Immunohistochemical Analysis of Intestinal and Central Nervous System Morphology in an Obese Animal Model (Danio rerio) Treated with 3,5-T2: A Possible Farm Management Practice?

SIMPLE SUMMARY: The obesity induced by overconsumption of nutrients leads to systemic inflammation and alters metabolic homeostasis by acting on central nervous system and peripheral tissues such as intestine. The 3,5-diiodo-L-thyronine (3,5-T2) is well-known for its positive role on fat mass and lipid metabolism, and at date, it is widely used as a drug for the treatment of obesity. However, the safe and effective dose as well as the possible adverse effects of this molecule have not been sufficiently explored. In this study, we analyzed the role of 3,5-T2 in regulating central and peripheral inflammation in diet-induced obese (D.I.O.) model of zebrafish. We found that 3,5-T2 sustained the intestinal alteration caused by D.I.O., as indicated by the high levels of pro-inflammatory cytokines, accompanied by a significant effect of 3,5-T2 on body weight and central inflammation in D.I.O. zebrafish. Therefore, the suggested potential use of 3,5-T2 to contrast obesity should be viewed with caution. We conclude that the zebrafish model can help to better understand the fundamental beneficial and side effects of 3,5-T2, which is of great importance to define the possible use of this metabolite of thyroid hormones as a drug in different diseases including obesity. ABSTRACT: The 3,5-diiodo-L-thyronine (3,5-T2) is an endogenous metabolite of thyroid hormones, whose administration to rodents fed high-fat diet (HFD) prevents body weight increase and reverts the expression pattern of pro-inflammatory factors associated to HFD. The diet-induced obese (D.I.O.) zebrafish (Danio rerio) has been recently used as an experimental model to investigate fundamental processes underlying central and peripheral obesity-driven inflammation. Herein, we aim to understand the role of 3,5-T2 in regulating central and peripheral inflammation in D.I.O. model of zebrafish. 3,5-T2 (10 nM and 100 nM) was administered with the obesity-inducing diet (D.I.O. with 3,5-T2) or after 4 weeks of obesity-inducing diet (D.I.O. flw 3,5-T2). 3,5-T2 significantly increased the body weight and serum triglyceride levels in D.I.O. zebrafish in both conditions. Moreover, 3,5-T2 sustained or increased inflammation in the anterior (AI) and mid (MI) intestine when administered with the obesity-inducing diet, as indicated by the immunoexpression of the inflammatory markers tumor-necrosis factor-α (TNFα), cyclooxygenase 2 (COX2), calnexin, caspase 3, and proliferating cell nuclear antigen (PCNA). On the contrary, when 3,5-T2 was administered after the obesity-inducing diet, partly reverted the intestinal alteration induced by D.I.O. In addition, brain inflammation, as indicated by the increase in the activation of microglia, was detected in D.I.O. zebrafish and D.I.O. treated with 3,5-T2. These findings reveal that the effects of 3,5-T2 on fish intestine and brain can deviate from those shown in obese mammals, opening new avenues to the investigation of the potential impact of this thyroid metabolite in different diseases including obesity.