Mild Impairment of Mitochondrial OXPHOS Promotes Fatty Acid Utilization in POMC Neurons and Improves Glucose Homeostasis in Obesity

Timper, Katharina; Paeger, Lars; Sánchez-Lasheras, Carmen; Varela, Luis; Jais, Alexander; Nolte, Hendrik; Vogt, Merly C.; Hausen, A.; Heilinger, Christian; Evers, Nadine; Pospisilik, J. Andrew; Penninger, Josef; Taylor, Eric B.; Horváth, Tamas L.; Kloppenburg, Peter

doi:10.1016/j.celrep.2018.09.034

Cited by 30 publications

(27 citation statements)

References 70 publications

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“…Thus, it is not surprising that deranged pyruvate metabolism contributes to a host of diseases (6). Since the molecular identification of the genes encoding the MPC (7,9), an increasing number of investigations have demonstrated the prominent role of mitochondrial pyruvate uptake in regulating cellular and organismal biology (11,12,15,23,(25)(26)(27). Here, we demonstrate that 2 MPC1 mutations identified in human patients with inborn errors in pyruvate metabolism cause MPC dysfunction by three different mechanisms.…”

Section: Discussionmentioning

confidence: 70%

Two human patient mitochondrial pyruvate carrier mutations reveal distinct molecular mechanisms of dysfunction

Oonthonpan¹,

Rauckhorst²,

Gray³

et al. 2019

JCI Insight

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Section: Discussionmentioning

confidence: 70%

Two human patient mitochondrial pyruvate carrier mutations reveal distinct molecular mechanisms of dysfunction

Oonthonpan¹,

Rauckhorst²,

Gray³

et al. 2019

JCI Insight

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“…This is different than in AgRP/NPY neurons where suppression of ROS instead promotes the activity of AgRP/NPY neurons and feeding (Diano et al 2011). Recently, it has been found that, when mitochondrial respiration is mildly impaired in POMC neurons of obese mice exposed to high-fat diet, mitochondrial fatty acid utilization is improved, ROS generation is maintained and neuronal activation continues to take place (Timper et al 2018).…”

Section: Disrupted Mitochondrial Function In Dio Impairs Activation Omentioning

confidence: 93%

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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“…with CNO, and immediately returned to their cages. Energy expenditure data was corrected for lean mass, as determined using an IVIS SpectrumCT scanner (Caliper LifeScience, USA) 34 .…”

Section: Methodsmentioning

confidence: 99%

NPY mediates the rapid feeding and glucose metabolism regulatory functions of AgRP neurons

Ruud¹,

Pereira²,

Solis³

et al. 2020

Nat Commun

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Activation of Agouti-Related Peptide (AgRP)-expressing neurons promotes feeding and insulin resistance. Here, we examine the contribution of neuropeptide Y (NPY)-dependent signaling to the diverse physiological consequences of activating AgRP neurons. NPYdeficient mice fail to rapidly increase food intake during the first hour of either chemo-or optogenetic activation of AgRP neurons, while the delayed increase in feeding is comparable between control and NPY-deficient mice. Acutely stimulating AgRP neurons fails to induce systemic insulin resistance in NPY-deficient mice, while increased locomotor activity upon AgRP neuron stimulation in the absence of food remains unaffected in these animals. Selective re-expression of NPY in AgRP neurons attenuates the reduced feeding response and reverses the protection from insulin resistance upon optogenetic activation of AgRP neurons in NPY-deficient mice. Collectively, these experiments reveal a pivotal role of NPYdependent signaling in mediating the rapid feeding inducing effect and the acute glucose regulatory function governed by AgRP neurons.

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Mild Impairment of Mitochondrial OXPHOS Promotes Fatty Acid Utilization in POMC Neurons and Improves Glucose Homeostasis in Obesity

Cited by 30 publications

References 70 publications

Two human patient mitochondrial pyruvate carrier mutations reveal distinct molecular mechanisms of dysfunction

Two human patient mitochondrial pyruvate carrier mutations reveal distinct molecular mechanisms of dysfunction

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

NPY mediates the rapid feeding and glucose metabolism regulatory functions of AgRP neurons

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