scholarly journals Endogenous nicotinamide riboside metabolism protects against diet-induced liver damage

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Audrey Sambeat ◽  
Joanna Ratajczak ◽  
Magali Joffraud ◽  
José L. Sanchez-Garcia ◽  
Maria P. Giner ◽  
...  
Keyword(s):  
Metabolic Disorders ◽  
Physiological Role ◽  
Whole Body ◽  
Nicotinamide Riboside ◽  
Hepatic Cells ◽  
Broad Array ◽  
Rate Limiting ◽  
Fat Feeding ◽  
Deficient Mice

Abstract Supplementation with the NAD+ precursor nicotinamide riboside (NR) ameliorates and prevents a broad array of metabolic and aging disorders in mice. However, little is known about the physiological role of endogenous NR metabolism. We have previously shown that NR kinase 1 (NRK1) is rate-limiting and essential for NR-induced NAD+ synthesis in hepatic cells. To understand the relevance of hepatic NR metabolism, we generated whole body and liver-specific NRK1 knockout mice. Here, we show that NRK1 deficiency leads to decreased gluconeogenic potential and impaired mitochondrial function. Upon high-fat feeding, NRK1 deficient mice develop glucose intolerance, insulin resistance and hepatosteatosis. Furthermore, they are more susceptible to diet-induced liver DNA damage, due to compromised PARP1 activity. Our results demonstrate that endogenous NR metabolism is critical to sustain hepatic NAD+ levels and hinder diet-induced metabolic damage, highlighting the relevance of NRK1 as a therapeutic target for metabolic disorders.

Pathophysiology of genetic deficiency in tissue kallikrein activity in mouse and man

2013 ◽  
Vol 110 (09) ◽  
pp. 476-483 ◽  
Author(s):  
Ludovic Waecke ◽  
Louis Potier ◽  
Christine Richer ◽  
Ronan Roussel ◽  
Nadine Bouby ◽  
...  
Keyword(s):  
Human Subjects ◽  
Physiological Role ◽  
Tissue Kallikrein ◽  
Site Mutation ◽  
Cardiac Ischaemia ◽  
Kinin Receptors ◽  
At1 Receptor Antagonists ◽  
Kallikrein Activity ◽  
Deficient Mice

SummaryStudy of mice rendered deficient in tissue kallikrein (TK) by gene inactivation and human subjects partially deficient in TK activity as consequence of an active site mutation has allowed recognising the physiological role of TK and its peptide products kinins in arterial function and in vasodilatation, in both species. TK appears as the major kinin forming enzyme in arteries, heart and kidney. Non-kinin mediated actions of TK may occur in epithelial cells in the renal tubule. In basal condition, TK deficiency induces mild defective phenotypes in the cardiovascular system and the kidney. However, in pathological situations where TK synthesis is typically increased and kinins are produced, TK deficiency has major, deleterious consequences. This has been well documented experimentally for cardiac ischaemia, diabetes renal disease, peripheral ischaemia and aldosterone-salt induced hypertension. These conditions are all aggravated by TK deficiency. The beneficial effect of ACE/kininase II inhibitors or angiotensin II AT1 receptor antagonists in cardiac ischaemia is abolished in TK-deficient mice, suggesting a prominent role for TK and kinins in the cardioprotective action of these drugs. Based on findings made in TK-deficient mice and additional evidence obtained by pharmacological or genetic inactivation of kinin receptors, development of novel therapeutic approaches relying on kinin receptor agonism may be warranted.

scholarly journals Dual Ablation of Grb10 and Grb14 in Mice Reveals Their Combined Role in Regulation of Insulin Signaling and Glucose Homeostasis

2009 ◽  
Vol 30 (5) ◽  
pp. 540-540
Author(s):  
Lowenna J. Holt ◽  
Ruth J. Lyons ◽  
Ashleigh S. Ryan ◽  
Susan M. Beale ◽  
Andrew Ward ◽  
...  
Keyword(s):  
Body Composition ◽  
Glucose Homeostasis ◽  
Insulin Signaling ◽  
Knockout Mice ◽  
Gene Knockout ◽  
Physiological Role ◽  
Whole Body ◽  
Regulatory Function ◽  
Double Knockout ◽  
Deficient Mice

ABSTRACT Growth factor receptor bound (Grb)10 and Grb14 are closely related adaptor proteins that bind directly to the insulin receptor (IR) and regulate insulin-induced IR tyrosine phosphorylation and signaling to IRS-1 and Akt. Grb10- and Grb14-deficient mice both exhibit improved whole-body glucose homeostasis as a consequence of enhanced insulin signaling and, in the case of the former, altered body composition. However, the combined physiological role of these adaptors has remained undefined. In this study we utilize compound gene knockout mice to demonstrate that although deficiency in one adaptor can enhance insulin-induced IRS-1 phosphorylation and Akt activation, insulin signaling is not increased further upon dual ablation of Grb10 and Grb14. Context-dependent limiting mechanisms appear to include IR hypophosphorylation and decreased IRS-1 expression. In addition, the compound knockouts exhibit an increase in lean mass comparable to Grb10-deficient mice, indicating that this reflects a regulatory function specific to Grb10. However, despite the absence of additive effects on insulin signaling and body composition, the double-knockout mice are protected from the impaired glucose tolerance that results from high-fat feeding, whereas protection is not observed with animals deficient for individual adaptors. These results indicate that, in addition to their described effects on IRS-1/Akt, Grb10 and Grb14 may regulate whole-body glucose homeostasis by additional mechanisms and highlight these adaptors as potential therapeutic targets for amelioration of the insulin resistance associated with type 2 diabetes.

scholarly journals APP deficiency results in resistance to obesity but impairs glucose tolerance upon high fat feeding

2018 ◽  
Vol 237 (3) ◽  
pp. 311-322 ◽  
Author(s):  
Juliane K Czeczor ◽  
Amanda J Genders ◽  
Kathryn Aston-Mourney ◽  
Timothy Connor ◽  
Liam G Hall ◽  
...  
Keyword(s):  
Energy Expenditure ◽  
Glucose Tolerance ◽  
Cell Mass ◽  
Tolerance Test ◽  
Whole Body ◽  
Dark Phase ◽  
High Fat ◽  
Neuronal Metabolism ◽  
Fat Feeding ◽  
Deficient Mice

The amyloid precursor protein (APP) generates a number of peptides when processed through different cleavage mechanisms, including the amyloid beta peptide that is implicated in the development of Alzheimer’s disease. It is well established that APP via its cleaved peptides regulates aspects of neuronal metabolism. Emerging evidence suggests that amyloidogenic processing of APP can lead to altered systemic metabolism, similar to that observed in metabolic disease states. In the present study, we investigated the effect of APP deficiency on obesity-induced alterations in systemic metabolism. Compared with WT littermates, APP-deficient mice were resistant to diet-induced obesity, which was linked to higher energy expenditure and lipid oxidation throughout the dark phase and was associated with increased spontaneous physical activity. Consistent with this lean phenotype, APP-deficient mice fed a high-fat diet (HFD) had normal insulin tolerance. However, despite normal insulin action, these mice were glucose intolerant, similar to WT mice fed a HFD. This was associated with reduced plasma insulin in the early phase of the glucose tolerance test. Analysis of the pancreas showed that APP was required to maintain normal islet and β-cell mass under high fat feeding conditions. These studies show that, in addition to regulating aspects of neuronal metabolism, APP is an important regulator of whole body energy expenditure and glucose homeostasis under high fat feeding conditions.

scholarly journals Impaired oxidative metabolism and inflammation are associated with insulin resistance in ERα-deficient mice

2010 ◽  
Vol 298 (2) ◽  
pp. E304-E319 ◽  
Author(s):  
Vicent Ribas ◽  
M. T. Audrey Nguyen ◽  
Darren C. Henstridge ◽  
Anh-Khoi Nguyen ◽  
Simon W. Beaven ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Whole Body ◽  
High Fat ◽  
Estrogen Action ◽  
Skeletal Muscle Insulin Resistance ◽  
The Metabolic Syndrome ◽  
Normal Chow ◽  
Fat Feeding ◽  
Deficient Mice ◽  
Pai 1

Impaired estrogen action is associated with the metabolic syndrome in humans. We sought to determine whether impaired estrogen action in female C57Bl6 mice, produced by whole body Esr1 ablation, could recapitulate aspects of this syndrome, including inflammation, insulin resistance, and obesity. Indeed, we found that global knockout (KO) of the estrogen receptor (ER)α leads to reduced oxygen uptake and caloric expenditure compared with wild-type (WT) mice. In addition, fasting insulin, leptin, and PAI-1 levels were markedly elevated, whereas adiponectin levels were reduced in normal chow-fed KO. Furthermore, ERα-KO mice exhibited impaired glucose tolerance and marked skeletal muscle insulin resistance that was accompanied by the accumulation of bioactive lipid intermediates, inflammation, and diminished PPARα, PPARδ, and UCP2 transcript levels. Although the relative glucose intolerance and insulin resistance phenotype in KO mice became more severe with high-fat feeding, WT mice were refractory to these dietary-induced effects, and this protection coincided with a marked increase in circulating adiponectin and heat shock protein 72 levels in muscle, liver, and fat. These data indicate that ERα is critical for the maintenance of whole body insulin action and protection against tissue inflammation during both normal chow and high-fat feeding.

scholarly journals What is the physiological role of hypothalamic tanycytes in metabolism?

2021 ◽  
Author(s):  
Matei Bolborea ◽  
Fanny Langlet
Keyword(s):  
Energy Balance ◽  
Metabolic Disorders ◽  
Neural Circuits ◽  
Physiological Function ◽  
Physiological Role ◽  
Optimal Conditions ◽  
Age Related ◽  
New Research ◽  
Opening Up

In vertebrates, the energy balance process is tightly controlled by complex neural circuits that sense metabolic signals and adjust food intake and energy expenditure in line with the physiological requirements of optimal conditions. Within neural networks controlling energy balance, tanycytes are peculiar ependymoglial cells that are nowadays recognized as multifunctional players in the metabolic hypothalamus. However, the physiological function of hypothalamic tanycytes remains unclear, creating a number of ambiguities in the field. Here, we review data accumulated over the years that demonstrate the physiological function of tanycytes in the maintenance of metabolic homeostasis, opening up new research avenues. The presumed involvement of tanycytes in the pathophysiology of metabolic disorders and age-related neurodegenerative diseases will be finally discussed.

scholarly journals miR-21 blocks obesity in mice: a potential therapy for humans

2020 ◽  
Author(s):  
Said Lhamyani ◽  
Adriana-Mariel Gentile ◽  
Rosa M. Giráldez-Pérez ◽  
Mónica Feijóo-Cuaresma ◽  
Silvana Yanina Romero-Zerbo ◽  
...  
Keyword(s):  
High Fat Diet ◽  
Drug Targets ◽  
Metabolic Disorders ◽  
Molecular Mechanisms ◽  
Caloric Intake ◽  
Physiological Role ◽  
Expression Of Genes ◽  
Obesity In Mice ◽  
Metabolically Healthy

AbstractmicroRNAs are promising drug targets in obesity and metabolic disorders. miR-21 expression is upregulated in obese white adipose tissue (WAT); however, its physiological role in WAT has not been fully explored. We aimed to dissect the underlying molecular mechanisms of miR-21 in treating obesity, diabetes, and insulin resistance. We demonstrated, in human and mice, that elevated miR-21 expression is associated with metabolically healthy obesity. miR-21 mimic affected the expression of genes associated with adipogenesis, thermogenesis, and browning in 3T3-L1 adipocytes. In addition, it blocked high fat diet-induced weight gain in obese mice, without modifying food intake or physical activity. This was associated with metabolic enhancements, WAT browning and thermogenic programming, and brown AT induction through VEGF-A, p53, and TGFβ1 signaling pathways. Our findings add a novel role of miR-21 in the regulation of obesity and a potential therapy for both obesity and T2D without altering caloric intake and physical activities.

scholarly journals Protrudin-deficient mice manifest depression-like behavior with abnormalities in activity, attention, and cued fear-conditioning

2020 ◽  
Vol 13 (1) ◽  
Author(s):  
Michiko Shirane ◽  
Hirotaka Shoji ◽  
Yutaka Hashimoto ◽  
Hiroyuki Katagiri ◽  
Shizuka Kobayashi ◽  
...  
Keyword(s):  
Fear Conditioning ◽  
Neuronal Development ◽  
Physiological Role ◽  
Loss Of Function ◽  
Reduced Body ◽  
Intermediate Phenotypes ◽  
Behavioral Abnormalities ◽  
And Behavior ◽  
Deficient Mice

Abstract Protrudin is a protein that resides in the membrane of the endoplasmic reticulum and is highly expressed in the nervous system. Although mutations in the human protrudin gene (ZFYVE27, also known as SPG33) give rise to hereditary spastic paraplegia (HSP), the physiological role of the encoded protein has been largely unclear. We therefore generated mice deficient in protrudin and subjected them to a battery of behavioral tests designed to examine their intermediate phenotypes. The protrudin-deficient mice were found to have a reduced body size and to manifest pleiotropic behavioral abnormalities, including hyperactivity, depression-like behavior, and deficits in attention and fear-conditioning memory. They exhibited no signs of HSP, however, consistent with the notion that HSP-associated mutations of protrudin may elicit neural degeneration, not as a result of a loss of function, but rather as a result of a gain of toxic function. Overall, our results suggest that protrudin might play an indispensable role in normal neuronal development and behavior.

Vascular development in chick embryos: a possible role for adenosine

1989 ◽  
Vol 256 (1) ◽  
pp. H240-H246 ◽  
Author(s):  
T. H. Adair ◽  
J. P. Montani ◽  
D. M. Strick ◽  
A. C. Guyton
Keyword(s):  
Growth Regulation ◽  
Vascular System ◽  
Biological Effects ◽  
Physiological Role ◽  
Ringer Solution ◽  
Whole Body ◽  
Chick Embryos ◽  
Endogenous Adenosine ◽  
Maximum Decrease

We studied the possible role of adenosine in the development of the vasculature using 217 chick embryos. Adenosine (2-32 mumol/day), inosine (16 mumol/day), dipyridamole (0.04-0.4 mumol/day), or aminophylline (400 and 800 micrograms/day) were administered twice each day into the air space on days 11-14. Control embryos received Ringer solution. Whole body vascularity was estimated on day 15 as the whole body structural vascular resistance (SVR), i.e., the hydraulic resistance of the maximally dilated vasculature. Adenosine decreased the SVR in a dose-related manner at the lower dosage amounts but caused a maximum decrease in SVR at the higher dosage amounts averaging 30% below the Ringer control values. Equimolar amounts of adenosine and inosine decreased the SVR by the same extent. Dipyridamole, which potentiates the biological effects of endogenous adenosine, also decreased the SVR in a dose-related manner to values averaging approximately 30% below control. When the effects of endogenous adenosine were blocked by aminophylline, the SVR increased in a dose-related manner to approximately 100% above control at the highest dosage amount. These results suggest that adenosine could have a physiological role in growth regulation of the vascular system in the chick embryo.

scholarly journals Inducible nitric oxide synthase provides protection against injury-induced thrombosis in female mice

2011 ◽  
Vol 301 (2) ◽  
pp. H617-H624 ◽  
Author(s):  
Rita K. Upmacis ◽  
Hao Shen ◽  
Lea Esther S. Benguigui ◽  
Brian D. Lamon ◽  
Ruba S. Deeb ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Ex Vivo ◽  
Physiological Role ◽  
Thrombotic Occlusion ◽  
Female Mice ◽  
Eicosanoid Production ◽  
Oxide Synthase ◽  
Deficient Mice ◽  
Inducible Nitric Oxide

Nitric oxide (NO) is an important vasoactive molecule produced by three NO synthase (NOS) enzymes: neuronal (nNOS), inducible (iNOS), and endothelial NOS (eNOS). While eNOS contributes to blood vessel dilation that protects against the development of hypertension, iNOS has been primarily implicated as a disease-promoting isoform during atherogenesis. Despite this, iNOS may play a physiological role via the modulation of cyclooxygenase and thromboregulatory eicosanoid production. Herein, we examined the role of iNOS in a murine model of thrombosis. Blood flow was measured in carotid arteries of male and female wild-type (WT) and iNOS-deficient mice following ferric chloride-induced thrombosis. Female WT mice were more resistant to thrombotic occlusion than male counterparts but became more susceptible upon iNOS deletion. In contrast, male mice (with and without iNOS deletion) were equally susceptible to thrombosis. Deletion of iNOS was not associated with a change in the balance of thromboxane A2 (TxA2) or antithrombotic prostacyclin (PGI2). Compared with male counterparts, female WT mice exhibited increased urinary nitrite and nitrate levels and enhanced ex vivo induction of iNOS in hearts and aortas. Our findings suggest that iNOS-derived NO in female WT mice may attenuate the effects of vascular injury. Thus, although iNOS is detrimental during atherogenesis, physiological iNOS levels may contribute to providing protection against thrombotic occlusion, a phenomenon that may be enhanced in female mice.

scholarly journals The substrate specificity of acid α-glucosidase from rabbit muscle

1971 ◽  
Vol 124 (4) ◽  
pp. 701-711 ◽  
Author(s):  
T. N. Palmer
Keyword(s):  
Substrate Inhibition ◽  
Physiological Role ◽  
Liver Glycogen ◽  
Rabbit Muscle ◽  
Ph Optimum ◽  
Enzyme Action ◽  
Rate Limiting ◽  
Kinetics Of ◽  
Hydrolysis Of

1. Acid α-glucosidase was purified 3500-fold from rabbit muscle. 2. The enzyme was activated by cations, the degree of activation varying with the substrate. Enzyme action on glycogen was most strongly activated and activation was apparently of a non-competitive type. With rabbit liver glycogen as substrate, the relative Vmax. increased 15-fold, accompanied by an increase in Km from 8.3 to 68.6mm-chain end over the cation range 2–200mm-Na+ at pH4.5. Action on maltose was only moderately activated (1.3-fold, non-competitively) and action on maltotriose was marginally and competitively inhibited. 3. The pH optimum at 2mm-Na+ was 4.5 (maltose) and 5.1 (glycogen). Cation activation of enzyme action on glycogen was markedly pH-dependent. At 200mm-Na+, the pH optimum was 4.8 and activity was maximally stimulated in the range pH4.5–3.3. 4. Glucosidase action on maltosaccharides was associated with pronounced substrate inhibition at concentrations exceeding 5mm. Of the maltosaccharides tested, the enzyme showed a preference for p-nitrophenyl α-maltoside (Km 1.2mm) and maltotriose (Km 1.8mm). The extrapolated Km for enzyme action on maltose was 3.7mm. 5. The macromolecular polysaccharide substrate glycogen differed from linear maltosaccharide substrates in the kinetics of its interaction with the enzyme. Activity was markedly dependent on pH, cation concentration and polysaccharide structure. There was no substrate inhibition. 6. The enzyme exhibited constitutive α-1,6-glucanohydrolase activity. The Km for panose was 20mm. 7. The enzyme catalysed the total conversion of glycogen into glucose. The hydrolysis of α-1,6-linkages was apparently rate-limiting during the hydrolysis of glycogen. 8. Enzyme action on glycogen and maltose released the α-anomer of d-glucose. 9. The results are discussed in terms of the physiological role of acid α-glucosidase in lysosomal glycogen catabolism.

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