Endocrine Abstracts

Obesity is a multifactorial disease in which environmental conditions and genetic factors play an important pathogenic role [1]. Interestingly, some of these obesogenic environmental and genetic conditions are shared with neurodegenerative diseases (NDD). The common biological mechanisms involved in obesity and NDD are insulin resistance, pro-inflammatory cytokines, and oxidative damage, in turn leading to cognitive dysfunction or cell death. In this aspect, a poly-pharmacological drug approach which targets multiple pathological pathways at the same time, should provide the best way to treat such complex networked diseases. Activation of thyroid hormone receptor β (THRβ) has shown beneficial effects on metabolic and neurologic alterations, without cardiotoxicity. Therefore, selective TRβ-agonists might represent promising multitarget agents for the treatment of interlinked diseases such as obesity and NDD. Recent investigations, allowed the selection of the novel thyromimetic TG68 as a very powerful lipid lowering, transthyretin (TTR) protein stabilizer, and antiamyloid agent [2,3]. With the aim to expand our knowledge on the multitarget potential of this novel TH analog, we investigated the effects on lipid metabolism, neuroinflammation and behavior produced by chronic administration of TG68 in high fat diet (HFD) obese and insulin resistant mice, a well established model of obesity/neuroinflammation neurotoxicity. Even though still at a preliminary level, the results of our study provided evidence that in HFD mice (24 CD-1 male mice exposed to HFD C1090-60 for 10 weeks), treatment with TG68 (10 mg/kg/day; 7days; in drinking water) significantly (P=0.02) reduced anxiety, as detected by performing stretch-attend posture (SAP) tests, while inducing a 20% body weight loss and a significant (P<0.05) decrease in blood lipid levels, including cholesterol and triglicerides. A significant (P<0.01) anti-inflammatory activity in LPS/THFa stimulated human microglial cells (HMC3) was also observed after treatment with 10 µM TG68, providing support to the ability of this novel THRβ-selective thyromimetic to efficiently modulate multiple pathological pathways involved in complex networked diseases, such as obesity and NDD.

References: [1] Flores-Dorantes M.T. et al., Front. Neurosci. 14:863. doi: 10.3389/fnins.2020.00863 [2] Saponaro F. et al., Front Med (Lausanne). 2020;7:331. doi: 10.3389/fmed.2020.00331 [3] Kim B. et al., Int J Mol Sci. 2021;22(7):3488. doi: 10.3390/ijms22073488