Defining POMC Neurons Using Transgenic Reagents: Impact of Transient Pomc Expression in Diverse Immature Neuronal Populations

Padilla, Stéphanie L.; Reef, Daniel; Zeltser, Lori M.

doi:10.1210/en.2011-1665

Cited by 109 publications

(103 citation statements)

References 56 publications

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“…It is important to note that endogenous Glp2r is not expressed in the brain regions where POMC-Cre is expressed highly transiently (40). Our data suggest that GLP-2R in Pomc-expressing progenitors is required for the control of feeding behavior and gastric emptying; yet it is unknown about the extent to which the Cremediated recombination in off-target sites (if any) may contribute to the observed metabolic phenotype.…”

Section: E862mentioning

confidence: 82%

“…It will be important to define if the 4th-ventricular GLP-2-mediated action is due to presynaptic effects of GLP-2R on axon terminals (arising from the ARC POMC neurons) and/or postsynaptic effects of GLP-2R on dendrites (of the NTS POMC neurons). We note that POMC-cre could be transiently expressed in embryonic non-POMC neurons in the brain (40), which might mediate recombination of GLP-2R in off-target cells. However, the POMC-Cre-mediated recombination of each floxed allele is unique, depending on endog- Fig.…”

Section: E861mentioning

confidence: 91%

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GLP-2 receptor in POMC neurons suppresses feeding behavior and gastric motility

Guan

Shi

et al. 2012

American Journal of Physiology-Endocrinology and Metabolism

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receptor in POMC neurons suppresses feeding behavior and gastric motility. Am J Physiol Endocrinol Metab 303: E853-E864, 2012. First published July 24, 2012; doi:10.1152/ajpendo.00245.2012.-Glucagon-like peptides (GLP-1/2) are cosecreted from endocrine L cells in the gut and preproglucagonergic neurons in the brain. Peripheral GLP-2 action is essential for maintaining intestinal homeostasis, improving absorption efficiency and blood flow, promoting immune defense, and producing efficacy in treatment of gastrointestinal diseases. However, it is unknown if CNS GLP-2 plays a physiological role in the control of energy homeostasis. Since GLP-1/2 are cotranslated from preproglucagongene and coproduced by prohormone convertase-1, it is challenging to knockout GLP-2 only. Instead, our laboratory has generated a Glp2r-floxed mouse line to dissect cellspecific GLP-2 receptor GLP-2R) action in the regulation of energy balance. Our objective was to determine if GLP-2R in the hypothalamus modulates feeding behavior and gastric emptying. We show that Glp2r mRNA and protein are highly expressed in the arcuate nucleus and dorsomedial nucleus of the mouse hypothalamus. Using the Cre-LoxP system, we generated mice that lack Glp2r expression in POMC neurons (KO; mainly in the hypothalamus). The KO mice showed hyperphagic behavior (such as increases in food intake and meal frequency), accelerated gastric emptying (assessed by [ 13 C]octanoic acid breath test), and late-onset obesity, yet there was no decrease in basal metabolic rate. Infusion of GLP-2 (2.5 nmol into the 4th ventricle) suppressed food intake and gastric emptying, while GLP-2-mediated effects were abolished in the melanocortin receptor-4 (MC4R) KO mice. We conclude that Glp2r deletion in POMC neurons enhances feeding behavior and gastric motility, whereas icv GLP-2R activation suppresses food intake and gastric emptying through the MC4R signaling pathway. This study indicates that CNS GLP-2R plays a physiological role in the control of feeding behavior and gastric emptying and that this is mediated probably through the melanocortin system. glucagon-like peptides; proopiomelanocortin; energy homeostasis; food intake; gastric emptying OBESITY AND TYPE 2 DIABETES affect millions of people and are major health problems in the United States. The hypothalamus, a primary site of convergence and integration in the brain for hormonal and nutritional signals, plays pivotal roles in the regulation of energy balance (42). In the arcuate nucleus (ARC) of the hypothalamus, neurons expressing proopiomelanocortin (POMC neurons) are perfectly positioned to integrate long-term adiposity and short-term satiety signals for energy homeostasis (12). POMC neuronal activation enhances energy expenditure and suppresses food intake, yet neuroendocrine mechanisms are not fully established. Notably, the gastrointestinal (GI) tract has a crucial role in digestion, absorption, and assimilation of nutrients (15), thus controlling energy intake at the first pass. Through the gut-brain axis, gut ho...

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Section: E862mentioning

confidence: 82%

Section: E861mentioning

confidence: 91%

GLP-2 receptor in POMC neurons suppresses feeding behavior and gastric motility

Guan

Shi

et al. 2012

American Journal of Physiology-Endocrinology and Metabolism

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“…However, Padilla et al 18 suggested that POMC is transiently expressed in several sites of the developing mouse brain and that this transient expression may be sufficient to cause recombination of floxed alleles in off-target neurons that could contribute to physiological phenotypes. However, the physiological significance of this transient expression of POMC in neurons has not, to our knowledge, been demonstrated.…”

Section: Discussionmentioning

confidence: 99%

Regulation of Blood Pressure, Appetite, and Glucose by Leptin After Inactivation of Insulin Receptor Substrate 2 Signaling in the Entire Brain or in Proopiomelanocortin Neurons

et al. 2016

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Insulin receptor substrate 2 (IRS2) is one of three major leptin receptor signaling pathways, but its role in mediating the chronic effects of leptin on blood pressure, food intake and glucose regulation is unclear. We tested if genetic inactivation of IRS2 in the entire brain (IRS2/Nestin-cre mice) or specifically in proopiomelanocortin (POMC) neurons (IRS2/POMC-cre mice) attenuates the chronic cardiovascular, metabolic and antidiabetic effects of leptin. Mice were instrumented with telemetry probes for measurement of blood pressure (BP) and heart rate (HR) and with venous catheters for intravenous infusions. After a 5-day control period, mice received leptin infusion (2 µg/kg/min) for 7 days. Compared to control IRS2flox/flox mice, IRS2/POMC-cre mice had similar body weight and food intake (33±1 vs. 35±1g and 3.6±0.5 vs. 3.8±0.2 g/day) but higher MAP and HR (110±2 vs. 102±2 mmHg and 641±9 vs. 616±5 bpm). IRS2/Nestin-cre mice were heavier (38±2 g), slightly hyperphagic (4.5±1.0 g/day), and had higher MAP and HR (108±2 mmHg and 659±9 bpm) compared to control mice. Leptin infusion gradually increased MAP despite decreasing food intake by 31% in IRS2flox/flox as well as in Nestin-cre control mice. In contrast, leptin infusion did not change MAP in IRS2/Nestin-cre or IRS2/POMC-cre mice. The anorexic and antidiabetic effects of leptin, however, were similar in all 3 groups. These results indicate that IRS2 signaling in the CNS, and particularly in POMC neurons, is essential for the chronic actions of leptin to raise MAP but not for its anorexic or antidiabetic effects.

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“…POMC is a precursor of a-MSH, which, when released from the axon terminals of POMC neurons, binds to and activates MC4R, thereby reducing food intake and body weight (Huszar et al 1997). In the adult rodent brain, the majority of POMC neurons are located in the hypothalamic arcuate nucleus (Cone 2005, Padilla et al 2012. Therefore, although we did not investigate POMC expression here in our micro-dissection of the arcuate nucleus, we assumed that our data for the whole hypothalamus approximately reflected Pomc mRNA levels in the arcuate nucleus.…”

Section: Discussionmentioning

confidence: 99%

Role of the neural pathway from hindbrain to hypothalamus in interaction of GLP1 and leptin in rats

Akieda-Asai

Poleni

Hasegawa

et al. 2013

Journal of Endocrinology

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Glucagon-like peptide-1 (GLP1) and leptin are anorectic hormones. Previously, we have shown that i.p. coadministration of subthreshold GLP1 with leptin dramatically reduced food intake in rats. In this study, by using midbrain-transected rats, we investigated the role of the neural pathway from the hindbrain to the hypothalamus in the interaction of GLP1 and leptin in reducing food intake. Food intake reduction induced by coinjection of GLP1 and leptin was blocked in midbrain-transected rats. These findings indicate that the ascending neural pathway from the hindbrain plays an important role in transmitting the anorectic signals provided by coinjection of GLP1 and leptin.Key Words " food intake

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Defining POMC Neurons Using Transgenic Reagents: Impact of Transient Pomc Expression in Diverse Immature Neuronal Populations

Cited by 109 publications

References 56 publications

GLP-2 receptor in POMC neurons suppresses feeding behavior and gastric motility

GLP-2 receptor in POMC neurons suppresses feeding behavior and gastric motility

Regulation of Blood Pressure, Appetite, and Glucose by Leptin After Inactivation of Insulin Receptor Substrate 2 Signaling in the Entire Brain or in Proopiomelanocortin Neurons

Role of the neural pathway from hindbrain to hypothalamus in interaction of GLP1 and leptin in rats

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