p75 Neurotrophin Receptor Regulates Energy Balance in Obesity

Baeza-Raja, Bernat; Sachs, Benjamin D.; Li, Pingping; Frank, Christian; Vagena, Eirini; Davalos, Dimitrios; Moan, Natacha Le; Ryu, Jae K.; Sikorski, Shoana L.; Chan, Justin; Scadeng, Miriam; Taylor, Susan S.; Houslay, Miles D.; Baillie, George S.; Saltiel, Alan R.; Olefsky, Jerrold M.; Akassoglou, Katerina

doi:10.1016/j.celrep.2015.12.028

Cited by 45 publications

(37 citation statements)

References 80 publications

(102 reference statements)

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“…Despite expression of neurotrophins and their receptors in peripheral metabolic tissues, little is known about peripheral mechanisms by which neurotrophins influence metabolism. Recently, p75 receptors in adipocytes were found to regulate energy expenditure and obesity, although this effect was independent of the p75 extracellular domain and neurotrophin binding (Baeza-Raja et al, 2016). Here, we report a direct role for NGF/TrkA signaling within pancreatic endocrine cells in controlling insulin secretion and blood glucose homeostasis.…”

Section: Discussionmentioning

confidence: 99%

Neurotrophin Signaling Is Required for Glucose-Induced Insulin Secretion

et al. 2016

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Summary Insulin secretion by pancreatic islet β-cells is critical for glucose homeostasis, and a blunted β-cell secretory response is an early deficit in type 2 diabetes. Here, we uncover a regulatory mechanism by which glucose recruits vascular-derived neurotrophins to control insulin secretion. Nerve Growth Factor (NGF), a classical trophic factor for nerve cells, is expressed in pancreatic vasculature while its TrkA receptor is localized to islet β-cells. High glucose rapidly enhances NGF secretion, and increases TrkA phosphorylation in mouse and human islets. Tissue-specific deletion of NGF, TrkA, or acute disruption of TrkA signaling impairs glucose tolerance and insulin secretion in mice. We show that internalized TrkA receptors promote insulin granule exocytosis via F-actin reorganization. Furthermore, NGF treatment augments glucose-induced insulin secretion in human islets. These findings reveal a non-neuronal role for neurotrophins, and identify a new regulatory pathway in insulin secretion that can be targeted to ameliorate β-cell dysfunction.

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Section: Discussionmentioning

confidence: 99%

Neurotrophin Signaling Is Required for Glucose-Induced Insulin Secretion

et al. 2016

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“…These results indicate a role of p75NTRs in lipid metabolism in hepatocytes and possibly in metabolic disorders. During the preparation of this manuscript, Baeza-Raja et al (45) reported that p75NTR signaling is involved in obesity and energy regulation in adipocytes. In particular, it was shown that p75NTR gene-deleted mice are protected against the effects of high fat diet, including insulin resistance and fatty liver (45).…”

Section: Discussionmentioning

confidence: 99%

“…During the preparation of this manuscript, Baeza-Raja et al (45) reported that p75NTR signaling is involved in obesity and energy regulation in adipocytes. In particular, it was shown that p75NTR gene-deleted mice are protected against the effects of high fat diet, including insulin resistance and fatty liver (45). Our results on the role of p75NTR in inducing LDLRs and lipoprotein uptake into hepatocytes are in accordance with this notion.…”

Section: Discussionmentioning

confidence: 99%

p75 Neurotrophin Receptor Signaling Activates Sterol Regulatory Element-binding Protein-2 in Hepatocyte Cells via p38 Mitogen-activated Protein Kinase and Caspase-3

Pham

Bruelle

et al. 2016

Journal of Biological Chemistry

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Nerve growth factor (NGF) influences the survival and differentiation of a specific population of neurons during development, but its role in non-neuronal cells has been less studied. We observed here that NGF and its pro-form, pro-NGF, are elevated in fatty livers from leptin-deficient mice compared with controls, concomitant with an increase in low density lipoprotein receptors (LDLRs). Stimulation of mouse primary hepatocytes with NGF or pro-NGF increased LDLR expression through the p75 neurotrophin receptor (p75NTR). Studies using Huh7 human hepatocyte cells showed that the neurotrophins activate the sterol regulatory element-binding protein-2 (SREBP2) that regulates genes involved in lipid metabolism. The mechanisms for this were related to stimulation of p38 mitogen-activated protein kinase (p38 MAPK) and activation of caspase-3 and SREBP2 cleavage following NGF and pro-NGF stimulations. Cell fractionation experiments showed that caspase-3 activity was increased particularly in the membrane fraction that harbors SREBP2 and caspase-2. Experiments showed further that caspase-2 interacts with pro-caspase-3 and that p38 MAPK reduced this interaction and caused caspase-3 activation. Because of the increased caspase-3 activity, the cells did not undergo cell death following p75NTR stimulation, possibly due to concomitant activation of nuclear factor-B (NF-B) pathway by the neurotrophins. These results identify a novel signaling pathway triggered by ligand-activated p75NTR that via p38 MAPK and caspase-3 mediate the activation of SREBP2. This pathway may regulate LDLRs and lipid uptake particularly after injury or during tissue inflammation accompanied by an increased production of growth factors, including NGF and pro-NGF.

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“…A study published in 2016 identified p75NTR as a novel therapeutic target in type 2 diabetes, on the basis of results using an adipocyte-specific conditional null mouse model shown to be resilient to high-fat-diet-induced obesity and insulin resistance 164 . p75NTR signalling increased adipocyte lipolysis via cyclic AMP and the protein kinase A pathway, thereby regulating energy balance 164 . The findings highlight the importance of this neurotrophin receptor for obesity and the metabolic syndrome.…”

Section: Impact Of Schwannopathy On Neuronsmentioning

confidence: 99%

Schwann cell interactions with axons and microvessels in diabetic neuropathy

et al. 2017

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The incidence of diabetes mellitus has increased dramatically over the past two to three decades. According to the International Diabetes Federation Diabetes Atlas, 415 million people worldwide had diabetes in 2015, and this number is expected to grow by 5% annually, predominantly as a result of increasing prevalence of type 2 diabetes. Furthermore, an estimated 100 million Europeans and 80 million Americans have impaired glucose tolerance or prediabetes. Few people die from acute diabetes in countries with comprehensive health care systems, but the disease is inflicting a huge medical, social and economic burden on society owing to the need for lifelong treatment of its systemic consequences and the insidious development of multi-organ damage.Peripheral neuropathy (BOXES 1,2) is a common but often neglected complication of long-term diabetes, and the lack of treatment options reflects an incomplete understanding of the pathogenic mechanisms. Hyperglycaemia is generally accepted as the primary pathogenic insult in type 1 and type 2 diabetic neuropathy, although roles are emerging for other factors, such as impaired insulin signalling, hypertension and dyslipidaemia (particularly for type 2 diabetes), which might precede overt hyperglycaemia 1 . Many preclinical studies, and occasional clinical studies, have indicated that diabetic neuropathy -like diabetic nephropathy and retinopathy -results from microvascular disease, with a focus on axonal degeneration as a consequence of ischaemia and/or hypoxia. This mechanism, however, is likely to be only one aspect of a more complex pathogenesis.The earliest descriptions of pathology in diabetic neuropathy indicated that Schwannopathy accompanied axonal degeneration. The majority of clinical and basic research in diabetic neuropathy since then has focused on the effects on neurons. However, accumulating data from research into the development and regeneration of the PNS has identified Schwann cells as equally indispensable components that maintain neuronal structure and function, nourish axons, and promote survival and growth upon injury. The early reports from 1979 that demonstrated morphological changes in Schwann cells in human diabetic neuropathy 2 are now supported by an increased awareness of molecular alterations in Schwann cells during diabetes 3 . Schwann cells express a wide range of receptors and, when they sense insults or danger signals, they upregulate synthesis and secretion of factors that stimulate neuroprotection, regrowth and remyelination, or factors that aggravate disease phenotypes 4 . The most recent studies have demonstrated that Schwann cells regulate many aspects of axonal function, so that disruption of their metabolism by diabetes results in the accumulation of neurotoxic intermediates and compromises production of neuronal support factors, contributing to axonal degeneration, endothelial dysfunction and diabetic neuropathy. Abstract | The prevalence of diabetes worldwide is at pandemic levels, with the number of patients increasing by 5% annu...

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p75 Neurotrophin Receptor Regulates Energy Balance in Obesity

Cited by 45 publications

References 80 publications

Neurotrophin Signaling Is Required for Glucose-Induced Insulin Secretion

Neurotrophin Signaling Is Required for Glucose-Induced Insulin Secretion

p75 Neurotrophin Receptor Signaling Activates Sterol Regulatory Element-binding Protein-2 in Hepatocyte Cells via p38 Mitogen-activated Protein Kinase and Caspase-3

Schwann cell interactions with axons and microvessels in diabetic neuropathy

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