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 Minimal impact of age and housing temperature on the metabolic phenotype of Acc2−/− mice

2015 ◽  
Vol 228 (3) ◽  
pp. 127-134 ◽  
Author(s):  
Amanda E Brandon ◽  
Ella Stuart ◽  
Simon J Leslie ◽  
Kyle L Hoehn ◽  
David E James ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Body Composition ◽  
Energy Expenditure ◽  
Glucose Tolerance ◽  
Fat Mass ◽  
Knockout Mice ◽  
Muscle Glycogen ◽  
Insulin Action ◽  
Metabolic Phenotype ◽  
Whole Body

An important regulator of fatty acid oxidation (FAO) is the allosteric inhibition of CPT-1 by malonyl-CoA produced by the enzyme acetyl-CoA carboxylase 2 (ACC2). Initial studies suggested that deletion of Acc2 (Acacb) increased fat oxidation and reduced adipose tissue mass but in an independently generated strain of Acc2 knockout mice we observed increased whole-body and skeletal muscle FAO and a compensatory increase in muscle glycogen stores without changes in glucose tolerance, energy expenditure or fat mass in young mice (12–16 weeks). The aim of the present study was to determine whether there was any effect of age or housing at thermoneutrality (29 °C; which reduces total energy expenditure) on the phenotype of Acc2 knockout mice. At 42–54 weeks of age, male WT and Acc2−/− mice had similar body weight, fat mass, muscle triglyceride content and glucose tolerance. Consistent with younger Acc2−/− mice, aged Acc2−/− mice showed increased whole-body FAO (24 h average respiratory exchange ratio=0.95±0.02 and 0.92±0.02 for WT and Acc2−/− mice respectively, P<0.05) and skeletal muscle glycogen content (+60%, P<0.05) without any detectable change in whole-body energy expenditure. Hyperinsulinaemic–euglycaemic clamp studies revealed no difference in insulin action between groups with similar glucose infusion rates and tissue glucose uptake. Housing Acc2−/− mice at 29 °C did not alter body composition, glucose tolerance or the effects of fat feeding compared with WT mice. These results confirm that manipulation of Acc2 may alter FAO in mice, but this has little impact on body composition or insulin action.

scholarly journals Lack of Syndecan-1 produces significant alterations in whole-body composition, metabolism and glucose homeostasis in mice

2020 ◽  
Vol 11 (4) ◽  
pp. 126-136
Author(s):  
Anil Kumar Jaiswal ◽  
Mohanraj Sadasivam ◽  
Susan Aja ◽  
Abdel Rahim A Hamad
Keyword(s):  
Body Composition ◽  
Glucose Homeostasis ◽  
Whole Body

scholarly journals A Hierarchical Whole-body Modeling Approach Elucidates the Link between in Vitro Insulin Signaling and in Vivo Glucose Homeostasis

2011 ◽  
Vol 286 (29) ◽  
pp. 26028-26041 ◽  
Author(s):  
Elin Nyman ◽  
Cecilia Brännmark ◽  
Robert Palmér ◽  
Jan Brugård ◽  
Fredrik H. Nyström ◽  
...  
Keyword(s):  
Glucose Homeostasis ◽  
Insulin Signaling ◽  
Whole Body ◽  
Modeling Approach

Defective water and glycerol transport in the proximal tubules of AQP7 knockout mice

2005 ◽  
Vol 289 (6) ◽  
pp. F1195-F1200 ◽  
Author(s):  
Eisei Sohara ◽  
Tatemitsu Rai ◽  
Jun-ichi Miyazaki ◽  
A. S. Verkman ◽  
Sei Sasaki ◽  
...  
Keyword(s):  
Knockout Mice ◽  
Water Channel ◽  
Physiological Role ◽  
Wild Type ◽  
Double Knockout ◽  
Straight Tubule ◽  
Glycerol Transport ◽  
Straight Tubules ◽  
Proximal Straight Tubule ◽  
Urinary Concentrating Ability

The aquaporin-7 (AQP7) water channel is known as a member of the aquaglyceroporins, which facilitate the transport of glycerol as well as water. Although AQP7 is abundantly expressed on the apical membrane of the proximal straight tubules in the kidney, the physiological role of AQP7 is still unknown. To investigate this, we generated AQP7 knockout mice. The water permeability of the proximal tubule brush-border membrane measured by the stopped-flow method was slightly but significantly reduced in the AQP7 knockout mice compared with that of wild-type mice (AQP7, 18.0 ± 0.4 × 10−3 cm/s vs. wild-type, 20.0 ± 0.3 × 10−3 cm/s). Although AQP7 solo-knockout mice did not exhibit a urinary concentrating defect, AQP1/AQP7 double-knockout mice had a reduction in urinary concentrating ability compared with AQP1 solo-knockout mice, suggesting that the amount of water reabsorbed through AQP7 in the proximal straight tubules is physiologically substantial. On the other hand, AQP7 knockout mice showed marked glyceroluria (AQP7, 1.7 ± 0.34 mg/ml vs. wild-type, 0.005 ± 0.002 mg/ml). This identified a novel glycerol reabsorption pathway in the proximal straight tubules. In two mouse models of proximal straight tubule injury, the cisplatin-induced acute renal failure (ARF) model and the ischemic ARF model, an increase in urine glycerol was observed (pretreatment, 0.007 ± 0.005 mg/ml; cisplatin, 0.063 ± 0.043 mg/ml; ischemia, 0.076 ± 0.02 mg/ml), suggesting that urine glycerol could be used as a new biomarker for detecting proximal straight tubule injury.

scholarly journals MFN1 and MFN2 Are Dispensable for Sperm Development and Functions in Mice

2021 ◽  
Vol 22 (24) ◽  
pp. 13507
Author(s):  
Junru Miao ◽  
Wei Chen ◽  
Pengxiang Wang ◽  
Xin Zhang ◽  
Lei Wang ◽  
...  
Keyword(s):  
Germ Cells ◽  
Knockout Mice ◽  
Seminiferous Tubules ◽  
Wild Type ◽  
Double Knockout ◽  
Wild Type Littermate ◽  
Mitofusin 2 ◽  
Sperm Development ◽  
Mitofusin 1 ◽  
Deficient Mice

MFN1 (Mitofusin 1) and MFN2 (Mitofusin 2) are GTPases essential for mitochondrial fusion. Published studies revealed crucial roles of both Mitofusins during embryonic development. Despite the unique mitochondrial organization in sperm flagella, the biological requirement in sperm development and functions remain undefined. Here, using sperm-specific Cre drivers, we show that either Mfn1 or Mfn2 knockout in haploid germ cells does not affect male fertility. The Mfn1 and Mfn2 double knockout mice were further analyzed. We found no differences in testis morphology and weight between Mfn-deficient mice and their wild-type littermate controls. Spermatogenesis was normal in Mfn double knockout mice, in which properly developed TRA98+ germ cells, SYCP3+ spermatocytes, and TNP1+ spermatids/spermatozoa were detected in seminiferous tubules, indicating that sperm formation was not disrupted upon MFN deficiency. Collectively, our findings reveal that both MFN1 and MFN2 are dispensable for sperm development and functions in mice.

scholarly journals Caspase-3/NLRP3 signaling in the mesenchymal stromal niche regulates myeloid-biased hematopoiesis

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Jing Zhang ◽  
Yaozhen Chen ◽  
Dandan Yin ◽  
Fan Feng ◽  
Qunxing An ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Knockout Mice ◽  
Caspase 3 ◽  
Ex Vivo ◽  
Gene Knockout ◽  
Hematopoietic Stem ◽  
Nlrp3 Gene ◽  
Gene Knockout Mice ◽  
Deficient Mice

Abstract Background The fate of hematopoietic stem cells (HSCs) is determined by a complex regulatory network that includes both intrinsic and extrinsic signals. In the past decades, many intrinsic key molecules of HSCs have been shown to control hematopoiesis homeostasis. Non-hematopoietic niche cells also contribute to the self-renewal, quiescence, and differentiation of HSCs. Mesenchymal stromal cells (MSCs) have been identified as important components of the niche. However, the regulatory role of MSCs in hematopoiesis has not been fully understood. Methods Caspase-3 and NLRP3 gene knockout mice were generated respectively, and hematopoietic development was evaluated in the peripheral circulation and bone marrow by flow cytometry, colony formation assay, and bone marrow transplantation. Bone-associated MSCs (BA-MSCs) were then isolated from gene knockout mice, and the effect of Caspase-3/NLRP3 deficient BA-MSCs on hematopoiesis regulation was explored in vivo and ex vivo. Results We report that Caspase-3 deficient mice exhibit increased myelopoiesis and an aberrant HSC pool. Ablation of Caspase-3 in BA-MSCs regulates myeloid lineage expansion by altering the expression of hematopoietic retention cytokines, including SCF and CXCL12. Interestingly, NLRP3 gene knockout mice share phenotypic similarities with Caspase-3 deficient mice. Additionally, we found that NLRP3 may play a role in myeloid development by affecting the cell cycle and apoptosis of hematopoietic progenitors. Conclusions Our data demonstrate that the Caspase-3/NLRP3 signaling functions as an important regulator in physiological hematopoiesis, which provides new insights regarding niche signals that influence hematopoiesis regulation in the bone marrow.

scholarly journals Specificity of aminergic status in skin and tumor of C57BL/6-PlautmI.IBug-This Plau6FDhu/GFDhu mice with B16/F10 melanoma

2020 ◽  
Vol 66 (6) ◽  
pp. 707-711
Author(s):  
Oleg Kit ◽  
Elena Frantsiyants ◽  
Irina Kaplieva ◽  
Ekaterina Surikova ◽  
Irina Neskubina ◽  
...  
Keyword(s):  
Biogenic Amines ◽  
Knockout Mice ◽  
Gene Knockout ◽  
Local Stress ◽  
Plasminogen Activation ◽  
Intact Skin ◽  
Gene Knockout Mice ◽  
Hydroxyindoleacetic Acid ◽  
Solitary Metastases ◽  
Deficient Mice

Background. Systems of plasminogen activation and biogenic amines are involved in carcinogenesis, but their relationship has not been established. Aim – study of the quantitative specificity of biogenic amines in the skin and melanoma in urokinase-gene knockout mice. Materials and methods.  Levels of catecholamines, histamine, serotonin and 5-hydroxyindoleacetic acid (HIAA) were determined by ELISA in the skin and В16/F10 melanoma of urokinase (uPA) -gene knockout mice of both genders (n=24); С57ВL/6 mice (n=64) were controls (C). Results. Differential characteristics of melanoma development in uPA-deficient mice included: an earlier onset of the primary tumor and its slow growth, more pronounced in females, in combination with hemorrhages in the lungs of males and solitary metastases in the lungs of females. This was facilitated by higher levels of norepinephrine in the skin of males/females – by 4.8/4.9 times, histamine – by 3.6/1.7 (p<0.05) times and serotonin – by 3.4/8.3 times. Dopamine accumulated in melanoma in all uPA-gene knockout mice: in females –1.6 times (p<0.05), in males – 2.1 times higher than in intact skin, with a 2.5 times reduction of norepinephrine in females. Levels of histamine decreased, but exceeded controls: in females – by 1.8 times (p<0.05), in males –by 3.5 times. Levels of serotonin in uPA-deficient females were as high, while in males they were 3.4 times lower than in intact skin. Conclusions. The specificity of the aminergic system in the skin of uPA-gene knockout mice demonstrated the inhibition of local stress and contributed to the reduction of malignant potential of melanoma by increasing immune properties of the skin.

scholarly journals Role of thin descending limb urea transport in renal urea handling and the urine concentrating mechanism

2011 ◽  
Vol 301 (6) ◽  
pp. F1251-F1259 ◽  
Author(s):  
Tianluo Lei ◽  
Lei Zhou ◽  
Anita T. Layton ◽  
Hong Zhou ◽  
Xuejian Zhao ◽  
...  
Keyword(s):  
Knockout Mice ◽  
Gene Knockout ◽  
Embryonic Stem ◽  
Urine Osmolality ◽  
Peripheral Circulation ◽  
Solute Concentration ◽  
Urine Concentration ◽  
Wild Type ◽  
Double Knockout ◽  
Knockout Mouse Model

Urea transporters UT-A2 and UT-B are expressed in epithelia of thin descending limb of Henle's loop and in descending vasa recta, respectively. To study their role and possible interaction in the context of the urine concentration mechanism, a UT-A2 and UT-B double knockout (UT-A2/B knockout) mouse model was generated by targeted deletion of the UT-A2 promoter in embryonic stem cells with UT-B gene knockout. The UT-A2/B knockout mice lacked detectable UT-A2 and UT-B transcripts and proteins and showed normal survival and growth. Daily urine output was significantly higher in UT-A2/B knockout mice than that in wild-type mice and lower than that in UT-B knockout mice. Urine osmolality in UT-A2/B knockout mice was intermediate between that in UT-B knockout and wild-type mice. The changes in urine osmolality and flow rate, plasma and urine urea concentration, as well as non-urea solute concentration after an acute urea load or chronic changes in protein intake suggested that UT-A2 plays a role in the progressive accumulation of urea in the inner medulla. These results suggest that in wild-type mice UT-A2 facilitates urea absorption by urea efflux from the thin descending limb of short loops of Henle. Moreover, UT-A2 deletion in UT-B knockout mice partially remedies the urine concentrating defect caused by UT-B deletion, by reducing urea loss from the descending limbs to the peripheral circulation; instead, urea is returned to the inner medulla through the loops of Henle and the collecting ducts.

scholarly journals Comparison of Ocular Pathologies in Vitamin A–Deficient Mice and RPE65 Gene Knockout Mice

2011 ◽  
Vol 52 (8) ◽  
pp. 5507 ◽  
Author(s):  
Yang Hu ◽  
Ying Chen ◽  
Gennadiy Moiseyev ◽  
Yusuke Takahashi ◽  
Robert Mott ◽  
...  
Keyword(s):  
Vitamin A ◽  
Knockout Mice ◽  
Gene Knockout ◽  
Gene Knockout Mice ◽  
Deficient Mice

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.

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