FOXO1 in the ventromedial hypothalamus regulates energy balance

Abstract

The transcription factor FOXO1 plays a central role in metabolic homeostasis by regulating leptin and insulin activity in many cell types, including neurons. However, the neurons mediating these effects and the identity of the molecular targets through which FOXO1 regulates metabolism remain to be defined. Here, we show that the ventral medial nucleus of the hypothalamus (VMH) is a key site of FOXO1 action. We found that mice lacking FOXO1 in steroidogenic factor 1 (SF-1) neurons of the VMH are lean due to increased energy expenditure. The mice also failed to appropriately suppress energy expenditure in response to fasting. Furthermore, these mice displayed improved glucose tolerance due to increased insulin sensitivity in skeletal muscle and heart. Gene expression profiling and sequence analysis revealed several pathways regulated by FOXO1. In addition, we identified the nuclear receptor SF-1 as a direct FOXO1 transcriptional target in the VMH. Collectively, our data suggest that the transcriptional networks modulated by FOXO1 in VMH neurons are key components in the regulation of energy balance and glucose homeostasis. IntroductionDefective regulation of energy balance results in obesity and components of metabolic syndrome, such as type 2 diabetes. Understanding the molecular and cellular mechanisms underlying the ability of the central nervous system to regulate energy balance and glucose homeostasis is an area of active investigation. Many proteins are involved in the modulation of metabolic homeostasis. This includes the transcription factor FOXO1, which has been demonstrated to regulate leptin and insulin action in the brain (1, 2). The biological significance of mammalian FOXO1 was initially reported in studies in Caenorhabditis elegans. Two independent groups identified Daf-16 (a homolog of the mammalian FOXO1) as a negative regulator of Daf2 (a homolog of the mammalian insulin receptor) signaling in C. elegans, implying that FOXO1 may play important roles in insulin signaling (3, 4). Subsequent studies using mouse models have confirmed the functional significance of FOXO1 as a critical mediator of insulin effects in many mammalian peripheral cells (1,5,6).Recently, critical metabolic roles of FOXO1 in the hypothalamus have been reported (2, 7). Both studies assessed the role of FOXO1 in melanocortin neurons in the arcuate nucleus of the hypothalamus (ARH). Specifically, they reported POMC and Agrp genes as direct targets of FOXO1. A subsequent report using POMC-specific FOXO1 KO mice demonstrated that FOXO1 plays important roles in regulation of food intake, body weight, and leptin sensitivity, partially depending on the expression of carboxypeptidase E (Cpe) (8). Furthermore, analyses of PDK1/FOXO1 pathways revealed critical roles of FOXO1 to control food intake, body length, and body weight in AGRP neurons of hypothalamus (9).FOXO1 is also highly expressed in many other hypothalamic nuclei, including the dorsomedial nucleus of the hypothalamus and the ventral medial nucleus of the hypothalamus (VMH) ...

Cognitive and autonomic determinants of energy homeostasis in obesity

“…137 SF1 neurons seem to be negatively modulated by the CB1 as its deletion in SF1 neurons reduces adiposity in mice. 142 SF1 is a direct transcriptional target of FOXO1 143 and mice with a selective deletion of Foxo1 in SF1-expressing neurons have reduced adiposity and increased energy expenditure. 143 Moreover, a subset of SF1 neurons expresses brain-derived neurotrophic factor, whose selective deletion in the VMH and adjacent DMH results in obesity.…”

Modulation of SIRT1-Foxo1 Signaling axis by Resveratrol: Implications in Skeletal Muscle Aging and Insulin Resistance

“…The concept that Foxo1 has pro-hyperglycemic properties is established based on a series of works that involve manipulations of the endogenous level and activity of Foxo1. Genetic ablation of Foxo1 in hypothalamus is known to enhance glucose uptake in gastrocnemius muscle [33]. Recent efforts have demonstrated that reducing the endogenous level of Foxo1 by knockdown approach abolished the elevation of MAPK phosphatase-3 (MKP-3), a factor known to induce transcriptional activation of gluconeogenic phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase complex (G6pase) in dexamethasone-treated hepatoma cells [34,35].…”

Ventromedial hypothalamus–specific Ptpn1 deletion exacerbates diet-induced obesity in female mice

“…Sections containing the VMH (bregma -1.20 to -2.22 mm) were analyzed by immunohistochemistry, as described (57,58). Immunostaining was performed using rabbit polyclonal pAKT (S473 D9E; 1:50; Cell Signaling Technology) and pFOXO1 (#28280, 1:50; Cell Signaling Technology) antibodies, based on previous publications (52,59). Primary antibodies were detected by using anti-rabbit IgG secondary antibodies, VECTA-STAIN Elite plus ABC kits, and NovaRed kits (Vector Laboratories Inc.).…”

“…In contrast, the obesity and decreased EE phenotype in Sf1-Ptpn1 -/-mice is consistent with several models in which genes encoding components of the insulin-signaling pathway have been deleted in SF-1 neurons. For example, deletion of Insr or Foxo1 in SF-1 neurons results in leanness (34,52). Conversely, deletion of Pten, another negative regulator of insulin signaling, results in obesity (34), similar to the effects of SF-1 deletion of Ptpn1.…”