[show abstract][hide abstract] 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.
The Journal of clinical investigation 06/2012; 122(7):2578-89. · 15.39 Impact Factor
[show abstract][hide abstract] ABSTRACT: The transcription factor steroidogenic factor 1 (SF-1) is exclusively expressed in the brain in the ventral medial hypothalamic nucleus (VMH) and is required for the development of this nucleus. However, the physiological importance of transcriptional programs regulated by SF-1 in the VMH is not well defined. To delineate the functional significance of SF-1 itself in the brain, we generated pre- and postnatal VMH-specific SF-1 KO mice. Both models of VMH-specific SF-1 KO were susceptible to high fat diet-induced obesity and displayed impaired thermogenesis after acute exposure to high fat diet. Furthermore, VMH-specific SF-1 KO mice showed significantly decreased LepR expression specifically in the VMH, leading to leptin resistance. Collectively, these results indicate that SF-1 directs transcriptional programs in the hypothalamus relevant to coordinated control of energy homeostasis, especially after excess caloric intake.
Proceedings of the National Academy of Sciences 06/2011; 108(26):10673-8. · 9.74 Impact Factor
[show abstract][hide abstract] ABSTRACT: The ventral medial hypothalamic nucleus (VMH) regulates food intake and body weight homeostasis. The nuclear receptor NR5A1 (steroidogenic factor 1; SF-1) is a transcription factor whose expression is highly restricted in the VMH and is required for the development of the nucleus. Neurons expressing SF-1 in the VMH have emerged as playing important roles in the regulation of body weight and energy homeostasis. Many of these studies have used site-specific gene KO approaches, providing insights into the molecular mechanisms underlying the regulation of energy homeostasis by the SF-1 neurons of the VMH. In this brief review, we will focus on recent studies defining the molecular mechanisms regulating energy homeostasis and body weight in the VMH, particularly stressing the SF-1 expressing neurons.
Molecular and Cellular Endocrinology 11/2010; 336(1-2):219-23. · 4.04 Impact Factor
[show abstract][hide abstract] ABSTRACT: The ventromedial hypothalamic nucleus (VMH) regulates a variety of homeostatic processes including female sexual behavior and reproduction. In the current study, we assessed the roles of steroidogenic factor 1 (SF-1) on reproductive function in the VMH using central nervous system-specific SF-1 knockout (SF-1 KO(nCre;F/-)) mice. Here we show that SF-1 KO(nCre;F/-) females exhibited marked impairment in female reproduction. Although male mice appeared to be normal in all aspects studied, including sexual behavior, SF-1 KO(nCre;F/-) females showed infertility or subfertility. Although adult SF-1 KO(nCre;F/-) females showed decreased or lacked corpora lutea, exogenous administration of gonadotropins induced the formation of multiple corpora lutea and induced normal ovulation, demonstrating that the ovaries are functionally intact. In addition, SF-1 KO(nCre;F/-) females stimulated with a synthetic GnRH agonist after priming exhibited markedly reduced LH secretion compared with wild-type littermates, arguing that disorganization in and around the VMH caused by SF-1 ablation interferes with the GnRH priming process or gonadotrope LH capacity. Furthermore, the SF-1 KO(nCre;F/-) females primed with estrogen benzoate and progesterone failed to induce steroid receptors around the VMH, consistent with impaired lordosis behavior in the SF-1 KO(nCre;F/-) females. Collectively, our results highlight that SF-1 in the VMH plays crucial roles in regulation of female reproductive function, presumably by organizing a precise neuronal connection and communication in and around the VMH.
[show abstract][hide abstract] ABSTRACT: Steroidogenic factor 1 (SF-1) is a nuclear receptor that plays important roles in the hypothalamus-pituitary-steroidogenic organ axis. Global knockout studies in mice revealed the essential in vivo roles of SF-1 in the ventromedial hypothalamic (VMH) nucleus, adrenal glands, and gonads. One limitation of global SF-1 knockout mice is their early postnatal death from adrenocortical insufficiency. To overcome limitations of the global knockout mice and to delineate the roles of SF-1 in the brain, we used Cre/loxP recombination technology to genetically ablate SF-1 specifically in the central nervous system (CNS). Mice with CNS-specific knockout of SF-1 mediated by nestin-Cre showed increased anxiety-like behavior, revealing a crucial role of SF-1 in a complex behavioral phenotype. Our studies with CNS-specific SF-1 KO mice also defined roles of SF-1 in regulating the VMH expression of target genes implicated in anxiety and energy homeostasis. Therefore, this review will focus on our recent studies defining the functional roles of SF-1 in the VMH linked to anxiety and energy homeostasis.
Molecular and Cellular Endocrinology 11/2008; 300(1-2):132-6. · 4.04 Impact Factor
[show abstract][hide abstract] ABSTRACT: Steroidogenic factor 1 (SF-1) plays key roles in adrenal and gonadal development, expression of pituitary gonadotropins, and development of the ventromedial hypothalamic nucleus (VMH). If kept alive by adrenal transplants, global knockout (KO) mice lacking SF-1 exhibit delayed-onset obesity and decreased locomotor activity. To define specific roles of SF-1 in the VMH, we used the Cre-loxP system to inactivate SF-1 in a central nervous system (CNS)-specific manner. These mice largely recapitulated the VMH structural defect seen in mice lacking SF-1 in all tissues. In multiple behavioral tests, mice with CNS-specific KO of SF-1 had significantly more anxiety-like behavior than wild-type littermates. The CNS-specific SF-1 KO mice had diminished expression or altered distribution in the mediobasal hypothalamus of several genes whose expression has been linked to stress and anxiety-like behavior, including brain-derived neurotrophic factor, the type 2 receptor for CRH (Crhr2), and Ucn 3. Moreover, transfection and EMSAs support a direct role of SF-1 in Crhr2 regulation. These findings reveal important roles of SF-1 in the hypothalamic expression of key regulators of anxiety-like behavior, providing a plausible molecular basis for the behavioral effect of CNS-specific KO of this nuclear receptor.
[show abstract][hide abstract] ABSTRACT: The nuclear receptor steroidogenic factor 1 (SF-1) plays essential roles in the development and function of the ventromedial hypothalamic nucleus (VMH). Considerable evidence links the VMH and SF-1 with the regulation of energy homeostasis. Here, we demonstrate that SF-1 colocalizes in VMH neurons with the cannabinoid receptor 1 (CB1R) and that a specific CB1R agonist modulates electrical activity of SF-1 neurons in hypothalamic slice preparations. We further show that SF-1 directly regulates CB1R gene expression via a SF-1-responsive element at -101 in its 5'-flanking region. Finally, we show that knockout mice with selective inactivation of SF-1 in the brain have decreased expression of CB1R in the region of the VMH and exhibit a blunted response to systemically administered CB1R agonists. These studies suggest that SF-1 directly regulates the expression of CB1R, which has been implicated in the regulation of energy homeostasis and anxiety-like behavior.
[show abstract][hide abstract] ABSTRACT: Chronic L-dopa treatment of Parkinson's disease (PD) often leads to debilitating involuntary movements, termed L-dopa-induced dyskinesia (LID), mediated by dopamine (DA) receptors. RGS9-2 is a GTPase accelerating protein that inhibits DA D2 receptor-activated G proteins. Herein, we assess the functional role of RGS9-2 on LID. In monkeys, Western blot analysis of striatal extracts shows that RGS9-2 levels are not altered by MPTP-induced DA denervation and/or chronic L-dopa administration. In MPTP monkeys with LID, striatal RGS9-2 overexpression--achieved by viral vector injection into the striatum--diminishes the involuntary movement intensity without lessening the anti-parkinsonian effects of the D1/D2 receptor agonist L-dopa. In contrasts, in these animals, striatal RGS9-2 overexpression diminishes both the involuntary movement intensity and the anti-parkinsonian effects of the D2/D3 receptor agonist ropinirole. In unilaterally 6-OHDA-lesioned rats with LID, we show that the time course of viral vector-mediated striatal RGS9-2 overexpression parallels the time course of improvement of L-dopa-induced involuntary movements. We also find that unilateral 6-OHDA-lesioned RGS9-/- mice are more susceptible to L-dopa-induced involuntary movements than unilateral 6-OHDA-lesioned RGS9+/+ mice, albeit the rotational behavior--taken as an index of the anti-parkinsonian response--is similar between the two groups of mice. Together, these findings suggest that RGS9-2 plays a pivotal role in LID pathophysiology. However, the findings also suggest that increasing RGS9-2 expression and/or function in PD patients may only be a suitable therapeutic strategy to control involuntary movements induced by nonselective DA agonist such as L-dopa.
Journal of Neuroscience 01/2008; 27(52):14338-48. · 6.91 Impact Factor
[show abstract][hide abstract] ABSTRACT: To establish genetic tools for conditional gene deletion in mouse neurons, we generated two independent neuron-specific enolase (Nse)-cre transgenic lines. The transgenic line termed Nse-cre(CK1) showed cre activity in most neuronal regions in the nervous system, while the Nse-cre(CK2) line exhibited a unique cre activity that has not been reported in other cre transgenic lines. Nse-cre(CK2) cre activity was detectable from embryogenesis and mostly restricted to neuronal regions. In postnatal brain, the Nse-cre(CK2) line exhibited cre activity limited to differentiated neurons in the cerebral cortex and hippocampus. Cre activity was assayed in several internal organs and sporadic activity was limited to the kidney and testis. We conclude that these cre lines will be useful for studying loss of gene function in specific neuronal populations.