Deletion of Protein Kinase C λ in POMC Neurons Predisposes to Diet-Induced Obesity

Dorfman, Mauricio D.; Krull, Jordan E.; Scarlett, Jarrad; Guyenet, Stephan J.; Sajan, Mini P.; Damian, Vincent; Nguyen, Hong T.; Leitges, Michael; Morton, Gregory J.; Farese, Robert V.; Schwartz, Michael W.; Thaler, Joshua P.

doi:10.2337/db16-0482

Cited by 21 publications

(16 citation statements)

References 69 publications

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“…2A). Male mice exposed to high-fat diet have increased propensity to develop obesity, glucose intolerance and insulin resistance when lacking PKCλ in POMC neurons (Dorfman et al 2017b). Together these data indicate that alterations of leptin and insulin signaling at multiple steps including both factors implicated in the onset of the signal and signal termination may contribute to hypothalamic resistance to these hormones in obesity.…”

Section: The Onset Of Selective Neuronal Resistance To Insulin and Lementioning

confidence: 81%

“…PI3K pathway also promotes phosphorylation and translocation of forkhead box protein O1 (FOXO1) from the nucleus to the cytosol, an effect that promotes transcription of POMC and increased expression of carboxypeptidase E (CPE) with increased processing of POMC to α-MSH, and suppression of food intake (Kim et al 2006, Plum et al 2009, Kwon et al 2016. The PI3K signaling pathway to control food intake and weight gain includes the atypical protein kinase C λ (aPKC λ) (Dorfman et al 2017b). An effect by leptin is to induce POMC neuron depolarization through a cation channel (Cowley et al 2001).…”

Section: Pomc Neurons and Leptin Signalingmentioning

confidence: 99%

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The melanocortin pathway and control of appetite-progress and therapeutic implications

Baldini

Phelan

2019

Journal of Endocrinology

171

125

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The initial discovery thatob/obmice become obese because of a recessive mutation of the leptin gene has been crucial to discover the melanocortin pathway to control appetite. In the melanocortin pathway, the fed state is signaled by abundance of circulating hormones such as leptin and insulin, which bind to receptors expressed at the surface of pro-opiomelanocortin (POMC) neurons to promote processing of POMC to the mature hormone α-melanocyte-stimulating hormone (α-MSH). The α-MSH released by POMC neurons then signals to decrease energy intake by binding to melanocortin-4 receptor (MC4R) expressed by MC4R neurons to the paraventricular nucleus (PVN). Conversely, in the ‘starved state’ activity of agouti-related neuropeptide (AgRP) and of neuropeptide Y (NPY)-expressing neurons is increased by decreased levels of circulating leptin and insulin and by the orexigenic hormone ghrelin to promote food intake. This initial understanding of the melanocortin pathway has recently been implemented by the description of the complex neuronal circuit that controls the activity of POMC, AgRP/NPY and MC4R neurons and downstream signaling by these neurons. This review summarizes the progress done on the melanocortin pathway and describes how obesity alters this pathway to disrupt energy homeostasis. We also describe progress on how leptin and insulin receptors signal in POMC neurons, how MC4R signals and how altered expression and traffic of MC4R change the acute signaling and desensitization properties of the receptor. We also describe how the discovery of the melanocortin pathway has led to the use of melanocortin agonists to treat obesity derived from genetic disorders.

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Section: The Onset Of Selective Neuronal Resistance To Insulin and Lementioning

confidence: 81%

Section: Pomc Neurons and Leptin Signalingmentioning

confidence: 99%

The melanocortin pathway and control of appetite-progress and therapeutic implications

Baldini

Phelan

2019

Journal of Endocrinology

171

125

View full text Add to dashboard Cite

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“…A lack of leptin receptors in the adenohypophysis can also disturb activities of most basophils, especially the gonadotrophs and POMC-making cells, thus alters SCs endogenous SC steroids production that further impact on peripheral neuropathy found with NIDDM of Zucker rats, and in similar human defects 262,263 when compared with normal subjects. 271 If neurosteroids can prevent myelin alterations caused by diabetes 272 , verifications of neurosteroid changes are yet to come in Zucker rat to comfort this influence on the sciatic nerve defects. Repairs can be promoted through an external neuroactive steroid-like progesterone (P) thus this sex steroid could then become a preventative or repair way to reestablish the lipid myelin alterations in diabetics.…”

Section: The Scs In the Obese Nerves And Neuroprogesteronementioning

confidence: 99%

The leptin receptor mutation of the obese Zucker rat causes sciatic nerve demyelination with a centripetal pattern defect

Gilloteaux

Subramanian

Solomon

et al. 2018

Ultrastructural Pathology

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Young male Zucker rats with a leptin receptor mutation are obese, have a non-insulin-dependent diabetes mellitus (NIDDM), and other endocrinopathies. Tibial branches of the sciatic nerve reveal a progressive demyelination that progresses out of the Schwann cells (SCs) where electron-contrast deposits are accumulated while the minor lines or intermembranous SC contacts display exaggerated spacings. Cajal bands contain diversely contrasted vesicles adjacent to the abaxonal myelin layer with blemishes; they appear dispatched centripetally out of many narrow electron densities, regularly spaced around the myelin annulus. These anomalies widen and yield into sectors across the stacked myelin layers. Throughout the worse degradations, the adaxonal membrane remains along the axonal neuroplasm. This peripheral neuropathy with irresponsive leptin cannot modulate hypothalamic-pituitaryadrenal axis and SC neurosteroids, thus exacerbates NIDDM condition. Additionally, the ultrastructure of the progressive myelin alterations may have unraveled a peculiar, centripetal mode of trafficking maintenance of the peripheral nervous system myelin, while some adhesive glycoproteins remain between myelin layers, somewhat hindering the axon mutilation. Heading title: Peripheral neuropathy and myelin ARTICLE HISTORY

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“…Considering that PKCs are at the front line of drug development for the treatment of diverse human disorders, such as tumorgenesis [ 10 ], diabetic complications [ 27 ], obesity [ 28 ], inflammation [ 29 ], and even viral infections [ 13 , 14 , 15 , 16 ], we have analyzed the effect of the inhibition of PKCs on WNV replication.…”

Section: Introductionmentioning

confidence: 99%

Pharmacological Inhibition of Protein Kinase C Reduces West Nile Virus Replication

Blázquez¹,

Vázquez-Calvo²,

Martín-Acebes³

et al. 2018

Viruses

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Flaviviruses are relevant animal and human pathogens that include West Nile virus (WNV), Japanese encephalitis virus, dengue virus, or Zika virus, among others. Currently, no licensed therapy is available to fight flaviviral infections. Protein kinases C (PKCs) constitute a family of multifunctional lipid-dependent isoenzymes that regulate a wide variety of cellular processes (apoptosis, differentiation, proliferation, cellular transformation, motility, adhesion, etc.) being currently considered at the front line of drug development for the treatment of diverse human disorders. PKCs have also been implicated in different steps during viral replication; however, nowadays, results regarding their role in flavivirus replication are controversial. Here we demonstrate that calphostin C and chelerythrine, two broad-PKC inhibitors that target conventional, novel and atypical PKCs, significantly inhibit WNV multiplication in cell culture without affecting cell viability. A reduction of viral yields was observed in treated cells when compared with mock-treated cells. Likewise, immunofluorescence detection of viral enveloped E protein was reduced in treated cells, as was the amount of viral RNA released to the supernatant, mainly in those treated with chelerythrine. On the other hand, two PKC inhibitors specific for conventional and novel isoforms (staurosporine and enzastaurine) did not show any significant effect in WNV multiplication. These results suggested that PKCs, more probably atypical PKCs, are likely involved in WNV multiplication, although both broad-spectrum tested drugs seem to act through different mechanisms, and point to them as potential antiviral candidates for WNV, as well as for other related flaviviruses.

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Deletion of Protein Kinase C λ in POMC Neurons Predisposes to Diet-Induced Obesity

Cited by 21 publications

References 69 publications

The melanocortin pathway and control of appetite-progress and therapeutic implications

The melanocortin pathway and control of appetite-progress and therapeutic implications

The leptin receptor mutation of the obese Zucker rat causes sciatic nerve demyelination with a centripetal pattern defect

Pharmacological Inhibition of Protein Kinase C Reduces West Nile Virus Replication

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