Gpr17 in AgRP Neurons Regulates Feeding and Sensitivity to Insulin and Leptin

Ren, Hongxia; Cook, Joshua R.; Kon, Ning; Accili, Domenico

doi:10.2337/db15-0390

Cited by 34 publications

(35 citation statements)

References 36 publications

(55 reference statements)

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“…[534,564]), whereas disruption of NPY expression in adult rats by AAV-mediated overexpression of antisense RNAs impairs feeding and causes weight loss [565]. It has also been proposed that the main effects of AgRP-neurons on appetite require the neurons themselves, but not necessarily AgRP or NPY [530,564]. Corrective adaptations to lifelong knock-out of Pomc do not seem to occur: those animals become obese, as expected (reviewed in Refs.…”

Section: Boxmentioning

confidence: 82%

“…4). Unphosphorylated FOXO1 in the nucleus promotes appetite by driving transcription of the orexigenic Agrp gene (and the possibly orexigenic Gpr17 gene) and by suppressing transcription of the anorexigenic Pomc gene [517,529,530,552]. Thus, AKT-mediated phosphorylation and exclusion of FOXO1 from the nucleus inhibits appetite by arresting FOXO1-dependent transcription of Agrp and Gpr17, while releasing the Pomc gene from FOXO1-dependent suppression ( Fig.…”

Section: Normal Effects Of Central Insulin On the Regulation Of Appetmentioning

confidence: 98%

“…In addition, these neurons abundantly express the G-protein-coupled receptor GPR17 [529]. This molecule has become the source of recent controversy whether it possesses significant orexigenic effects [530] or not [531]. A distinct group of first-order arcuate neurons produces anorexigenic (appetite-suppressing) neuropeptides, chiefly POMC and cocaine-and amphetamine-regulated transcript (CART).…”

Section: Normal Effects Of Central Insulin On the Regulation Of Appetmentioning

confidence: 99%

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Imbalanced insulin action in chronic over nutrition: Clinical harm, molecular mechanisms, and a way forward

Williams

2016

Atherosclerosis

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The growing worldwide prevalence of overnutrition and underexertion threatens the gains that we have made against atherosclerotic cardiovascular disease and other maladies. Chronic overnutrition causes the atherometabolic syndrome, which is a cluster of seemingly unrelated health problems characterized by increased abdominal girth and body-mass index, high fasting and postprandial concentrations of cholesterol- and triglyceride-rich apoB-lipoproteins (C-TRLs), low plasma HDL levels, impaired regulation of plasma glucose concentrations, hypertension, and a significant risk of developing overt type 2 diabetes mellitus (T2DM). In addition, individuals with this syndrome exhibit fatty liver, hypercoagulability, sympathetic overactivity, a gradually rising set-point for body adiposity, a substantially increased risk of atherosclerotic cardiovascular morbidity and mortality, and--crucially--hyperinsulinemia. Many lines of evidence indicate that each component of the atherometabolic syndrome arises, or is worsened by, pathway-selective insulin resistance and responsiveness (SEIRR). Individuals with SEIRR require compensatory hyperinsulinemia to control plasma glucose levels. The result is overdrive of those pathways that remain insulin-responsive, particularly ERK activation and hepatic de-novo lipogenesis (DNL), while carbohydrate regulation deteriorates. The effects are easily summarized: if hyperinsulinemia does something bad in a tissue or organ, that effect remains responsive in the atherometabolic syndrome and T2DM; and if hyperinsulinemia might do something good, that effect becomes resistant. It is a deadly imbalance in insulin action. From the standpoint of human health, it is the worst possible combination of effects. In this review, we discuss the origins of the atherometabolic syndrome in our historically unprecedented environment that only recently has become full of poorly satiating calories and incessant enticements to sit. Data are examined that indicate the magnitude of daily caloric imbalance that causes obesity. We also cover key aspects of healthy, balanced insulin action in liver, endothelium, brain, and elsewhere. Recent insights into the molecular basis and pathophysiologic harm from SEIRR in these organs are discussed. Importantly, a newly discovered oxide transport chain functions as the master regulator of the balance amongst different limbs of the insulin signaling cascade. This oxide transport chain--abbreviated 'NSAPP' after its five major proteins--fails to function properly during chronic overnutrition, resulting in this harmful pattern of SEIRR. We also review the origins of widespread, chronic overnutrition. Despite its apparent complexity, one factor stands out. A sophisticated junk food industry, aided by subsidies from willing governments, has devoted years of careful effort to promote overeating through the creation of a new class of food and drink that is low- or no-cost to the consumer, convenient, savory, calorically dense, yet weakly satiating. It is past time for the rest of us ...

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Section: Boxmentioning

confidence: 82%

Section: Normal Effects Of Central Insulin On the Regulation Of Appetmentioning

confidence: 98%

Section: Normal Effects Of Central Insulin On the Regulation Of Appetmentioning

confidence: 99%

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Imbalanced insulin action in chronic over nutrition: Clinical harm, molecular mechanisms, and a way forward

Williams

2016

Atherosclerosis

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“…In a subsequent study, leptin and insulin were shown to coordinately regulate FoxO1 activity, increasing the expression of NPY and AgRP and suppressing POMC expression 115 , 116 . Recently, Gpr17, the target of FoxO1, was shown to regulate feeding and sensitivity through insulin and leptin in AgRP neurons 117 , 118 . However, leptin and insulin-mediated PI3K signalling was only shown to play a role in POMC expression in the presence of short-term alterations in leptin levels.…”

Section: Pi3k/akt Pathway In the Brainmentioning

confidence: 99%

The PI3K/AKT pathway in obesity and type 2 diabetes

et al. 2018

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Obesity and type 2 diabetes mellitus are complicated metabolic diseases that affect multiple organs and are characterized by hyperglycaemia. Currently, stable and effective treatments for obesity and type 2 diabetes mellitus are not available. Therefore, the mechanisms leading to obesity and diabetes and more effective ways to treat obesity and diabetes should be identified. Based on accumulated evidences, the PI3K/AKT signalling pathway is required for normal metabolism due to its characteristics, and its imbalance leads to the development of obesity and type 2 diabetes mellitus. This review focuses on the role of PI3K/AKT signalling in the skeletal muscle, adipose tissue, liver, brain and pancreas, and discusses how this signalling pathway affects the development of the aforementioned diseases. We also summarize evidences for recently identified therapeutic targets of the PI3K/AKT pathway as treatments for obesity and type 2 diabetes mellitus. PI3K/AKT pathway damaged in various tissues of the body leads to obesity and type 2 diabetes as the result of insulin resistance, and in turn, insulin resistance exacerbates the PI3K/AKT pathway, forming a vicious circle.

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“…Other hormones, such as leptin and insulin, may control activity of AgRP/NPY neurons in feeding and metabolism. In this respect, leptin signals to reduce food intake by inducing exclusion of Foxo1 from the nucleus of AgRP/NPY neurons and downstream expression of a purinergic G-protein-coupled receptors (GPCR), Gpr17 (Kitamura et al 2006, Ren et al 2012, Ren et al 2015. Insulin signaling also takes place in AgRP/NPY neurons to decrease their activity by inducing neuronal hyperpolarization.…”

Section: Signaling In Agrp/npy Neuronsmentioning

confidence: 99%

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

Baldini

Phelan

2019

Journal of Endocrinology

174

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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Gpr17 in AgRP Neurons Regulates Feeding and Sensitivity to Insulin and Leptin

Cited by 34 publications

References 36 publications

Imbalanced insulin action in chronic over nutrition: Clinical harm, molecular mechanisms, and a way forward

Imbalanced insulin action in chronic over nutrition: Clinical harm, molecular mechanisms, and a way forward

The PI3K/AKT pathway in obesity and type 2 diabetes

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

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