Thyroid hormone acts independently of the thyroid hormone receptor beta in hepatocytes to improve systemic insulin sensitivity.

backgroundInsulin resistance plays a key role in the development of type 2 diabetes and predates the development of frank hyperglycemia. Thyroid hormone (TH) signaling plays a critical role in glucose homeostasis, as both hyperthyroidism and hypothyroidism have been linked to the development of insulin resistance and diabetes. The mechanism behind the effects of TH action on insulin sensitivity is incompletely understood, but the liver is thought to play a key role. Indeed, resmetirom, a selective thyroid hormone receptor beta (THRβ) agonist, has recently been approved for treatment of liver fibrosis, and more THRβ agonists are currently in phase 2-3 clinical trials for use in metabolic dysfunction-associated fatty liver disease. As insulin resistance is closely associated with this disease, it is crucial that we understand the role of hepatic THRβ in glucose homeostasis. Thus, we hypothesized that TH, acting via the THRβ, is a key regulator of hepatic glucose metabolism.

methodsIn wild-type (WT) and liver-specific THRβ knock-out (L-TRBKO) mice we analyzed the effect of changes in thyroid status and diet on glucose homeostasis and insulin signaling. Mice were assessed under basal conditions on a chow fed diet, under hypothyroid conditions using a propylthiouracil/low iodine diet with and without T3 treatment and following a high-fat diet. We measured glucose tolerance, hepatic insulin signaling, liver histology, energy expenditure and skeletal muscle metabolism. In high-fat diet fed WT and L-TRBKO mice we addidionally analyzed the effect of a single i.p. injection of T3. Finally we studied insulin signaling in human induced pluripotent stem cells differentiated to hepatocytes (iHeps) both with and without THRβ expression.

resultsIn contrast to our hypothesis, we found that insulin signaling in mice was not impacted by the selective deletion of THRβ only in hepatocytes. Both WT and L-TRBKO mice have similar glucose homeostasis under basal conditions and developed hyperglycemia on a high-fat diet. Further, a single dose of T3 administered to high-fat diet fed insulin-resistant mice improves insulin sensitivity to the levels of control chow-fed mice in both WT and L-TRBKO male mice. This single dose of T3 also increased glucose transporter expression in skeletal muscle. In iHeps, THRβ1 was not required to activate insulin signaling, and T3 treatment did not affect insulin signaling.

conclusionT3 signaling impacts glucose homeostasis independently of its actions through the THRβ1 in hepatocytes in both a murine and human model.