Immortalized neurons for the study of hypothalamic function

Dalvi, Prasad S.; Nazarians-Armavil, Anaies; Tung, Stephanie; Belsham, Denise D.

doi:10.1152/ajpregu.00649.2010

Cited by 39 publications

(30 citation statements)

References 263 publications

(306 reference statements)

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“…9). Such a decrease in cAMP production per mg of protein (ϳ25%) was also observed in the untransfected N2A cells and in immortalized hypothalamic N-42 and GT1-7 neurons, which express endogenous MC4R (54). These experiments show that reduced cell cholesterol leads over time to a net loss of response to ␣-MSH in cells expressing endogenous MC4R.…”

Section: Reduced Cell Cholesterol Impairs Mc4r Traffic Specifically Asupporting

confidence: 60%

Constitutive Cholesterol-dependent Endocytosis of Melanocortin-4 Receptor (MC4R) Is Essential to Maintain Receptor Responsiveness to α-Melanocyte-stimulating Hormone (α-MSH)

McDaniel

Molden

Mohammad

et al. 2012

Journal of Biological Chemistry

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Background: MC4R is essential for energy homeostasis and cycles continuously. Results: MC4R internalization is blocked by clathrin and cholesterol depletion, reducing receptor response to ␣-MSH, which is partially recovered by mutations at Thr-312/Ser-329. Conclusion: Constitutive internalization of MC4R is cholesterol-dependent and required for receptor function. Significance: These findings provide a potentially novel mechanism by which hypothalamic cell cholesterol content can affect appetite control.

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Section: Reduced Cell Cholesterol Impairs Mc4r Traffic Specifically Asupporting

confidence: 60%

Constitutive Cholesterol-dependent Endocytosis of Melanocortin-4 Receptor (MC4R) Is Essential to Maintain Receptor Responsiveness to α-Melanocyte-stimulating Hormone (α-MSH)

McDaniel

Molden

Mohammad

et al. 2012

Journal of Biological Chemistry

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“…Belsham et al have managed to develop cell lines that are representative of the enormous range of hypothalamic cell types [2,14]. N39, developed from primary mouse fetal hypothalamic cultures, is one such homologous neuronal cell line.…”

Section: Introductionmentioning

confidence: 99%

Regulation of corticotropin-releasing factor and urocortin 2/3 mRNA by leptin in hypothalamic N39 cells

et al. 2013

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Corticotropin-releasing factor (CRF) activates the pituitary-adrenal axis during stress, and shows anorectic effects via CRF type 1 receptors in the hypothalamus.Both urocortin (Ucn) 2 and Ucn3 also act as anorectic neuropeptides via CRF type 2 receptors. Leptin, a product of the obesity gene secreted mainly from adipose tissue, reduces food intake and increases energy expenditure. A possible interaction between leptin and CRF/Ucns has been suggested, as leptin can regulate expression and activation of CRF and Ucns in the hypothalamus. This study aimed to explore the possible function of leptin in the hypothalamus, and its effects in regulating CRF and Ucns. The study identified mRNA expression of the leptin receptor (Ob-R) and its subtypes, CRF, and Ucn2/3 in mouse hypothalamic N39 cells. Leptin stimulated signal transducer and activators of transcription type 3 (STAT3) phosphorylation, directly increased the mRNA levels of both CRF and Ucn2/3 in hypothalamic cells, and increased Ob-Rb mRNA levels. A Janus kinase inhibitor inhibited the leptin-mediated increase in STAT3 phosphorylation, and then the increases in CRF and Ucn2/3 mRNA levels. Leptin may contribute to a stress response or anorectic effect via the regulation 2 of CRF and Ucn2/3 in the hypothalamus.

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“…The generation of these cell lines has been described earlier (24), and their characteristics and application have been reviewed (25).…”

Section: Hypothalamic Cell Linementioning

confidence: 99%

“…We used an immortalized hypothalamic cell line as a homogenous model system (24,25). These cells express markers of mature neurons, like neuron-specific enolase and neurofilament, as well as syntaxin and neurosecretory granules (25).…”

Section: Pharmacological Gcs Inhibition Leads To Increased Ir Levels mentioning

confidence: 99%

Fasting-Induced Lipolysis and Hypothalamic Insulin Signaling Are Regulated by Neuronal Glucosylceramide Synthase

et al. 2015

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Central nervous regulation of body weight and adipose tissue function is mainly conducted by hypothalamic neurons. Neuronal function depends on the integrity of the membrane lipid microenvironment. Lipid microdomains contain large quantities of cholesterol and glycosphingolipids, including glucosylceramide synthase (GCS) (gene Ugcg)-derived gangliosides. The current study demonstrates that Ugcgf/f//CamKCreERT2 mice with genetic GCS deletion in forebrain neurons, dominantly targeting mediobasal hypothalamus (MBH), display impaired fasting-induced lipolysis accompanied by a decreased norepinephrine content in white adipose tissue (WAT). MBH insulin receptor (IR) levels and signaling are increased in Ugcgf/f//CamKCreERT2 mice. These results are in concordance with reports stating that MBH insulin signaling restrains sympathetic nervous outflow to WAT in fasted mice. In line with the in vivo data, pharmacological GCS inhibition by Genz123346 also increases IR levels as well as IR phosphorylation in insulin-stimulated hypothalamic cells. In addition to studies suggesting that simple gangliosides like GM3 regulate peripheral IR signaling, this work suggests that complex neuronal gangliosides also modulate hypothalamic IR signaling and protein levels. For example, the complex ganglioside GD1a interacts dynamically with the IRs on adult hypothalamic neurons. In summary, our results suggest that neuronal GCS expression modulates MBH insulin signaling and WAT function in fasted mice.The central nervous system (CNS) balances energy intake to energy expenditure, termed body energy homeostasis. Among several other brain regions, the hypothalamic arcuate nucleus (Arc) harbors first-order neurons sensing peripheral energy signals, such as leptin and insulin (1,2). Subsequently, these neurons adapt energy intake to the energy needs of the body by altering their firing pattern and neurotransmitter expression (1-3).Most hypothalamic neuronal subpopulations possess receptors for the energy signals leptin and insulin. In the CNS, both hormones exert anorexic actions by suppressing food intake (4,5). Many reports (6,7) support the hypothesis that hypothalamic insulin and leptin systems act in a concerted manner in order to regulate feeding and glucose homeostasis, as well as body weight. In line with this, a novel concept of hypothalamic insulin/leptin cross talk demonstrates that leptin receptor signaling regulates mitochondrial function in hypothalamic neurons, which directly influences their insulin sensitivity (8). In the hypothalamic Arc, leptin signaling depolarizes anorexigenic proopiomelanocortin (POMC) neurons (3) and hyperpolarizes Agouti-related peptide (AgRP) neurons (9), thereby regulating energy homeostasis and body weight. In addition, central insulin signaling is an important regulator of peripheral glucose homeostasis and fat tissues (10,11). Signaling pathways for leptin and insulin converge on insulin receptor (IR) substrate/phosphatidylinositol 3 kinase (PI3K) in hypothalamic neurons (6,7). It has, however, also ...

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Immortalized neurons for the study of hypothalamic function

Cited by 39 publications

References 263 publications

Constitutive Cholesterol-dependent Endocytosis of Melanocortin-4 Receptor (MC4R) Is Essential to Maintain Receptor Responsiveness to α-Melanocyte-stimulating Hormone (α-MSH)

Constitutive Cholesterol-dependent Endocytosis of Melanocortin-4 Receptor (MC4R) Is Essential to Maintain Receptor Responsiveness to α-Melanocyte-stimulating Hormone (α-MSH)

Regulation of corticotropin-releasing factor and urocortin 2/3 mRNA by leptin in hypothalamic N39 cells

Fasting-Induced Lipolysis and Hypothalamic Insulin Signaling Are Regulated by Neuronal Glucosylceramide Synthase

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