A combined docosahexaenoic acid–thyroid hormone protocol upregulates rat liver β-Klotho expression and downstream components of FGF21 signaling as a potential novel approach to metabolic stress conditions

Abstract

Liver preconditioning by a docosahexaenoic acid (DHA) and triiodothyronine (T₃) combined protocol underlies peroxisome-proliferator activated receptor α (PPARα)-fibroblast growth factor 21 (FGF21) upregulation, the study of the regulatory mechanisms involved being the aim of this work. Combined DHA (daily doses of 300 mg kg⁻¹ for 3 days)–T₃ (0.05 mg kg⁻¹ at the fourth day) administration elicited higher levels of liver DHA and serum T₃, with enhanced hepatic nuclear/cytosolic PPARα ratios, upregulation of FGF21 and β-Klotho expression, and a small reduction in that of FGF receptor 1 (FGFR1), compared with the respective controls. Concomitantly, the components of the FGF21 cascade extracellular-signal-regulated kinase 1/2 (ERK1/2), FGF receptor substrate 2α (FRS2α), cFos, ribosomal S6 kinase 1 (RSK1), liver kinase B1 (LKB1), and AMP-activated protein kinase (AMPK) were activated. The upregulation of liver PPARα-FGF21-AMPK signaling by the combined DHA–T₃ protocol resulted in values significantly higher than those elicited by the addition of the data obtained for DHA and T₃ alone. It is concluded that combined DHA–T₃ supplementation achieves synergistic effects on liver PPARα-FGF21-AMPK signaling, which may result in significant metabolic changes associated with energy expenditure that are of importance in the treatment of obesity and other metabolic disorders.