Neuromedin B and Gastrin-Releasing Peptide Excite Arcuate Nucleus Neuropeptide Y Neurons in a Novel Transgenic Mouse Expressing Strong<i>Renilla</i>Green Fluorescent Protein in NPY Neurons

Pol, Anthony N. van den; Yao, Yang; Fu, Li-Ying; Foo, Kylie S.; Huang, Hao; Coppari, Roberto; Lowell, Bradford B.; Broberger, Christian

doi:10.1523/jneurosci.3249-08.2009

Cited by 207 publications

(192 citation statements)

References 89 publications

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“…C57BL/6, FVB, and ob/ob mice were obtained from The Jackson Laboratory. NPY-hrGFP mice were a gift of Brad Lowell (Beth Israel Deaconess Medical Center) (41). The NPY-hrGFP mice used were on a FVB background (this strain has been subsequently backcrossed to C57BL/6, generating The Jackson Laboratory strain 006417).…”

Section: Methodsmentioning

confidence: 99%

Remodeling of the arcuate nucleus energy-balance circuit is inhibited in obese mice

McNay¹,

Briançon²,

Kokoeva³

et al. 2012

J. Clin. Invest.

274

299

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In the CNS, the hypothalamic arcuate nucleus (ARN) energy-balance circuit plays a key role in regulating body weight. Recent studies have shown that neurogenesis occurs in the adult hypothalamus, revealing that the ARN energy-balance circuit is more plastic than originally believed. Changes in diet result in altered gene expression and neuronal activity in the ARN, some of which may reflect hypothalamic plasticity. To explore this possibility, we examined the turnover of hypothalamic neurons in mice with obesity secondary to either high-fat diet (HFD) consumption or leptin deficiency. We found substantial turnover of neurons in the ARN that resulted in ongoing cellular remodeling. Feeding mice HFD suppressed neurogenesis, as demonstrated by the observation that these mice both generated fewer new neurons and retained more old neurons. This suppression of neuronal turnover was associated with increased apoptosis of newborn neurons. Leptin-deficient mice also generated fewer new neurons, an observation that was explained in part by a loss of hypothalamic neural stem cells. These data demonstrate that there is substantial postnatal turnover of the arcuate neuronal circuitry in the mouse and reveal the unexpected capacity of diet and leptin deficiency to inhibit this neuronal remodeling. This insight has important implications for our understanding of nutritional regulation of energy balance and brain function. IntroductionThe hypothalamus is a critical regulator of energy balance. Lesions of the ventromedial nucleus (1) or arcuate nucleus (ARN) (2) result in obesity, while lesions of the lateral hypothalamic area (3) result in weight loss. Energy-related signals such as leptin (4, 5) are integrated by responsive neurons in the ARN and ventromedial hypothalamus. In particular, leptin stimulates the anorexigenic proopiomelanocortin (POMC) neurons and inhibits orexigenic neuropeptide Y (NPY) neurons. In situations of negative energy balance, reduced leptin levels inhibit the activity of POMC neurons and activate NPY neurons. While this feedback circuit is essential for normal energy homeostasis (see review refs. 6, 7), most obesity is associated with dysregulation of the circuit and leptin resistance (8).Two commonly studied mouse models of obesity, the high-fat diet-induced (HFD-induced) obesity (DIO) model (9) and the more severe obesity arising from the lack of leptin (4, 5), share features such as increased fat mass, hyperglycemia, hyperinsulinemia, and activation of the adrenal axis but are distinct in that DIO mice have elevated peripheral leptin levels and are resistant to both endogenous and exogenous leptin (8). DIO mice also become resistant to centrally administered leptin (10). This phenomenon is reversible, with leptin responsiveness returning several months after cessation of HFD consumption (11).The molecular and cellular mechanisms underlying hypothalamic dysfunction in the context of obesity over long-time frames are still not fully understood. Possible mechanisms include impaired leptin transport acr...

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Section: Methodsmentioning

confidence: 99%

Remodeling of the arcuate nucleus energy-balance circuit is inhibited in obese mice

McNay¹,

Briançon²,

Kokoeva³

et al. 2012

J. Clin. Invest.

274

299

View full text Add to dashboard Cite

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“…C57BL/6J wild-type mice, NPY(GFP) mice (NpyhrGFP BAC) (32), and 129S-NPY tm1Rpa /J NPY knockout mice (49) were purchased from The Jackson Laboratory. All experiments were performed using male mice [postnatal day (P) 24 to P50] that received ad libitum access to food unless otherwise specified.…”

Section: Methodsmentioning

confidence: 99%

“…The increase in NPY-ir could be caused by a reduction in peptide secretion or an increase in synthesis. To distinguish between these possibilities, we used an NPY(GFP) BAC transgenic mouse in which GFP expression is driven by regulatory elements in the NPY gene (32). Therefore, an increase in GFP expression would reflect a transcriptional activation of the NPY gene (or less likely, a decrease in GFP degradation).…”

Section: Fasting Alters the Adrenal Expression Of Npy But Not Tyrosinementioning

confidence: 99%

Fasting induces a form of autonomic synaptic plasticity that prevents hypoglycemia

Wang

Whim

2016

Proc. Natl. Acad. Sci. U.S.A.

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During fasting, activation of the counter-regulatory response (CRR) prevents hypoglycemia. A major effector arm is the autonomic nervous system that controls epinephrine release from adrenal chromaffin cells and, consequently, hepatic glucose production. However, whether modulation of autonomic function determines the relative strength of the CRR, and thus the ability to withstand food deprivation and maintain euglycemia, is not known. Here we show that fasting leads to altered transmission at the preganglionic → chromaffin cell synapse. The dominant effect is a presynaptic, long-lasting increase in synaptic strength. Using genetic and pharmacological approaches we show this plasticity requires neuropeptide Y, an adrenal cotransmitter and the activation of adrenal Y5 receptors. Loss of neuropeptide Y prevents a fasting-induced increase in epinephrine release and results in hypoglycemia in vivo. These findings connect plasticity within the sympathetic nervous system to a physiological output and indicate the strength of the final synapse in this descending pathway plays a decisive role in maintaining euglycemia.hypoglycemia | autonomic nervous system | synaptic plasticity | adrenal | chromaffin cells F ailure to avoid hypoglycemia can lead to dysphoria, ventricular arrhythmia, and even sudden death (1). That these effects are rare and observed only in response to prolonged fasting or severe insulin-induced hypoglycemia is because of the remarkable effectiveness of the counter-regulatory response (CRR). This sensory-motor homeostatic feedback loop detects a fall in blood glucose through central and peripheral receptors and initiates a neuronal, endocrine, and behavioral response that restores euglycemia (2). One of the principal effector arms of the CRR is the sympatho-adrenal branch of the autonomic nervous system. Hypoglycemia elevates sympathetic activity, increasing hepatic glucose production and the release of gluconeogenic substrates while suppressing insulin and potentiating glucagon secretion (3, 4).During fasting, these autonomic actions are mediated by epinephrine, which enters the systemic circulation after release from adrenal neuroendocrine chromaffin cells and by norepinephrine, secreted directly onto target tissues from postganglionic sympathetic neurons. The importance of sympathetic activity, and in particular circulating epinephrine in the CRR, is illustrated by the poor recovery from insulin-induced hypoglycemia when the release of this hormone is suppressed during hypoglycemia-associated autonomic failure (5, 6), and by recent work showing that deletion of melanocortin 4 receptors from preganglionic sympathetic neurons leads to elevated levels of blood glucose (7).Given the involvement of the sympathetic nervous system in the CRR, modulation of autonomic activity is thus likely to alter the ability to respond to a hypoglycemic challenge. However, unlike in the CNS, where long-lasting changes in synaptic strength are known to be associated with functional consequences (8-10), whether the output ...

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“…To label AgRP-neurons, we used two transgenic mouse models. The Npy-hrGFP transgenic mouse is an ideal model to label AgRP-neurons with GFP in developing embryos, because GFP expression is driven by the promoter of the Npy gene, which is turned on in embryonic AgRP-neurons prior to the expression of AgRP (van den Pol et al, 2009). To label AgRPneurons postnatally, we generated Agrp-ires-Cre;Rosa26 CAG-tdTomato mice, in which a red fluorescent protein (tdTomato) is specifically and postnatally expressed in AgRP-neurons by means of expression of Cre driven by the Agrp promoter and the resulting Cre-mediated recombination only in AgRP-neurons (Tong et al, 2008;Madisen et al, 2010).…”

Section: Expression Of Isl1 In Developing Arcuate Nucleus Neuronsmentioning

confidence: 99%

The LIM-homeobox transcription factor Isl1 plays crucial roles in the development of multiple arcuate nucleus neurons

Lee

2016

Development

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Neurons in the hypothalamic arcuate nucleus relay and translate important cues from the periphery into the central nervous system. However, the gene regulatory program directing their development remains poorly understood. Here, we report that the LIMhomeodomain transcription factor Isl1 is expressed in several subpopulations of developing arcuate neurons and plays crucial roles in their fate specification. Mice with conditional deletion of the Isl1 gene in developing hypothalamus display severe deficits in both feeding and linear growth. Consistent with these results, their arcuate nucleus fails to express key fate markers of Isl1-expressing neurons that regulate feeding and growth. These include the orexigenic neuropeptides AgRP and NPY for specifying AgRP-neurons, the anorexigenic neuropeptide αMSH for POMC-neurons, and two growth-stimulatory peptides, growth hormone-releasing hormone (GHRH) for GHRH-neurons and somatostatin (Sst) for Sst-neurons. Finally, we show that Isl1 directly enhances the expression of AgRP by cooperating with the key orexigenic transcription factors glucocorticoid receptor and brain-specific homeobox factor. Our results identify Isl1 as a crucial transcription factor that plays essential roles in the gene regulatory program directing development of multiple arcuate neuronal subpopulations.

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Neuromedin B and Gastrin-Releasing Peptide Excite Arcuate Nucleus Neuropeptide Y Neurons in a Novel Transgenic Mouse Expressing StrongRenillaGreen Fluorescent Protein in NPY Neurons

Cited by 207 publications

References 89 publications

Remodeling of the arcuate nucleus energy-balance circuit is inhibited in obese mice

Remodeling of the arcuate nucleus energy-balance circuit is inhibited in obese mice

Fasting induces a form of autonomic synaptic plasticity that prevents hypoglycemia

The LIM-homeobox transcription factor Isl1 plays crucial roles in the development of multiple arcuate nucleus neurons

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