Transient Receptor Potential Vanilloid Type 1–Dependent Regulation of Liver-Related Neurons in the Paraventricular Nucleus of the Hypothalamus Diminished in the Type 1 Diabetic Mouse

Gao, Hong; Miyata, Kayoko; Bhaskaran, Muthu D.; Derbenev, Andrei V.; Zsombok, Andrea

doi:10.2337/db11-0820

Cited by 47 publications

(56 citation statements)

References 51 publications

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“…The elimination of TRPV1 ϩ HPV neurons significantly suppresses the sympathoadrenal response to hypoglycemia, highlighting the importance of these neurons in glucose sensing (9). Furthermore, TRPV1-mediated regulation of liver-related paraventricular nucleus (PVN) neurons has also been shown, suggesting a direct influence of TRPV1 in the regulation of hepatic glucose production (10). Interestingly, TRPV1-mediated excitation of liver-related PVN neurons was found to be reduced in a mouse model of type 1 diabetes, and this activity was restored by insulin administration in a phosphatidylinositol 3-kinase/protein kinase C-dependent manner, illustrating the ability of insulin to control TRPV1 activity (10).…”

Section: E85 Insulin Clearance In Trpm8mentioning

confidence: 97%

“…Furthermore, TRPV1-mediated regulation of liver-related paraventricular nucleus (PVN) neurons has also been shown, suggesting a direct influence of TRPV1 in the regulation of hepatic glucose production (10). Interestingly, TRPV1-mediated excitation of liver-related PVN neurons was found to be reduced in a mouse model of type 1 diabetes, and this activity was restored by insulin administration in a phosphatidylinositol 3-kinase/protein kinase C-dependent manner, illustrating the ability of insulin to control TRPV1 activity (10). This phenotype is reminiscent of human subjects who have undergone liver transplant and highlights the influence of hepatic innervation on insulin clearance.…”

Section: E85 Insulin Clearance In Trpm8mentioning

confidence: 99%

“…Numerous nonselective cation channels of the TRP family have been implicated in the regulation of insulin. Their involvement has been shown at the cellular level in ␤-cells, as well as at the neuronal level via afferent innervation of the liver and pancreas (10,11,30). TRP channels of the TRPC (C1-6), TRPM (M3-5), TRPV (TRPV1-2, -V4), and TRPA (A1) subfamilies are reportedly expressed in mammalian pancreatic ␤-cells (7,11).…”

Section: E85 Insulin Clearance In Trpm8mentioning

confidence: 99%

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Enhanced insulin clearance in mice lacking TRPM8 channels

McCoy

Zhou

Nguyen

et al. 2013

American Journal of Physiology-Endocrinology and Metabolism

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McCoy DD, Zhou L, Nguyen A, Watts AG, Donovan CM, McKemy DD. Enhanced insulin clearance in mice lacking TRPM8 channels. Am J Physiol Endocrinol Metab 305: E78 -E88, 2013. First published May 7, 2013; doi:10.1152/ajpendo.00542.2012.-Blood glucose concentration is tightly regulated by the rate of insulin secretion and clearance, a process partially controlled by sensory neurons serving as metabolic sensors in relevant tissues. The activity of these neurons is regulated by the products of metabolism which regulate transmitter release, and recent evidence suggests that neuronally expressed ion channels of the transient receptor potential (TRP) family function in this critical process. Here, we report the novel finding that the cold and menthol-gated channel TRPM8 is necessary for proper insulin homeostasis. Mice lacking TRPM8 respond normally to a glucose challenge while exhibiting prolonged hypoglycemia in response to insulin. Additionally, Trpm8Ϫ/Ϫ mice have increased rates of insulin clearance compared with wild-type animals and increased expression of insulin-degrading enzyme in the liver. TRPM8 channels are not expressed in the liver, but TRPM8-expressing sensory afferents innervate the hepatic portal vein, suggesting a TRPM8-mediated neuronal control of liver insulin clearance. These results demonstrate that TRPM8 is a novel regulator of serum insulin and support the role of sensory innervation in metabolic homeostasis.insulin; clearance; TRPM8; neuronal; sensitivity MANY TRP FAMILY CATION CHANNELS are essential for the detection of environmental stimuli and their functional role in somatosensation is well established (2). However, these channels are also expressed in primary sensory neurons innervating internal tissues, where the environment changes little, and likely monitor the body's internal environment (30). For example, pancreatic sensory neurons expressing TRPV1, a noxious heat-gated ion channel that is the receptor for capsaicin, the "hot" ingredient in chili peppers, mediate insulin resistance and islet inflammation (24). Furthermore, TRPV1 ϩ neurons innervate the hepatic portal vein (HPV) and are involved in the detection of hypoglycemia (9). Complicating the neuronal role of these channels, recent evidence suggests that many are also expressed in nonneuronal tissues and are involved in other cellular processes related to glucose metabolism. TRPV1 expression has been reported in pancreatic ␤-cell lines, where it may modulate insulin secretion (1), although it is not clear whether TRPV1 is expressed in native ␤-cells (30). Similarly, TRPA1, a broad-spectrum irritant receptor (12), is found in native ␤-cells, and its activation by endogenous ligands induces insulin release via an increase in intracellular calcium (7). Last, several TRPM channels mediate insulin secretion by sensing changes in intracellular second messengers such as Ca 2ϩ and NAD metabolites and are integral in regulation through hormone receptors (30). Thus, TRP ion channels appear to be novel regulators of insulin secretion and pancr...

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Section: E85 Insulin Clearance In Trpm8mentioning

confidence: 97%

Section: E85 Insulin Clearance In Trpm8mentioning

confidence: 99%

Section: E85 Insulin Clearance In Trpm8mentioning

confidence: 99%

See 1 more Smart Citation

Enhanced insulin clearance in mice lacking TRPM8 channels

McCoy

Zhou

Nguyen

et al. 2013

American Journal of Physiology-Endocrinology and Metabolism

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“…However, for a long time, there has been limited amount of information about the location, phenotype, and connectivity of preautonomic neurons. The development of neural tract tracing methods, including the use of transsynaptic retrograde viral tracers, allowed the identification of specific brain nuclei and a more accurate distribution of organ-related neurons and led to the description of detailed neural pathways connecting the hypothalamus and visceral organs, including the brain-liver pathways (6,10,18).…”

Section: Control Of the Liver By Preautonomic Pvn Neurons: Anatomic Amentioning

confidence: 99%

“…Our laboratory used retrograde viral labeling to identify liver-related PVN neurons (10,74). The excitatory neurotransmission of preautonomic liver-related PVN neurons was investigated in a control and a type 1 diabetic mouse model (10).…”

Section: E186 Preautonomic Neurons In the Pvn And Control Of The Livermentioning

confidence: 99%

Brain-liver connections: role of the preautonomic PVN neurons

O’Hare

Zsombok

2016

American Journal of Physiology-Endocrinology and Metabolism

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O'Hare JD, Zsombok A. Brain-liver connections: role of the preautonomic PVN neurons. Am J Physiol Endocrinol Metab 310: E183-E189, 2016. First published December 8, 2015; doi:10.1152/ajpendo.00302.2015.-Diabetes mellitus and the coexisting conditions and complications, including hypo-and hyperglycemic events, obesity, high cholesterol levels, and many more, are devastating problems. Undoubtedly, there is a huge demand for treatment and prevention of these conditions that justifies the search for new approaches and concepts for better management of whole body metabolism. Emerging evidence demonstrates that the autonomic nervous system is largely involved in the regulation of glucose homeostasis; however, the underlying mechanisms are still under investigation. Within the hypothalamus, the paraventricular nucleus (PVN) is in a unique position to integrate neural and hormonal signals to command both the autonomic and neuroendocrine outflow. This minireview will provide a brief overview on the role of preautonomic PVN neurons and the importance of the PVN-liver pathway in the regulation of glucose homeostasis. paraventricular nucleus; liver-related neurons; glucose homeostasis DIABETES MELLITUS is the most common metabolic disorder. The National Diabetes Statistics Report from 2014 published by the Centers for Disease Control and Prevention (8a) estimated that 29.1 million people, which is 9.3% of the US population, suffer from diabetes mellitus. Even more alarming information is that the number of new diabetes cases showed an increase of 1.7 million within 2 yr, and in 2010 diabetes mellitus was listed as the seventh leading cause of death. The coexisting conditions and complications of diabetes mellitus are severe, including hypo-and hyperglycemic events, high blood pressure, obesity, high cholesterol levels, and many more. Undoubtedly, there is a huge demand for treatment and prevention of these conditions that justifies the search for new approaches and solutions for better management of whole body metabolism. One possibility, which has recently attracted more interest, is the role of the brain in the regulation of metabolism (46, 50), particularly the contribution of the autonomic nervous system (ANS) to metabolic control (51,69,73,75).The hypothalamus has been known as one of the critical brain structures that is involved in the regulation and coordination of homeostatic functions. Traditionally, the hypothalamus was appreciated for its neuroendocrine control system; however, its control over the ANS has also been recognized (17,46,51,69,75

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Medicinal Chemistry, Pharmacology, and Clinical Implications of TRPV1 Receptor Antagonists

Tabrizi

Baraldi

et al. 2016

Medicinal Research Reviews

120

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Transient receptor potential vanilloid 1 (TRPV1) is an ion channel expressed on sensory neurons triggering an influx of cations. TRPV1 receptors function as homotetramers responsive to heat, proinflammatory substances, lipoxygenase products, resiniferatoxin, endocannabinoids, protons, and peptide toxins. Its phosphorylation increases sensitivity to both chemical and thermal stimuli, while desensitization involves a calcium-dependent mechanism resulting in receptor dephosphorylation. TRPV1 functions as a sensor of noxious stimuli and may represent a target to avoid pain and injury. TRPV1 activation has been associated to chronic inflammatory pain and peripheral neuropathy. Its expression is also detected in nonneuronal areas such as bladder, lungs, and cochlea where TRPV1 activation is responsible for pathology development of cystitis, asthma, and hearing loss. This review offers a comprehensive overview about TRPV1 receptor in the pathophysiology of chronic pain, epilepsy, cough, bladder disorders, diabetes, obesity, and hearing loss, highlighting how drug development targeting this channel could have a clinical therapeutic potential. Furthermore, it summarizes the advances of medicinal chemistry research leading to the identification of highly selective TRPV1 antagonists and their analysis of structure-activity relationships (SARs) focusing on new strategies to target this channel.

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Transient Receptor Potential Vanilloid Type 1–Dependent Regulation of Liver-Related Neurons in the Paraventricular Nucleus of the Hypothalamus Diminished in the Type 1 Diabetic Mouse

Cited by 47 publications

References 51 publications

Enhanced insulin clearance in mice lacking TRPM8 channels

Enhanced insulin clearance in mice lacking TRPM8 channels

Brain-liver connections: role of the preautonomic PVN neurons

Medicinal Chemistry, Pharmacology, and Clinical Implications of TRPV1 Receptor Antagonists

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