scholarly journals Nicotinamide Nucleotide Transhydrogenase (Nnt) is Related to Obesity in Mice

2020 ◽  
Vol 52 (12) ◽  
pp. 877-881
Author(s):  
Anne Kunath ◽  
John T. Heiker ◽  
Matthias Kern ◽  
Joanna Kosacka ◽  
Gesine Flehmig ◽  
...  
Keyword(s):  
Fat Mass ◽  
Metabolic Diseases ◽  
Body Weight Gain ◽  
Wild Type ◽  
Inner Mitochondrial Membrane ◽  
Nicotinamide Nucleotide Transhydrogenase ◽  
Diet Induced Obesity ◽  
Highly Sensitive ◽  
Obesity In Mice

AbstractThe C57BL/6J (B6J) mouse strain has been widely used as a control strain for the study of metabolic diseases and diet induced obesity (DIO). B6J mice carry a spontaneous deletion mutation in the nicotinamide nucleotide transhydrogenase (Nnt) gene eliminating exons 7–11, resulting in expression of a truncated form of Nnt, an enzyme that pumps protons across the inner mitochondrial membrane. It has been proposed that this mutation in B6J mice is associated with epigonadal fat mass and altered sensitivity to diet induced obesity. To define the role of Nnt in the development of diet induced obesity, we generated first backcross (BC1) hybrids of wild type Nnt C57BL/6NTac and mutated Nnt C57BL/6JRj [(C57BL/6NTac×C57BL/6JRj)F1×C57BL/6NTac]. Body weight gain and specific fat-pad depot mass were measured in BC1 hybrids under high fat diet conditions. Both sexes of BC1 hybrids indicate that mice with Nnt wild type allele are highly sensitive to DIO and exhibit higher relative fat mass. In summary, our data indicate that the Nnt mutation in mice is associated with sensitivity to DIO and fat mass.

scholarly journals Knockout of inositol-requiring enzyme 1α in pro-opiomelanocortin neurons decreases fat mass via increasing energy expenditure

Open Biology ◽  
2016 ◽  
Vol 6 (8) ◽  
pp. 160131 ◽  
Author(s):  
Yuzhong Xiao ◽  
Tingting Xia ◽  
Junjie Yu ◽  
Yalan Deng ◽  
Hao Liu ◽  
...  
Keyword(s):  
Energy Expenditure ◽  
Metabolic Diseases ◽  
Critical Role ◽  
Liver Steatosis ◽  
Leptin Resistance ◽  
Hormone Production ◽  
Melanocyte Stimulating Hormone ◽  
Diet Induced Obesity ◽  
Brown Adipose

Although numerous functions of inositol-requiring enzyme 1α (IRE1α) have been identified, a role of IRE1α in pro-opiomelanocortin (POMC) neurons in the arcuate nucleus of the hypothalamus is largely unknown. Here, we showed that mice lacking IRE1α specifically in POMC neurons (PIKO) are lean and resistant to high-fat diet-induced obesity and obesity-related insulin resistance, liver steatosis and leptin resistance. Furthermore, PIKO mice had higher energy expenditure, probably due to increased thermogenesis in brown adipose tissue. Additionally, α-melanocyte-stimulating hormone production was increased in the hypothalamus of PIKO mice. These results demonstrate that IRE1α in POMC neurons plays a critical role in the regulation of obesity and obesity-related metabolic disorders. Our results also suggest that IRE1α is not only an endoplasmic reticulum stress sensor, but also a new potential therapeutic target for obesity and obesity-related metabolic diseases.

scholarly journals Recombination Can Cause Telomere Elongations as Well as Truncations Deep within Telomeres in Wild-Type Kluyveromyces lactis Cells

2010 ◽  
Vol 10 (2) ◽  
pp. 226-236 ◽  
Author(s):  
Laura H. Bechard ◽  
Nathan Jamieson ◽  
Michael J. McEachern
Keyword(s):  
Great Increase ◽  
Kluyveromyces Lactis ◽  
High Rate ◽  
Wild Type ◽  
Content Type ◽  
Normal Length ◽  
Highly Sensitive ◽  
Significant Process ◽  
Type Size

ABSTRACT In this study, we examined the role of recombination at the telomeres of the yeast Kluyveromyces lactis . We demonstrated that an abnormally long and mutationally tagged telomere was subject to high rates of telomere rapid deletion (TRD) that preferentially truncated the telomere to near-wild-type size. Unlike the case in Saccharomyces cerevisiae , however, there was not a great increase in TRD in meiosis. About half of mitotic TRD events were associated with deep turnover of telomeric repeats, suggesting that telomeres were often cleaved to well below normal length prior to being reextended by telomerase. Despite its high rate of TRD, the long telomere showed no increase in the rate of subtelomeric gene conversion, a highly sensitive test of telomere dysfunction. We also showed that the long telomere was subject to appreciable rates of becoming elongated substantially further through a recombinational mechanism that added additional tagged repeats. Finally, we showed that the deep turnover that occurs within normal-length telomeres was diminished in the absence of RAD52 . Taken together, our results suggest that homologous recombination is a significant process acting on both abnormally long and normally sized telomeres in K. lactis .

TRPV4 deficiency increases skeletal muscle metabolic capacity and resistance against diet-induced obesity

2012 ◽  
Vol 112 (7) ◽  
pp. 1223-1232 ◽  
Author(s):  
Tatsuya Kusudo ◽  
Zhonghua Wang ◽  
Atsuko Mizuno ◽  
Makoto Suzuki ◽  
Hitoshi Yamashita
Keyword(s):  
Skeletal Muscle ◽  
Energy Metabolism ◽  
Phosphoenolpyruvate Carboxykinase ◽  
Transient Receptor Potential ◽  
Thermal Sensation ◽  
Chow Diet ◽  
Type I ◽  
Wild Type ◽  
Diet Induced Obesity ◽  
Obesity In Mice

Transient receptor potential channel V4 (TRPV4) functions as a nonselective cation channel in various cells and plays physiological roles in osmotic and thermal sensation. However, the function of TRPV4 in energy metabolism is unknown. Here, we report that TRPV4 deficiency results in increased muscle oxidative capacity and resistance to diet-induced obesity in mice. Although no difference in body weight was observed between wild-type and Trpv4−/− mice when fed a standard chow diet, obesity phenotypes induced by a high-fat diet were significantly improved in Trpv4−/− mice, without any change in food intake. Quantitative analysis of mRNA revealed the constitutive upregulation of many genes, including those for transcription factors such as peroxisome proliferator-activated receptor α and for metabolic enzymes such as phosphoenolpyruvate carboxykinase. These upregulated genes were especially prominent in oxidative skeletal muscle, in which the activity of Ca2+-dependent phosphatase calcineurin was elevated, suggesting that other Ca2+ channels function in the skeletal muscle of Trpv4−/− mice. Indeed, gene expressions for TRPC3 and TRPC6 increased in the muscles of Trpv4−/− mice compared with those of wild-type mice. The number of oxidative type I fiber also increased in the mutant muscles following myogenin gene induction. These results strongly suggested that inactivation of Trpv4 induces compensatory increases in TRPC3 and TRPC6 production, and elevation of calcineurin activity, affecting energy metabolism through increased expression of genes involved in fuel oxidation in skeletal muscle and thereby contributing to increased energy expenditure and protection from diet-induced obesity in mice.

scholarly journals L-Theanine Activates the Browning of White Adipose Tissue through the AMPK/α-Ketoglutarate/Prdm16 Axis and Ameliorates Diet-induced Obesity in Mice

2021 ◽  
Author(s):  
Wan-Qiu Peng ◽  
Gang Xiao ◽  
Bai-Yu Li ◽  
Ying-Ying Guo ◽  
Liang Guo ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
White Adipose Tissue ◽  
Intraperitoneal Administration ◽  
Dna Demethylation ◽  
Active Dna Demethylation ◽  
Diet Induced Obesity ◽  
Elevated Expression ◽  
Obesity In Mice

L-Theanine is a nonprotein amino acid with much beneficial efficacy. We found that intraperitoneal treatment of the mice with L-Theanine(100mg/kg/day) enhanced adaptive thermogenesis and induced the browning of inguinal white adipose tissue (iWAT) with elevated expression of Prdm16, Ucp1 and other thermogenic genes. Meanwhile, administration of the mice with L-Theanine increased energy expenditure. In vitro studies indicated that L-Theanine induced the development of brown-like features in adipocytes. The shRNA-mediated depletion of Prdm16 blunted the role of L-Theanine in promoting the brown-like phenotypes in adipocytes and in the iWAT of mice. L-Theanine treatment enhanced AMPKα phosphorylation both in adipocytes and in iWAT. Knockdown of AMPKα ablolished L-Theanine-induced upregulation of Prdm16 and adipocytes browning. L-Theanine increased the α-ketoglutarate (α-KG) level in adipocytes, which may increase the transcription of Prdm16 by inducing active DNA demethylation on its promoter. AMPK activation was required for L-Theanine-induced increase of α-KG and DNA demethylation on Prdm16 promoter. Moreover, intraperitoneal administration with L-Theanine ameliorated obesity, improved glucose tolerance and insulin sensitivity, and reduced plasma triglyceride, total cholesterol and free fatty acid in the high fat diet-fed mice. Our results suggest a potential role of L-Theanine in combating diet-induced obesity in mice, which may involve L-Theanine-induced browning of white adipose tissue.

scholarly journals Inactivation of Ppp1r15a minimises weight gain and insulin resistance during caloric excess in mice

2018 ◽  
Author(s):  
Vruti Patel ◽  
Guillaume Bidault ◽  
Joseph E. Chambers ◽  
Stefania Carobbio ◽  
Angharad J. T. Everden ◽  
...  
Keyword(s):  
Weight Gain ◽  
Food Intake ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
Standard Diet ◽  
Wild Type ◽  
Diet Induced Obesity ◽  
Caloric Excess ◽  
Deficient Mice

AbstractPhosphorylation of the translation initiation factor eIF2α within the mediobasal hypothalamus is known to suppress food intake, but the role of the eIF2α phosphatases in regulating body weight is poorly understood. Mice deficient in active PPP1R15A, a stress-inducible eIF2α phosphatase, are healthy and more resistant to endoplasmic reticulum stress than wild type controls. We report that when Ppp1r15a mutant mice are fed a high fat diet they gain less weight than wild type littermates owing to reduced food intake. This results in healthy leaner Ppp1r15a mutant animals with reduced hepatic steatosis and improved insulin sensitivity, albeit with a modest defect in insulin secretion. By contrast, no weight differences are observed between wild type and Ppp1r15a deficient mice fed a standard diet. We conclude that mice lacking the C-terminal PP1-binding domain of PPP1R15A show reduced dietary intake and preserved glucose tolerance. Our data indicate that this results in reduced weight gain and protection from diet-induced obesity.

scholarly journals Role of miRNA in the Transmission of Metabolic Diseases Associated With Paternal Diet-Induced Obesity

2019 ◽  
Vol 10 ◽  
Author(s):  
Charlotte Dupont ◽  
Laurent Kappeler ◽  
Sarah Saget ◽  
Valérie Grandjean ◽  
Rachel Lévy
Keyword(s):  
Metabolic Diseases ◽  
Diet Induced Obesity

Highly Sensitive Quenching Probe (QProbe) Method Is Useful to Detect c-Kit Mutation and to Predict Relapse of t(8;21)(q22;q22) Acute Myeloid Leukemia.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2646-2646
Author(s):  
Satoshi Wakita ◽  
Hiroki Yamaguchi ◽  
Yoshio Mitamura ◽  
Fumiko Kosaka ◽  
Koiti Inokuchi ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Stem Cell ◽  
Myeloid Leukemia ◽  
Direct Sequence ◽  
Wild Type ◽  
Kit Mutation ◽  
Highly Sensitive ◽  
Quenching Probe ◽  
Acute Myeloid

Abstract Abstract 2646 Poster Board II-622 Background: t(8;21)(q22;q22) acute myeloid leukemia (t(8;21) AML) show a high rate of complete remission (CR) and prolonged CR duration, especially following consolidation chemotherapy with high-dose cytarabine (HD-ARAC), and are thought to have a better prognosis than other AML patients. Nevertheless, only approximately 50% of patients were alive at 5 years. This suggests that some patients have more aggressive leukemic phenotypes and indicates the need for predictive molecular marker of relapse and treatment optimization with novel and/or more aggressive therapies such as stem cell transplantation.Recently, several groups reported that c-kit mutation (MutKIT) defined an unfavorable subgroup in t(8;21) AML. However MutKIT has been reported approximately 20% at diagnostic samples of core binding factor leukemia. It is possible that MutKIT are more high frequency at relapse sample of t(8;21) AML. In the present study, we analyzed samples collected at diagnosis and relapse to investigate the role of MutKIT s and Flt3 internal tandem duplication (ITD) in t(8;21) AML. Methods: We analyzed MutKIT and Flt3 ITD among 32 t(8;21) AML patients diagnosed between 1991 to 2009 at the Nippon Medical School. All of them were succeeded achieving CR, but 18 patients (56.3%) relapsed, became refractory chemotherapy, and poor prognosis. Exon 8 and 17 of MutKIT were analyzed by direct sequence and QProbe-system (ARKRAY, Inc. Kyoto, Japan). QProbe-system was high sensitivity mutation screening method, detected approximately 1% MutKIT using mutation specific guanine quenching probe (Leukemia Res 32 (2008) 1462–1467). FLT3 ITD was analyzed by PCR amplification. Results: Using direct sequence, MutKITs were found in 5 (18.5%) of the 27 patients at diagnosis (D816V: 3 patients AN822K: 2 patients), and 7 (46.6%) of 15 patients at relapse. Interestingly 3 patients were detected MutKIT at only relapse (D816V: 2 patients AN822K: 1 patient). All mutations found in exon 17 clustered within the A-loop. Next we analyzed to detected very slight amount of mutation by QProbe-system. N822K were newly found of the 3 patients at diagnosis in spite of negative by direct sequence Finally MutKIT were found 8 (29.6%) at diagnosis. Flt3 ITD were found in 2 (9.5%) of the 21 patents at diagnosis, and none of 15 patients at relapse. 2 patients with Flt3 ITD were not accompanied MutKIT. All of N822K newly found by QProbe-system and Flt3 ITD positive patients were relapsed but turn to mutation negative. To evaluate the importance of MutKIT as a predicted relapse, we analyzed the cumulative incidence of relapse (CIR) and relapse free survival (RFS) of these patients with Kaplan-Meier method. The CIR was higher for patients with MutKIT (p=0.040, Wild type c-kit (WtKIT): 45.8% vs MutKIT: 87.5%). In direct sequencing method, The RFS tend to be shorter for patient with MutKIT, but no significant differences (p=0.260; WtKIT: 30 months vs MutKIT: 11 months).On the other hand, in QProbe-system, the median RFS was shorter for patients with MutKIT (p=0.033; WtKIT: 64 months vs MutKIT: 11 months). In addition of FLT3-ITD analysis, median RFS was shorter for patients with MutKIT or FLT3 ITD (p=0.005; Wild type of both genes: 64 months vs MutKIT or FLT3 ITD: 10 months). Additionally, we compared overall survival (OS) of wild type of both genes with MutKIT or FLT3 ITD. The OS tend to be shorter for patient with MutKIT or FLT3 ITD, but no significant differences. Discussion: In this study, we confirmed the prognostic significance of MutKIT in patients with t(8;21) AML when we use the highly sensitive quenching probe method (QProbe-system). We showed that QProbe-system is quite useful in predicting the prognosis of patients with t(8;21) AML and in determining its therapeutic strategy including tyrosine kinase inhibitors and/or up-front stem cell transplantation. We also revealed the important role of MutKIT (46.7%) at relapse, but several questions were still remained. It is unknown for some patients how to gain MutKIT at only relapse and why mutations detected at diagnosis were disappeared at relapse. We need further study to clarify the function and commitment of MutKIT in relapse of t(8;21) AML. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Role of Muscle c-Jun NH2-Terminal Kinase 1 in Obesity-Induced Insulin Resistance

2009 ◽  
Vol 30 (1) ◽  
pp. 106-115 ◽  
Author(s):  
Guadalupe Sabio ◽  
Norman J. Kennedy ◽  
Julie Cavanagh-Kyros ◽  
Dae Young Jung ◽  
Hwi Jin Ko ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
High Fat Diet ◽  
Wild Type ◽  
High Fat ◽  
Akt Activation ◽  
Peripheral Insulin Resistance ◽  
Diet Induced Obesity

ABSTRACT Obesity caused by feeding of a high-fat diet (HFD) is associated with an increased activation of c-Jun NH2-terminal kinase 1 (JNK1). Activated JNK1 is implicated in the mechanism of obesity-induced insulin resistance and the development of metabolic syndrome and type 2 diabetes. Significantly, Jnk1 − / − mice are protected against HFD-induced obesity and insulin resistance. Here we show that an ablation of the Jnk1 gene in skeletal muscle does not influence HFD-induced obesity. However, muscle-specific JNK1-deficient (MKO) mice exhibit improved insulin sensitivity compared with control wild-type (MWT) mice. Thus, insulin-stimulated AKT activation is suppressed in muscle, liver, and adipose tissue of HFD-fed MWT mice but is suppressed only in the liver and adipose tissue of MKO mice. These data demonstrate that JNK1 in muscle contributes to peripheral insulin resistance in response to diet-induced obesity.

scholarly journals The cGAS/STING Pathway Is Important for Dendritic Cell Activation but Is Not Essential to Induce Protective Immunity against Mycobacterium tuberculosis Infection

2018 ◽  
Vol 10 (3) ◽  
pp. 239-252 ◽  
Author(s):  
Fabio V. Marinho ◽  
Sulayman Benmerzoug ◽  
Stephanie  Rose ◽  
Priscila C. Campos ◽  
João T. Marques ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Cell Activation ◽  
Body Weight Gain ◽  
Host Cells ◽  
Health Concern ◽  
Wild Type ◽  
Activation Markers ◽  
Sting Pathway

Mycobacterium tuberculosis (Mtb) infection remains a major public health concern. The STING (stimulator of interferon genes) pathway contributes to the cytosolic surveillance of host cells. Most studies on the role of STING activation in Mtb infection have focused on macrophages. Moreover, a detailed investigation of the role of STING during Mtb infection in vivo is required. Here, we deciphered the involvement of STING in the activation of dendritic cells (DCs) and the host response to Mtb infection in vivo. In DCs, this adaptor molecule was important for Ifn-β expression and IL-12 production as well as for the surface expression of the activation markers CD40 and CD86. We also documented that Mtb DNA induces STING activation in murine fibroblasts. In vivo Mtb aerogenic infection induced the upregulation of the STING and cGAS (cyclic GMP-AMP synthase) genes, and Ifn-β pulmonary expression was dependent on both sensors. However, mice deficient for STING or cGAS presented a similar outcome to wild-type controls, with no major alterations in body weight gain, bacterial burden, or survival. Lung inflammation, proinflammatory cytokine production, and inflammatory cell recruitment were similar in STING- and cGAS-deficient mice compared to wild-type controls. In summary, although the STING pathway seems to be crucial for DC activation during Mtb infection, it is dispensable for host protection in vivo.

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