Thyroid Hormone Regulates Hepatic Expression of Fibroblast Growth Factor 21 in a PPARα-dependent Manner

Abstract

Thyroid hormone has profound and diverse effects on liver metabolism. Here we show that tri-iodothyronine (T3) treatment in mice acutely and specifically induces hepatic expression of the metabolic regulator fibroblast growth factor 21 (FGF21). Mice treated with T3 showed a dose-dependent increase in hepatic FGF21 expression with significant induction at doses as low as 100 g/kg. Time course studies determined that induction is seen as early as 4 h after treatment with a further increase in expression at 6 h after injection. As FGF21 expression is downstream of the nuclear receptor peroxisome proliferatoractivated receptor ␣ (PPAR␣), we treated PPAR␣ knock-out mice with T3 and found no increase in expression, indicating that hepatic regulation of FGF21 by T3 in liver is via a PPAR␣-dependent mechanism. In contrast, in white adipose tissue, FGF21 expression was suppressed by T3 treatment, with other T3 targets unaffected. In cell culture studies with an FGF21 reporter construct, we determined that three transcription factors are required for induction of FGF21 expression: thyroid hormone receptor ␤ (TR␤), retinoid X receptor (RXR), and PPAR␣. These findings indicate a novel regulatory pathway whereby T3 positively regulates hepatic FGF21 expression, presenting a novel therapeutic target for diseases such as non-alcoholic fatty liver disease.The biochemical pathways mediating the metabolism of carbohydrates, lipids, and proteins are all regulated to some degree by thyroid hormone and the thyroid hormone receptors (␣ and ␤) (1, 2), which belong to the nuclear hormone receptor superfamily (1). In the liver, the ␤ isoform of the thyroid hormone receptor (TR␤) is responsible for mediating the majority of the actions of tri-iodothyronine (T3), 2 whereas in other tissues such as the heart and brown adipose tissue, the ␣ isoform (TR␣) is the main mediator of thyroid hormone effects (3, 4). FGF21 is a member of the endocrine FGF subfamily, which also includes FGF19 and FGF23, all of which circulate and have hormone-like actions (5, 6). FGF21 is known to stimulate glucose uptake in mouse 3T3-L1 adipocytes and in primary cultures of human adipocytes and can improve glucose homeostasis when administered to obese mice (6) and non-human primates (7). Transgenic mice overexpressing FGF21 in liver display improved insulin sensitivity and glucose clearance, reduced plasma triglyceride concentrations, and are resistant to weight gain when fed a high fat diet (6).Subsequent studies showed that administration of FGF21 to mice with high fat diet-induced obesity led to increased fat utilization and energy expenditure and reduced plasma glucose, insulin, serum lipid concentrations, and hepatic triglyceride concentrations (6,8). In one study, it was shown that the decrease in hepatic triglyceride concentrations was accompanied by a decrease in lipogenic gene expression (8).FGF21 expression is known to be downstream of the nuclear receptor PPAR␣, which itself plays a significant role in lipid oxidation. FGF21 is physiologically induced u...

Mouse Betaine-Homocysteine S-Methyltransferase Deficiency Reduces Body Fat via Increasing Energy Expenditure and Impairing Lipid Synthesis and Enhancing Glucose Oxidation in White Adipose Tissue

“…Thyroid hormone induced cholesterol 7␣-hydroxylase (CYP7A1), the rate-limiting enzyme in bile acid synthesis from cholesterol (44,45), and there was an inverse relationship between thyroid hormone level and serum cholesterol (46). Thyroid hormone also induced hepatic Fgf21 expression in mice (47). Bile acids enhanced the conversion of T 4 to T 3 within tissues, resulting in increased energy expenditure in mice (21).…”

FGF21 Maintains Glucose Homeostasis by Mediating the Cross Talk Between Liver and Brain During Prolonged Fasting

“…FGF21 has also been shown to act as a key downstream effector of PPARa, mediating several metabolic adaptation responses to starvation, including hepatic fatty acid oxidation, ketogenesis, and growth hormone resistance (1,2,7). In addition, FGF21 is implicated in hepatic gluconeogenesis, although it remains controversial whether hepatocytes are a direct action site of FGF21 (8,9). There is an obvious dichotomy between the effects of endogenous FGF21 and pharmacological actions of the recombinant peptide with respect to hepatic metabolism (4,6,9).…”

Development of a Novel Long-Acting Antidiabetic FGF21 Mimetic by Targeted Conjugation to a Scaffold Antibody

“…FGF21 is a secreted protein abundantly expressed in liver, pancreas, adipose tissue, and skeletal muscle (Beenken and Mohammadi, 2009). Its expression is induced by fasting, ketogenic diet, peroxisome proliferatoractivated receptor a (PPARa) and g agonists (Badman et al, 2007;Inagaki et al, 2007;Muise et al, 2008), thyroid hormone (Adams et al, 2010), and thermogenic activation (Chartoumpekis et al, 2011;Hondares et al, 2011). FGF21 signals through an FGF receptor (FGFR)/bKlotho receptor complex, leading to biologic effects in liver, adipose tissue, and pancreas.…”