scholarly journals Insulin signalling in tanycytes gates hypothalamic insulin uptake and regulation of AgRP neuron activity

2021 ◽  
Vol 3 (12) ◽  
pp. 1662-1679
Author(s):  
Marta Porniece Kumar ◽  
Anna Lena Cremer ◽  
Paul Klemm ◽  
Lukas Steuernagel ◽  
Sivaraj Sundaram ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Stress Responses ◽  
Arcuate Nucleus ◽  
Protein Quality ◽  
Insulin Signalling ◽  
Critical Role ◽  
Mitochondrial Protein ◽  
Insulin Receptors ◽  
Brain Regions ◽  
Neuron Activity

AbstractInsulin acts on neurons and glial cells to regulate systemic glucose metabolism and feeding. However, the mechanisms of insulin access in discrete brain regions are incompletely defined. Here we show that insulin receptors in tanycytes, but not in brain endothelial cells, are required to regulate insulin access to the hypothalamic arcuate nucleus. Mice lacking insulin receptors in tanycytes (IR∆Tan mice) exhibit systemic insulin resistance, while displaying normal food intake and energy expenditure. Tanycytic insulin receptors are also necessary for the orexigenic effects of ghrelin, but not for the anorexic effects of leptin. IR∆Tan mice exhibit increased agouti-related peptide (AgRP) neuronal activity, while displaying blunted AgRP neuronal adaptations to feeding-related stimuli. Lastly, a highly palatable food decreases tanycytic and arcuate nucleus insulin signalling to levels comparable to those seen in IR∆Tan mice. These changes are rooted in modifications of cellular stress responses and of mitochondrial protein quality control in tanycytes. Conclusively, we reveal a critical role of tanycyte insulin receptors in gating feeding-state-dependent regulation of AgRP neurons and systemic insulin sensitivity, and show that insulin resistance in tanycytes contributes to the pleiotropic manifestations of obesity-associated insulin resistance.

scholarly journals Endothelial insulin receptors differentially control insulin signaling kinetics in peripheral tissues and brain of mice

2017 ◽  
Vol 114 (40) ◽  
pp. E8478-E8487 ◽  
Author(s):  
Masahiro Konishi ◽  
Masaji Sakaguchi ◽  
Samuel M. Lockhart ◽  
Weikang Cai ◽  
Mengyao Ella Li ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Endothelial Cells ◽  
Food Intake ◽  
Insulin Signaling ◽  
Insulin Action ◽  
Insulin Receptors ◽  
Brain Regions ◽  
Peripheral Tissues ◽  
Systemic Insulin Resistance

Insulin receptors (IRs) on endothelial cells may have a role in the regulation of transport of circulating insulin to its target tissues; however, how this impacts on insulin action in vivo is unclear. Using mice with endothelial-specific inactivation of the IR gene (EndoIRKO), we find that in response to systemic insulin stimulation, loss of endothelial IRs caused delayed onset of insulin signaling in skeletal muscle, brown fat, hypothalamus, hippocampus, and prefrontal cortex but not in liver or olfactory bulb. At the level of the brain, the delay of insulin signaling was associated with decreased levels of hypothalamic proopiomelanocortin, leading to increased food intake and obesity accompanied with hyperinsulinemia and hyperleptinemia. The loss of endothelial IRs also resulted in a delay in the acute hypoglycemic effect of systemic insulin administration and impaired glucose tolerance. In high-fat diet-treated mice, knockout of the endothelial IRs accelerated development of systemic insulin resistance but not food intake and obesity. Thus, IRs on endothelial cells have an important role in transendothelial insulin delivery in vivo which differentially regulates the kinetics of insulin signaling and insulin action in peripheral target tissues and different brain regions. Loss of this function predisposes animals to systemic insulin resistance, overeating, and obesity.

Synaptic Regulation of Proopiomelanocortin Neurons Can Occur Distal to the Arcuate Nucleus

2007 ◽  
Vol 97 (5) ◽  
pp. 3298-3304 ◽  
Author(s):  
Shane T. Hentges
Keyword(s):  
Cell Body ◽  
Energy Homeostasis ◽  
Arcuate Nucleus ◽  
Critical Role ◽  
Brain Slices ◽  
Gaba Release ◽  
Afferent Input ◽  
Inhibitory Synapses ◽  
Body Region ◽  
Neuron Activity

Energy homeostasis is controlled to a large extent by various signals that are integrated in the hypothalamus. It is generally considered that neurons in each of the hypothalamic nuclei are regulated by afferent projections that terminate within the cell body region of the nucleus. However, here it is shown that hypothalamic proopiomelanocortin (POMC) neurons receive synaptic inputs onto distal dendrites that reside outside of the cell body region in the arcuate nucleus. Previous studies using whole cell recordings from identified neurons in brain slices have shown that cannabinoids reduce GABA release from inhibitory synapses onto the POMC cells. Here it was found that endocannabinoids inhibited GABAergic inhibitory postsynaptic currents in POMC neurons only in intact sagittal brain slices, but not coronal, horizontal, or sagittal slices that were truncated rostrally at the level of the optic chiasm. Thus endocannabinoids inhibited presynaptic GABA release only at an anatomically distinct subset of POMC–neuron dendrites that extends rostrally beyond the arcuate nucleus into preoptic hypothalamic regions. There are two key results. First, the activity of POMC neurons can be regulated by afferent input at sites much farther from the soma than previously recognized. Second, endocannabinoids can act to inhibit inputs only at selective dendrites. POMC neurons play a critical role in the maintenance of body weight. Therefore these data suggest that energy balance may be regulated, in part, by modulation of POMC neuron activity at sites outside of the arcuate nucleus.

scholarly journals Mir-338-3p Mediates Tnf-A-Induced Hepatic Insulin Resistance by Targeting PP4r1 to Regulate PP4 Expression

2017 ◽  
Vol 41 (6) ◽  
pp. 2419-2431 ◽  
Author(s):  
Lin Dou ◽  
Shuyue Wang ◽  
Libo Sun ◽  
Xiuqing Huang ◽  
Yang Zhang ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Protein Phosphatase ◽  
Insulin Signalling ◽  
Critical Role ◽  
Transcriptional Regulator ◽  
Signalling Pathway ◽  
Hepatic Insulin Resistance ◽  
Luciferase Assay ◽  
Insulin Signalling Pathway ◽  
Tnf Α

Objective: Insulin resistance is a critical factor contributing to the pathogenesis of type 2 diabetes and other metabolic diseases. Recent studies have indicated that miR-338-3p plays an important role in cancer. Here, we investigated whether miR-338-3p mediates tumour necrosis factor-α (TNF-α)-induced hepatic insulin resistance. Methods: The activation of the insulin signalling pathway and the level of glycogenesis were examined in the livers of the db/db and high fat diet (HFD)-fed mice and in HEP1-6 cells transfected with miR-338-3p mimic or inhibitor. Computational prediction of microRNA target, luciferase assay and Western blot were used to assess the miR-338-3p target. Chromatin immunoprecipitation (ChIP) assay was used to determine the transcriptional regulator of miR-338-3p. Results: miR-338-3p was down-regulated in the livers of the db/db, HFD-fed and TNF-α-treated C57BL/6J mice, as well as in mouse HEP1-6 hepatocytes treated with TNF-α. Importantly the down-regulation of miR-338-3p induced insulin resistance, as indicated by impaired glucose tolerance and insulin tolerance. Further research showed that the down-regulated miR-338-3p resulted in the impaired AKT/ glycogen synthase kinase 3 beta (GSl·Gβ) signalling pathway and glycogen synthesis. In contrast, hepatic over-expression of miR-338-3p rescued the TNF-α-induced insulin resistance. Moreover, protein phosphatase 4 regulator subunit 1 (PP4R1) was identified as a direct target of miR-338-3p that mediated hepatic insulin signalling by regulating protein phosphatase 4 (PP4). Finally we identified hepatic nuclear factor 4 alpha (HNF-4α) as the transcriptional regulator of miRNA-338-3p. Conclusions: Our studies provide novel insight into the critical role and molecular mechanism by which miR-338-3p is involved in TNF-α-induced hepatic insulin resistance. miR-338-3p might mediate TNF-α-induced hepatic insulin resistance by targeting PP4R1 to regulate PP4 expression.

High-fat diets induce a rapid loss of the insulin anorectic response in the amygdala

2009 ◽  
Vol 297 (5) ◽  
pp. R1302-R1311 ◽  
Author(s):  
Stéphane Boghossian ◽  
Karalee Lemmon ◽  
MieJung Park ◽  
David A. York
Keyword(s):  
Insulin Resistance ◽  
Food Intake ◽  
Insulin Response ◽  
Insulin Receptors ◽  
Brain Regions ◽  
Sprague Dawley ◽  
High Fat ◽  
Sd Rats ◽  
High Fat Diets ◽  
Fat Diets

Intracerebroventricular insulin decreases food intake (FI) . The central bed nucleus of the amygdala (CeA), as other regions of the brain regulating feeding behavior, expresses insulin receptors. Our objectives were to show an insulin anorectic response in the amygdala, study the effect of high-fat diets on this response, and map the neural network activated by CeA insulin using c-Fos immunohistochemistry. Sprague-Dawley (SD) rats fitted with unilateral CeA cannulas were adapted to a low-fat (LFD) diet before they were fed a high-fat diet (HFD). Their feeding response to CeA saline or insulin (8 mU) was tested after 24 h, 72 h, or 7 days of being on a HFD. In a second experiment, SD rats were fed the HFD for 3, 7, or 49 days and were then refed with the LFD. They were tested for their insulin response before and after an HFD and every 3 days for the following weeks. Insulin tolerance tests were performed in a parallel group of rats. The CeA insulin stimulation c-Fos expression was studied to identify the distribution of activated neuronal populations. Feeding an HFD for 72 h or more induced a CeA, but not peripheral, insulin resistance, which was slowly reversed by LFD refeeding. The duration of HFD feeding determined the time frame for reversal of the insulin resistance. CeA insulin increased c-Fos in multiple brain regions, including the arcuate nucleus/paraventricular nucleus region of the hypothalamus. We conclude that the amygdala may be an important site for insulin regulation of food intake and may have a significant role in determining susceptibility to HFD-induced obesity.

scholarly journals Estrogen-Negative Feedback and Estrous Cyclicity Are Critically Dependent Upon Estrogen Receptor-α Expression in the Arcuate Nucleus of Adult Female Mice

Endocrinology ◽  
2014 ◽  
Vol 155 (8) ◽  
pp. 2986-2995 ◽  
Author(s):  
Shel-Hwa Yeo ◽  
Allan E. Herbison
Keyword(s):  
Estrogen Receptor ◽  
Negative Feedback ◽  
Arcuate Nucleus ◽  
Critical Role ◽  
Estrogen Receptor Α ◽  
Feedback Mechanism ◽  
Neuron Activity ◽  
Female Mice ◽  
Negative Feedback Mechanism ◽  
Estrous Cyclicity

The location and characteristics of cells within the brain that suppress GnRH neuron activity to contribute to the estrogen-negative feedback mechanism are poorly understood. Using adeno-associated virus (AAV)-mediated Cre-LoxP recombination in estrogen receptor-α (ERα) floxed mice (ERαflox/flox), we aimed to examine the role of ERα-expressing neurons located in the arcuate nucleus (ARN) in the estrogen-negative feedback mechanism. Bilateral injection of AAV-Cre into the ARN of ERαflox/flox mice (n = 14) resulted in the time-dependent ablation of up to 99% of ERα-immunoreactive cell numbers throughout the rostrocaudal length of the ARN. These mice were all acyclic by 5 weeks after AAV-Cre injections with most mice in constant estrous. Control wild-type mice injected with AAV-Cre (n = 13) were normal. Body weight was not altered in ERαflox/flox mice. After ovariectomy, a significant increment in LH secretion was observed in all genotypes, although its magnitude was reduced in ERαflox/flox mice. Acute and chronic estrogen-negative feedback were assessed by administering 17β-estradiol to mice as a bolus (LH measured 3 h later) or SILASTIC brand capsule implant (LH measured 5 d later). This demonstrated that chronic estrogen feedback was absent in ERαflox/flox mice, whereas the acute feedback was normal. These results reveal a critical role for ERα-expressing cells within the ARN in both estrous cyclicity and the chronic estrogen negative feedback mechanism in female mice. This suggests that ARN cells provide a key indirect, transsynpatic route through which estradiol suppresses the activity of GnRH neurons.

scholarly journals Oxidative stress during insulin resistance in prediabetes : a review on role of antioxidants

2020 ◽  
Vol 11 (3) ◽  
pp. 3511-3520
Author(s):  
Mohsina Hyder ◽  
Raja D ◽  
Visakh Varma ◽  
Ponnusankar S
Keyword(s):  
Oxidative Stress ◽  
Insulin Resistance ◽  
Vitamin C ◽  
Structural Integrity ◽  
Cell Function ◽  
Islet Cells ◽  
Insulin Signalling ◽  
Insulin Receptors ◽  
Redox Balance ◽  
Peroxyl Radicals

Oxidative stress is one of the major causal factors behind insulin resistance during prediabetes. It can impair insulin signalling by triggering stress activated signaling pathways and can also directly oxidize and damage the proteins of these pathways. Although cells have impressive stock of antioxidant enzymes and minor antioxidant moieties, these agents may not be adequate to maintain the redox balance during oxidative stress. The important functional antioxidant vitamins for tissue protection from excess free radicals comprises vitamin C, E and A. Vitamin C can improve insulin resistance by altering endothelial function and reducing oxidative stress. Vitamin E is an excellent trap for peroxyl radicals which suppresses ROS production in the pancreas, preserves pancreatic β cell function and maintains structural integrity of pancreatic islet cells. Vitamin A prevents tissue oxidative damage as well as exhibits a regenerative role in the pancreas. Like vitamins, minerals play a crucial role during oxidative stress and insulin resistance. Zinc is crucial for insulin actions and carbohydrate metabolism. Chromium activates insulin receptors through the oligopeptidechromudulin, which occurs in the insulin sensitive cells that binds to the insulin receptor, thereby increasing insulin signal transduction and sensitivity. Selenium up regulates glutathione peroxidase activity can inhibit NF-kappa B activation. The risk of diabetes and its complications will be more with elevating oxidative stress. Interventions with these antioxidants have proven beneficial role in reducing oxidative stress which can be utilized for reduction of insulin resistance in prediabetes.

Individual arcuate nucleus proopiomelanocortin neurons project to select target sites

2021 ◽  
Author(s):  
Marissa J Metz ◽  
Caitlin M Daimon ◽  
Connie M. King ◽  
Andrew R. Rau ◽  
Shane T Hentges
Keyword(s):  
Arcuate Nucleus ◽  
Brain Regions ◽  
Small Population ◽  
Retrograde Tracing ◽  
Neuron Activity ◽  
Synaptic Connections ◽  
Toxin B ◽  
Cholera Toxin B ◽  
Afferent Projections ◽  
Target Sites

Proopiomelanocortin (POMC) neurons in the arcuate nucleus of the hypothalamus (ARH) are a diverse group of neurons that project widely to different brain regions. It is unknown how this small population of neurons organizes its afferent projections. In this study, we hypothesized that individual ARH POMC neurons exclusively innervate select target regions. To investigate this hypothesis, we first verified that only a fraction of ARH POMC neurons innervate the lateral hypothalamus (LH), the paraventricular nucleus of the hypothalamus (PVN), the periaqueductal gray (PAG), or the ventral tegmental area (VTA) using the retrograde tracer cholera toxin B (CTB). Next, two versions of CTB conjugated to distinct fluorophores were injected bilaterally into two of the regions such that PVN and VTA, PAG and VTA, or LH and PVN received tracers simultaneously. These pairs of target sites were chosen based on function and location. Few individual ARH POMC neurons projected to two brain regions at once, suggesting that there are ARH POMC neuron subpopulations organized by their afferent projections. We also investigated whether increasing the activity of POMC neurons could increase the number of ARH POMC neurons labeled with CTB, implying an increase in new synaptic connections to downstream regions. However, chemogenetic enhancement of POMC neuron activity did not increase retrograde tracing of CTB back to ARH POMC neurons from either the LH, PVN, or VTA. Overall, subpopulations of ARH POMC neurons with distinct afferent projections may serve as a way for the POMC population to organize its many functions.

scholarly journals Shot-Gun Proteomic Analysis on Roots of Arabidopsis pldα1 Mutants Suggesting the Involvement of PLDα1 in Mitochondrial Protein Import, Vesicular Trafficking and Glucosinolate Biosynthesis

2018 ◽  
Vol 20 (1) ◽  
pp. 82 ◽  
Author(s):  
Tomáš Takáč ◽  
Olga Šamajová ◽  
Pavol Vadovič ◽  
Tibor Pechan ◽  
Jozef Šamaj
Keyword(s):  
Endoplasmic Reticulum ◽  
Stress Responses ◽  
Proteomic Analysis ◽  
Protein Import ◽  
Protein Quality ◽  
Mitochondrial Protein ◽  
Biotic And Abiotic Stress ◽  
Mitochondrial Protein Import ◽  
Enzymatic Production ◽  
Glucosinolate Biosynthesis

Phospholipase Dα1 (PLDα1) belongs to phospholipases, a large phospholipid hydrolyzing protein family. PLDα1 has a substrate preference for phosphatidylcholine leading to enzymatic production of phosphatidic acid, a lipid second messenger with multiple cellular functions. PLDα1 itself is implicated in biotic and abiotic stress responses. Here, we present a shot-gun differential proteomic analysis on roots of two Arabidopsis pldα1 mutants compared to the wild type. Interestingly, PLDα1 deficiency leads to altered abundances of proteins involved in diverse processes related to membrane transport including endocytosis and endoplasmic reticulum-Golgi transport. PLDα1 may be involved in the stability of attachment sites of endoplasmic reticulum to the plasma membrane as suggested by increased abundance of synaptotagmin 1, which was validated by immunoblotting and whole-mount immunolabelling analyses. Moreover, we noticed a robust abundance alterations of proteins involved in mitochondrial import and electron transport chain. Notably, the abundances of numerous proteins implicated in glucosinolate biosynthesis were also affected in pldα1 mutants. Our results suggest a broader biological involvement of PLDα1 than anticipated thus far, especially in the processes such as endomembrane transport, mitochondrial protein import and protein quality control, as well as glucosinolate biosynthesis.

scholarly journals Failure to Guard: Mitochondrial Protein Quality Control in Cancer

2021 ◽  
Vol 22 (15) ◽  
pp. 8306
Author(s):  
Joseph E. Friedlander ◽  
Ning Shen ◽  
Aozhuo Zeng ◽  
Sovannarith Korm ◽  
Hui Feng
Keyword(s):  
Quality Control ◽  
Stress Responses ◽  
Surveillance System ◽  
Protein Quality ◽  
Protein Translocation ◽  
Mitochondrial Protein ◽  
Protein Quality Control ◽  
Mitochondrial Proteins ◽  
Anti Cancer ◽  
Key Pathways

Mitochondria are energetic and dynamic organelles with a crucial role in bioenergetics, metabolism, and signaling. Mitochondrial proteins, encoded by both nuclear and mitochondrial DNA, must be properly regulated to ensure proteostasis. Mitochondrial protein quality control (MPQC) serves as a critical surveillance system, employing different pathways and regulators as cellular guardians to ensure mitochondrial protein quality and quantity. In this review, we describe key pathways and players in MPQC, such as mitochondrial protein translocation-associated degradation, mitochondrial stress responses, chaperones, and proteases, and how they work together to safeguard mitochondrial health and integrity. Deregulated MPQC leads to proteotoxicity and dysfunctional mitochondria, which contributes to numerous human diseases, including cancer. We discuss how alterations in MPQC components are linked to tumorigenesis, whether they act as drivers, suppressors, or both. Finally, we summarize recent advances that seek to target these alterations for the development of anti-cancer drugs.

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