlinked diseases such as obesity and NDD.