FoxO1 in dopaminergic neurons regulates energy homeostasis and targets tyrosine hydroxylase

Abstract

Dopaminergic (DA) neurons are involved in the integration of neuronal and hormonal signals to regulate food consumption and energy balance. Forkhead transcriptional factor O1 (FoxO1) in the hypothalamus plays a crucial role in mediation of leptin and insulin function. However, the homoeostatic role of FoxO1 in DA system has not been investigated. Here we report that FoxO1 is highly expressed in DA neurons and mice lacking FoxO1 specifically in the DA neurons (FoxO1 KODAT) show markedly increased energy expenditure and interscapular brown adipose tissue (iBAT) thermogenesis accompanied by reduced fat mass and improved glucose/insulin homoeostasis. Moreover, FoxO1 KODAT mice exhibit an increased sucrose preference in concomitance with higher dopamine and norepinephrine levels. Finally, we found that FoxO1 directly targets and negatively regulates tyrosine hydroxylase (TH) expression, the rate-limiting enzyme of the catecholamine synthesis, delineating a mechanism for the KO phenotypes. Collectively, these results suggest that FoxO1 in DA neurons is an important transcriptional factor that directs the coordinated control of energy balance, thermogenesis and glucose homoeostasis.

Estrogen Signaling in Arcuate Kiss1 Neurons Suppresses a Sex-Dependent Circuit That Promotes Dense Strong Bones in Female Mice

“…Although Kiss1 neurons appear to be sufficient in mediating the central effects of ERa on bone, defining the contribution of DAT ARC neurons to this circuit awaits development of better genetic tools. Unfortunately, consistent with earlier studies showing limited efficacy of Slc6a3-Cre in the hypothalamus 49,50 , ERa remained intact in DAT+ ARC neurons in Esr1 Slc6a3Cre mice (data not shown). Because dopaminergic ARC neurons are modulated by Kiss1 51 , it will be of interest to determine how these two estrogen responsive ARC modules communicate to coordinate female bone and energy metabolism before, during, and after pregnancy.…”

Loss of SATB1 Induces p21-Dependent Cellular Senescence in Post-mitotic Dopaminergic Neurons

“…During the process of p21-mediated cellular senescence, transcription factors such as SMAD3 or FOXO1 increase CDKN1A gene expression (Martinez-Zamudio et al, 2017). Both SMAD3 and FOXO1 play crucial regulatory roles in DA neurons (Doan et al, 2016;Tapia-Gonzá lez et al, 2011). Correspondingly, their expression is higher in DA compared with CTX neurons ( Figure S6K).…”

FOXO in Neural Cells and Diseases of the Nervous System

“…When challenged with glucose FOXO1 sympathetic knockout mice exhibited enhanced insulin secretion which may explain their enhanced glucose clearance. FOXO1 has also been specifically knocked out in dopaminergic neurons using DAT-IRES-Cre (Doan et al, 2016). These mice demonstrated resistance to weight gain, improved glucose clearance, increased serum levels of norepinephrine, increased midbrain levels of dopamine and increased interscapular brown adipose tissue thermogenesis.…”

“…Of the four mammalian homologs FOXO1, 3 and 6 are the ones most implicated in neuronal function (Hoekman et al, 2006). FOXOs have roles ranging from neural progenitor cell maintenance, reactive oxygen species (ROS) suppression, induction of apoptosis, promotion of survival by engagement of autophagy and regulation of catecholamine biosynthesis (Paik et al, 2009; Renault et al, 2009; Gilley, Coffer & Ham, 2003; Xu, Das, Reilly & Davis, 2011; Kajimura, Paone, Mann & Karsenty, 2014; Doan et al, 2016). The response of FOXOs to a given input (i.e.…”