Adipose Tissue and FoxO1: Bridging Physiology and Mechanisms

Abstract

Forkhead box O class proteins (FoxOs) are expressed nearly in all tissues and are involved in different functions such as energy metabolism, redox homeostasis, differentiation, and cell cycle arrest. The plasticity of FoxOs is demonstrated by post-translational modifications that determine diverse levels of transcriptional regulations also controlled by their subcellular localization. Among the different members of the FoxO family, we will focus on FoxO1 in adipose tissue, where it is abundantly expressed and is involved in differentiation and transdifferentiation processes. The capability of FoxO1 to respond differently in dependence of adipose tissue subtype underlines the specific involvement of the transcription factor in energy metabolism and the “browning” process of adipocytes. FoxO1 can localize to nuclear, cytoplasm, and mitochondrial compartments of adipocytes responding to different availability of nutrients and source of reactive oxygen species (ROS). Specifically, fasted state produced-ROS enhance the nuclear activity of FoxO1, triggering the transcription of lipid catabolism and antioxidant response genes. The enhancement of lipid catabolism, in combination with ROS buffering, allows systemic energetic homeostasis and metabolic adaptation of white/beige adipocytes. On the contrary, a fed state induces FoxO1 to accumulate in the cytoplasm, but also in the mitochondria where it affects mitochondrial DNA gene expression. The importance of ROS-mediated signaling in FoxO1 subcellular localization and retrograde communication will be discussed, highlighting key aspects of FoxO1 multifaceted regulation in adipocytes.

MiR-144-3p Targets FoxO1 to Reduce Its Regulation of Adiponectin and Promote Adipogenesis

“…miR-144 targets FoxO1, thus reducing its expression and inhibiting its promotional effect on adiponectin, thereby alleviating the inhibitory effect of adiponectin on adipogenesis. signaling pathway inhibition, whereas, in the feeding condition the reverse is seen (Assimacopoulos-Jeannet et al, 1995;Lettieri Barbato et al, 2014;Ioannilli et al, 2020).…”

“…FoxO1 regulates the process of adipogenesis, it achieves this by acting as a regulator in insulin signaling. In detail, fasting stimulates the activation of the lipolytic pathway and promotes the breakdown of triglycerides and the releases of free fatty acids from adipose tissue, FoxO1, in this context, transcribes genes involved in lipid catabolism by signaling pathway inhibition, whereas, in the feeding condition the reverse is seen ( Assimacopoulos-Jeannet et al, 1995 ; Lettieri Barbato et al, 2014 ; Ioannilli et al, 2020 ).…”

Thermogenic Fat: Development, Physiological Function, and Therapeutic Potential

“…Several TFs and activating cofactors are shown to have negative effects on beige/brown fat formation and function including Hes1 [ 122 ], Irx3 [ 123 ], Irx5 [ 123 ], Rip140 [ 124 , 125 , 126 ], Tle3 [ 127 ], Zfp423 [ 128 , 129 ], Hoxc8 [ 130 ], Hoxc10 [ 131 ], Twist1 [ 132 ], Foxa3 [ 133 , 134 ], Foxo1 [ 135 , 136 ], Foxp1 [ 137 ], Rb [ 138 ], Src2 (Tif2), Smad3 [ 139 ], Usf1 [ 140 ], Mrtfa [ 141 ], Lxr [ 142 ], and P107 [ 143 , 144 , 145 ]. Transcriptional repressors such as Ctbp1 and Ctbp2 [ 90 , 146 ] suppress the WAT gene expression and promote the browning of WAT.…”

Exploring the Genetic Conception of Obesity via the Dual Role of FoxO

“…These findings imply that the relation between the acetylation of FoxO1 and phosphorylation is not organized, where the acetylation of FoxO1 is an upward stream of phosphorylation and the phosphorylation of FoxO1 specifically represses FoxO1’s transcriptional behavior. When FoxO1 phosphorylation is disrupted [ 55 ], adipocyte differentiation is suppressed, indicating that the phosphorylation of FoxO1 is necessary for fat cell differentiation and that adipocyte differentiation can be negatively regulated by FoxO1 dephosphorylation.…”

“…Growing research also shows that through FoxO1 [ 55 ], microRNAs (miRs) perform lipid-regulating mechanisms, which suggest that FoxO1 could be implicated in the genetic changes implicated in obesity. Elevated concentrations of acetylated/phosphorylated FoxO1 increase the function of the hypothalamic-pituitary-thyroid axis in the CNS of diet-implicated obese animals, which promotes energy consumption due to lower body weight and food intake [ 133 ].…”