FoxO1 as a tissue-specific therapeutic target for type 2 diabetes

Abstract

Forkhead box O (FoxO) proteins are transcription factors that mediate many aspects of physiology and thus have been targeted as therapeutics for several diseases including metabolic disorders such as type 2 diabetes mellitus (T2D). The role of FoxO1 in metabolism has been well studied, but recently FoxO1’s potential for diabetes prevention and therapy has been debated. For example, studies have shown that increased FoxO1 activity in certain tissue types contributes to T2D pathology, symptoms, and comorbidities, yet in other tissue types elevated FoxO1 has been reported to alleviate symptoms associated with diabetes. Furthermore, studies have reported opposite effects of active FoxO1 in the same tissue type. For example, in the liver, FoxO1 contributes to T2D by increasing hepatic glucose production. However, FoxO1 has been shown to either increase or decrease hepatic lipogenesis as well as adipogenesis in white adipose tissue. In skeletal muscle, FoxO1 reduces glucose uptake and oxidation, promotes lipid uptake and oxidation, and increases muscle atrophy. While many studies show that FoxO1 lowers pancreatic insulin production and secretion, others show the opposite, especially in response to oxidative stress and inflammation. Elevated FoxO1 in the hypothalamus increases the risk of developing T2D. However, increased FoxO1 may mitigate Alzheimer’s disease, a neurodegenerative disease strongly associated with T2D. Conversely, accumulating evidence implicates increased FoxO1 with Parkinson’s disease pathogenesis. Here we review FoxO1’s actions in T2D conditions in metabolic tissues that abundantly express FoxO1 and highlight some of the current studies targeting FoxO1 for T2D treatment.

Roles of heat shock protein A12A in the development of diabetic cardiomyopathy

“…Evidence has demonstrated an involvement of Akt/FOXO1 signaling in the pathogenesis of diabetic complications, including DCM. 32 , 33 FOXO1 is one of four mammalian isoforms of the FOXO transcription factor family. When localizing in the nucleus, FOXO1 has the ability to regulate the transcription of its target genes including the proapoptotic genes.…”

Epigenetic modifications in obesity‐associated diseases

“…The upregulation of circ LRP6 in damaged β cells leads to increased apoptosis, decreased insulin release, and induction of oxidative stress, exacerbating T2D by targeting the miR‐9‐5p/protein N‐arginine methyltransferase‐1 (PRMT1) signaling pathway 194 . Forkhead box O1 (FOXO1) is a negative regulator of insulin signal and plays an important role in the regulation of blood glucose 195 . Oleic acid can promote the activation of circ HIPK3, leading to increased fat deposition and IR by sponging miR‐192‐5p and upregulating FOXO1 196 …”

“…194 Forkhead box O1 (FOXO1) is a negative regulator of insulin signal and plays an important role in the regulation of blood glucose. 195 Oleic acid can promote the activation of circ HIPK3, leading to increased fat deposition and IR by sponging miR-192-5p and upregulating FOXO1. 196 Due to their tissue specificity and conservation, circR-NAs can serve as potential biomarkers for diagnosing coronary artery disease.…”

Post-Translational Modifications and Diabetes

“…Forkhead box protein O1 (FoxO1) is a transcription factor that has been implicated in metabolism regulation and T2D pathology [ 84 ]. Specifically, insulin-promoted PI3K/AKT activation is known to phosphorylate FoxO1 and enhance its cytoplasmic retention [ 85 , 86 ].…”

“…Specifically, insulin-promoted PI3K/AKT activation is known to phosphorylate FoxO1 and enhance its cytoplasmic retention [ 85 , 86 ]. On the contrary, insulin resistance compromises PI3K/AKT signaling to enhance FoxO1 nuclear retention and transcriptional activity [ 84 ]. The phosphorylation status of FoxO1 is also under the control of progestin and adipoQ receptor 3 (PAQR3), a Golgi membrane protein [ 51 ].…”