Exogenous Thyroxine Increases Cardiac AS160 Phosphorylation in Insulin Resistant OLETF Rats

Abstract

Thyroxine (T4) is the most abundant thyroid hormone secreted by thyroid gland and contributes to glucose metabolism via both insulin and non-insulin dependent pathways. Akt substrate 160 (AS160) is a Rab-GDP activating protein and a downstream effector of protein kinase B (Akt) required for glucose transport and upregulation of GLUT4 activating vesicle (GSV). The phosphorylation of AS160 (p-AS160) is required for the regulation of GLUT4 translocation to the membrane. It is also involved in insulin-mediated traffcking of GLUT4 in skeletal muscle and adipose tissues. The accumulation of AS160 has also been implicated in promoting cardiac hypertrophy, which is commonly associated with the metabolic syndrome (MetS). This study explores how thyroid hormones can affect the phosphorylation status of cardiac AS160 during insulin resistance. Under normal conditions, AS160 is phosphorylated by Akt to upregulate GSV, allowing glucose to cross the cell membrane through GLUT4. We hypothesize that exogenous T4 increases cardiac phosphorylation of AS160 expression during insulin resistance. Insulin resistant, Otsuka Long Evans Tokushima Fatty (OLETF) rats were used to assess the effects of exogenous thyroxine (T4) on cardiac p-AS160. Rats were assigned to four groups: (1) lean, Long Evans Tokushima Otsuka (LETO; n=6), (2) LETO + T4 (8 μg/100g BM/d × 5 wks; n=7), (3) untreated OLETF (n=6), and (4) OLETF + T4 (n=7). Exogenous T4 did not significantly alter native AS160 protein expression among all four groups. However, p-AS160 was reduced in the non-treated OLETF group by 61% (p<0.01) compared to healthy LETO control group. Exogenous T4 increased p-AS160 by 16% (p<0.05) compared to non-treated OLETF group and by 36% (p<0.05) in treated LETO compared to control LETO group. We have previously demonstrated that exogenous T4 increased the translocation of cardiac GLUT4 and the present findings suggest that this increased translocation is mediated by activation of AS160, resulting in improved glucose metabolism in the heart during insulin resistance. American Heart Association. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.