Estradiol Drives the Anorexigenic Activity of Proopiomelanocortin Neurons in Female Mice

Stincic, Todd L.; Grachev, Pasha; Bosch, Martha A.; Rønnekleiv, Oline K.

doi:10.1523/eneuro.0103-18.2018

Cited by 40 publications

(58 citation statements)

References 89 publications

(130 reference statements)

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“…Using a newly developed CRISPR strategy, we have shown that this single vector approach reduced the expression of Kcnq3 in NPY/AgRP neurons, resulting in molecular, cellular, and behavioral changes. While this approach was previously validated [41], we have extended this finding using a stringent method of harvesting healthy cells paired with a quantitative measure of relative gene expression [53]. Furthermore, we have confirmed that this change was not due to the surgery, SaCas9-alone, or fluorophore.…”

Section: Discussionsupporting

confidence: 57%

“…After three weeks, mice underwent OVX and were subsequently given EB-treatment on the two days prior to sacrifice. Brain slices were prepared, and cells harvested as previously described [53] and analyzed with qPCR. We found that the KCNQ3-KD group displayed a reduction in relative expression of Kcnq3 in NPY/AgRP neurons compared to the control group (Fig 2B), but Kcnq2 mRNA was not changed in NPY/AgRP neurons in response to Kcnq3 KD (Fig 2C).…”

Section: Crispr Kcnq3 Significantly Decreases Kcnq3 Expressionmentioning

confidence: 99%

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CRISPR Knockdown ofKcnq3Attenuates the M-current in NPY/AgRP Neurons

Stincic¹,

Bosch²,

Hunker

et al. 2020

Preprint

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Arcuate nucleus Neuropeptide Y/Agouti-related peptide (NPY/AgRP) neurons drive ingestive behavior in response to the internal and external environment of an organism. NPY/AgRP neurons are adjacent to the median eminence, a circumventricular organ, and circulating metabolic factors and hormones communicate the energy state of the animal via these neurons by altering the excitability of NPY/AgRP neurons, which produces an appropriate change in behavior to maintain homeostasis. One example of this plasticity is seen in the M-current, a subthreshold, non-inactivating K + current that acts to modulate excitability. Fasting decreases while estradiol increases the M-current through regulation of subunit mRNA expression of Kcnq 2, 3, & 5. KCNQ2/3 heteromers are thought to mediate the majority of the M-current. Here we used a recently developed single adeno-associated viral (AAV) vector containing a recombinasedependent Staphylococcus aureus Cas9 (SaCas9) and a single guide RNA against Kcnq3 to selectively delete Kcnq3 in NPY/AgRP neurons to produce a loss of function in the M-current. We found that this virus was effective at knocking down Kcnq3 but not Kcnq2 expression. With the reduced KCNQ3 channel expression NPY/AgRP neurons were more depolarized, exhibited a higher input resistance, and the rheobase current needed to induce firing was significantly reduced, indicative of increased excitability. Although the resulting decrease in the M-current did not overtly alter ingestive behavior, it did significantly reduce the locomotor activity as measured in open field testing. Therefore, the SaCas9-sgKcnq3 is efficient to knock down Kcnq3 expression thereby reducing the M-current and increasing the excitability of NPY/AgRP neurons.

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Section: Discussionsupporting

confidence: 57%

Section: Crispr Kcnq3 Significantly Decreases Kcnq3 Expressionmentioning

confidence: 99%

CRISPR Knockdown ofKcnq3Attenuates the M-current in NPY/AgRP Neurons

Stincic¹,

Bosch²,

Hunker

et al. 2020

Preprint

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“…neurons excites Kiss1 ARH neurons, an indication that POMC neurons may signal to Kiss1 ARH neurons the metabolic status of the organism. 76 Chronically, OVX Kiss1R KO females develop obesity, hyperleptinemia, reduced metabolism, and glucose intolerance in comparison to OVX females. 58 Therefore, the Kiss1R (GPR54) may play a role to link metabolic changes to reproduction in female rodents.…”

Section: Role Of Kiss1r (Gpr54) and Neuropeptide Ff Receptor 1 In Enementioning

confidence: 99%

Arcuate Kisspeptin Neurons Coordinate Reproductive Activities with Metabolism

2019

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Hypothalamic control of fertility is the quintessential homeostatic function. However, fertility is metabolically demanding; so, there must be coordination between energy states and reproductive functions. Because gonadotropin-releasing hormone (GnRH) neurons are devoid of many of the critical metabolic hormone receptors for sensing nutrient levels, it has long been recognized that the sensing of energy stores had to be done by neurons presynaptic to GnRH neurons. Some of the obvious players have been the anorexigenic proopiomelanocortin (POMC) and orexigenic neuropeptide Y (NPY)/agouti-related peptide (AgRP) neurons, both of which are in close apposition to the median eminence, a circumventricular organ. Indeed, POMC and NPY/AgRP neurons are inversely regulated by glucose and metabolic hormones including insulin and leptin. However, their synaptic connections with GnRH neurons are sparse and/or GnRH neurons are lacking the postsynaptic receptors to mediate the appropriate physiological response. Kisspeptin neurons were discovered in the early part of this century and subsequently shown to project to and control GnRH neuronal excitability. In fact, more recently the arcuate kisspeptin neurons have been identified as the command neurons driving pulsatile release of GnRH. Subsequently, it was shown that arcuate kisspeptin neurons express not only steroid hormone receptors but also metabolic hormone receptors such that similar to POMC neurons, they are excited by insulin and leptin. Therefore, based on the premise that arcuate kisspeptin neurons are the key neurons coordinating energy states with reproduction, we will review not only how these vital neurons control pulsatile GnRH release but how they control energy homeostasis through their synaptic connections with POMC and NPY/AgRP neurons and ultimately how E2 can regulate their excitability.

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“…Importantly, glutamate has been described to mediate the effect (excitation) that Kiss1 ARC neurons exert on POMC neurons, and to selectively inhibit AgRP neurons (10,64), which strongly supports a glutamatergic component in the phenotype of the Kiss1 ARC silenced mouse model (57). Moreover, the glutamatergic action of Kiss1 neurons onto neighboring POMC and AgRP neurons is gonadal hormone dependent, as it is enhanced by E2 in females (64,65), in line with the sex-dependent effect of kisspeptin on food intake in jerboa (50) and BW in Kiss1rKO mice (43), restricted to females (Fig. 1).…”

Section: Kiss1 Neurons Display Bidirectional Interactions With Agrp Amentioning

confidence: 82%

Novel insights into the metabolic action of Kiss1 neurons

Talbi

Navarro

2020

Endocrine Connections

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Kiss1 neurons are essential regulators of the hypothalamic–pituitary–gonadal (HPG) axis by regulating gonadotropin-releasing hormone (GnRH) release. Compelling evidence suggests that Kiss1 neurons of the arcuate nucleus (Kiss1ARC), recently identified as the hypothalamic GnRH pulse generator driving fertility, also participate in the regulation of metabolism through kisspeptinergic and glutamatergic interactions with, at least, proopiomelanocortin (POMC) and agouti-related peptide (AgRP)/neuropeptide Y (NPY) neurons, located in close apposition with Kiss1ARC. This review offers a comprehensive overview of the recent developments, mainly derived from animal models, on the role of Kiss1 neurons in the regulation of energy balance, including food intake, energy expenditure and the influence of circadian rhythms on this role. Furthermore, the possible neuroendocrine pathways underlying this effect, and the existing controversies related to the anorexigenic action of kisspeptin in the different experimental models, are also discussed.

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Estradiol Drives the Anorexigenic Activity of Proopiomelanocortin Neurons in Female Mice

Cited by 40 publications

References 89 publications

CRISPR Knockdown ofKcnq3Attenuates the M-current in NPY/AgRP Neurons

CRISPR Knockdown ofKcnq3Attenuates the M-current in NPY/AgRP Neurons

Arcuate Kisspeptin Neurons Coordinate Reproductive Activities with Metabolism

Novel insights into the metabolic action of Kiss1 neurons

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