scholarly journals Hepatocyte-Specific Phgdh-Deficient Mice Culminate in Mild Obesity, Insulin Resistance, and Enhanced Vulnerability to Protein Starvation

Nutrients ◽  
2021 ◽  
Vol 13 (10) ◽  
pp. 3468
Author(s):  
Momoko Hamano ◽  
Kayoko Esaki ◽  
Kazuki Moriyasu ◽  
Tokio Yasuda ◽  
Sinya Mohri ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Stress Responses ◽  
De Novo ◽  
Molecular Signatures ◽  
Significant Gain ◽  
Phosphoglycerate Dehydrogenase ◽  
Protein Free Diet ◽  
Protein Starvation ◽  
Mild Obesity ◽  
Deficient Mice

L-Serine (Ser) is synthesized de novo from 3-phosphoglycerate via the phosphorylated pathway committed by phosphoglycerate dehydrogenase (Phgdh). A previous study reported that feeding a protein-free diet increased the enzymatic activity of Phgdh in the liver and enhanced Ser synthesis in the rat liver. However, the nutritional and physiological functions of Ser synthesis in the liver remain unclear. To clarify the physiological significance of de novo Ser synthesis in the liver, we generated liver hepatocyte-specific Phgdh KO (LKO) mice using an albumin-Cre driver. The LKO mice exhibited a significant gain in body weight compared to Floxed controls at 23 weeks of age and impaired systemic glucose metabolism, which was accompanied by diminished insulin/IGF signaling. Although LKO mice had no apparent defects in steatosis, the molecular signatures of inflammation and stress responses were evident in the liver of LKO mice. Moreover, LKO mice were more vulnerable to protein starvation than the Floxed mice. These observations demonstrate that Phgdh-dependent de novo Ser synthesis in liver hepatocytes contributes to the maintenance of systemic glucose tolerance, suppression of inflammatory response, and resistance to protein starvation.

scholarly journals Impaired liver regeneration and lipid homeostasis in CCl4 treated WDR13 deficient mice

2019 ◽  
Author(s):  
Arun Prakash Mishra ◽  
Archana B Siva ◽  
Chandrashekaran Gurunathan ◽  
Y Komala ◽  
B Jyothi Lakshmi
Keyword(s):  
De Novo ◽  
Recovery Period ◽  
Lipid Homeostasis ◽  
Hepatic Regeneration ◽  
Impaired Liver ◽  
Age Dependent ◽  
Regeneration Phase ◽  
Mild Obesity ◽  
Deficient Mice ◽  
Ppar Pathway

AbstractBackground and AimWDR13 - a WD repeat protein, is abundant in pancreas, liver, ovary and testis. Absence of this protein in mice has been seen to be associated with pancreatic β-cell proliferation, hyperinsulinemia and age dependent mild obesity. Previously, we have reported that the absence of WDR13 in diabetic Leprdb/db mice helps in amelioration of fatty liver phenotype along with diabetes and systemic inflammation. This intrigued us to study direct liver injury and hepatic regeneration in Wdr13−/0 mice using hepatotoxin CCl4.MethodsMice were injected with CCl4 twice a week for 8 consecutive weeks. Controls were injected with vehicle (olive oil) similarly. After the last injection, mice were given a 10-days of recovery period and then sacrificed for physiological and molecular analyses.ResultsIn the present study we report slower hepatic regeneration in Wdr13−/0 mice as compared to their wild type littermates after CCl4 administration. Interestingly, during the regeneration phase, hepatic hypertriglyceridemia was observed in Wdr13−/0 mice. Further analyses revealed an upregulation of PPAR pathway in the liver of CCl4-administered Wdr13−/0 mice, causing de novo lipogenesis.ConclusionsThe slower hepatic regeneration observed in CCl4 administered Wdr13−/0 mice, may be linked to liver hypertriglyceridemia because of activation of PPAR pathway.

scholarly journals Impaired liver regeneration and lipid homeostasis in CCl4 treated WDR13 deficient mice

2020 ◽  
Vol 36 (1) ◽  
Author(s):  
Arun Prakash Mishra ◽  
Archana B. Siva ◽  
Chandrashekaran Gurunathan ◽  
Y. Komala ◽  
B. Jyothi Lakshmi
Keyword(s):  
De Novo ◽  
De Novo Lipogenesis ◽  
Lipid Homeostasis ◽  
Hepatic Regeneration ◽  
Impaired Liver ◽  
Age Dependent ◽  
Regeneration Phase ◽  
Mild Obesity ◽  
Deficient Mice ◽  
Ppar Pathway

AbstractWDR13 - a WD repeat protein, is abundant in pancreas, liver, ovary and testis. Absence of this protein in mice has been seen to be associated with pancreatic β-cell proliferation, hyperinsulinemia and age dependent mild obesity. Previously, we have reported that the absence of WDR13 in diabetic Leprdb/db mice helps in amelioration of fatty liver phenotype along with diabetes and systemic inflammation. This intrigued us to study direct liver injury and hepatic regeneration in Wdr13−/0 mice using hepatotoxin CCl4. In the present study we report slower hepatic regeneration in Wdr13−/0 mice as compared to their wild type littermates after CCl4 administration. Interestingly, during the regeneration phase, hepatic hypertriglyceridemia was observed in Wdr13−/0 mice. Further analyses revealed an upregulation of PPAR pathway in the liver of CCl4- administered Wdr13−/0 mice, causing de novo lipogenesis. The slower hepatic regeneration observed in CCl4 administered Wdr13−/0 mice, may be linked to liver hypertriglyceridemia because of activation of PPAR pathway.

Hypocortisolism and impaired stress responses in Bmal1-deficient mice

2013 ◽  
Vol 121 (10) ◽  
Author(s):  
A Leliavski ◽  
A Shostak ◽  
J Husse ◽  
H Oster
Keyword(s):  
Stress Responses ◽  
Deficient Mice

Reduced bone formation and increased adiposity with insulin resistance in interleukin-11 deficient mice

2014 ◽  
Author(s):  
Bingzi Dong ◽  
Takeshi Kondo ◽  
Yukiyo Ohnishi ◽  
Itsuro Endo ◽  
Masahiro Abe ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Bone Formation ◽  
Interleukin 11 ◽  
Deficient Mice

Association of Insulin Resistance with de novo Coronary Stenosis after Percutaneous Coronary Artery Intervention in Hemodialysis Patients

2008 ◽  
Vol 109 (1) ◽  
pp. c9-c17 ◽  
Author(s):  
Masato Nishimura ◽  
Toshiko Tokoro ◽  
Masasya Nishida ◽  
Tetsuya Hashimoto ◽  
Hiroyuki Kobayashi ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Coronary Artery ◽  
Coronary Stenosis ◽  
De Novo ◽  
Hemodialysis Patients ◽  
Percutaneous Coronary

scholarly journals Cellular Stresses and Stress Responses in the Pathogenesis of Insulin Resistance

2018 ◽  
Vol 2018 ◽  
pp. 1-27 ◽  
Author(s):  
Arnold N. Onyango
Keyword(s):  
Insulin Resistance ◽  
Stress Responses ◽  
Environmental Pollutants ◽  
Stress Generation ◽  
Target Cells ◽  
Inflammasome Activation ◽  
Related Factor ◽  
The Metabolic Syndrome ◽  
Cellular Stresses ◽  
The Unfolded Protein Response

Insulin resistance (IR), a key component of the metabolic syndrome, precedes the development of diabetes, cardiovascular disease, and Alzheimer’s disease. Its etiological pathways are not well defined, although many contributory mechanisms have been established. This article summarizes such mechanisms into the hypothesis that factors like nutrient overload, physical inactivity, hypoxia, psychological stress, and environmental pollutants induce a network of cellular stresses, stress responses, and stress response dysregulations that jointly inhibit insulin signaling in insulin target cells including endothelial cells, hepatocytes, myocytes, hypothalamic neurons, and adipocytes. The insulin resistance-inducing cellular stresses include oxidative, nitrosative, carbonyl/electrophilic, genotoxic, and endoplasmic reticulum stresses; the stress responses include the ubiquitin-proteasome pathway, the DNA damage response, the unfolded protein response, apoptosis, inflammasome activation, and pyroptosis, while the dysregulated responses include the heat shock response, autophagy, and nuclear factor erythroid-2-related factor 2 signaling. Insulin target cells also produce metabolites that exacerbate cellular stress generation both locally and systemically, partly through recruitment and activation of myeloid cells which sustain a state of chronic inflammation. Thus, insulin resistance may be prevented or attenuated by multiple approaches targeting the different cellular stresses and stress responses.

scholarly journals 12/15-Lipoxygenase signaling in the endoplasmic reticulum stress response

2012 ◽  
Vol 302 (6) ◽  
pp. E654-E665 ◽  
Author(s):  
Banumathi K. Cole ◽  
Norine S. Kuhn ◽  
Shamina M. Green-Mitchell ◽  
Kendall A. Leone ◽  
Rebekah M. Raab ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Endoplasmic Reticulum ◽  
Stress Response ◽  
Er Stress ◽  
Pancreatic Islets ◽  
High Fat Diet ◽  
Wild Type ◽  
High Fat ◽  
Stress Markers ◽  
Deficient Mice

Central obesity is associated with chronic inflammation, insulin resistance, β-cell dysfunction, and endoplasmic reticulum (ER) stress. The 12/15-lipoxygenase enzyme (12/15-LO) promotes inflammation and insulin resistance in adipose and peripheral tissues. Given that obesity is associated with ER stress and 12/15-LO is expressed in adipose tissue, we determined whether 12/15-LO could mediate ER stress signals. Addition of 12/15-LO lipid products 12(S)-HETE and 12(S)-HPETE to differentiated 3T3-L1 adipocytes induced expression and activation of ER stress markers, including BiP, XBP-1, p-PERK, and p-IRE1α. The ER stress inducer, tunicamycin, upregulated ER stress markers in adipocytes with concomitant 12/15-LO activation. Addition of a 12/15-LO inhibitor, CDC, to tunicamycin-treated adipocytes attenuated the ER stress response. Furthermore, 12/15-LO-deficient adipocytes exhibited significantly decreased tunicamycin-induced ER stress. 12/15-LO action involves upregulation of interleukin-12 (IL-12) expression. Tunicamycin significantly upregulated IL-12p40 expression in adipocytes, and IL-12 addition increased ER stress gene expression; conversely, LSF, an IL-12 signaling inhibitor, and an IL-12p40-neutralizing antibody attenuated tunicamycin-induced ER stress. Isolated adipocytes and liver from 12/15-LO-deficient mice fed a high-fat diet revealed a decrease in spliced XBP-1 expression compared with wild-type C57BL/6 mice on a high-fat diet. Furthermore, pancreatic islets from 12/15-LO-deficient mice showed reduced high-fat diet-induced ER stress genes compared with wild-type mice. These data suggest that 12/15-LO activity participates in ER stress in adipocytes, pancreatic islets, and liver. Therefore, reduction of 12/15-LO activity or expression could provide a new therapeutic target to reduce ER stress and downstream inflammation linked to obesity.

scholarly journals Estrogens Protect against High-Fat Diet-Induced Insulin Resistance and Glucose Intolerance in Mice

Endocrinology ◽  
2009 ◽  
Vol 150 (5) ◽  
pp. 2109-2117 ◽  
Author(s):  
Elodie Riant ◽  
Aurélie Waget ◽  
Haude Cogo ◽  
Jean-François Arnal ◽  
Rémy Burcelin ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
Glucose Intolerance ◽  
High Fat Diet ◽  
Chow Diet ◽  
High Fat ◽  
Normal Chow ◽  
Visceral Adipose ◽  
Deficient Mice ◽  
Normal Chow Diet

Although corroborating data indicate that estrogens influence glucose metabolism through the activation of the estrogen receptor α (ERα), it has not been established whether this pathway could represent an effective therapeutic target to fight against metabolic disturbances induced by a high-fat diet (HFD). To this end, we first evaluated the influence of chronic 17β-estradiol (E2) administration in wild-type ovariectomized mice submitted to either a normal chow diet or a HFD. Whereas only a modest effect was observed in normal chow diet-fed mice, E2 administration exerted a protective effect against HFD-induced glucose intolerance, and this beneficial action was abolished in ERα-deficient mice. Furthermore, E2 treatment reduced HFD-induced insulin resistance by 50% during hyperinsulinemic euglycemic clamp studies and improved insulin signaling (Akt phosphorylation) in insulin-stimulated skeletal muscles. Unexpectedly, we found that E2 treatment enhanced cytokine (IL-6, TNF-α) and plasminogen activator inhibitor-1 mRNA expression induced by HFD in the liver and visceral adipose tissue. Interestingly, although the proinflammatory effect of E2 was abolished in visceral adipose tissue from chimeric mice grafted with bone marrow cells from ERα-deficient mice, the beneficial effect of the hormone on glucose tolerance was not altered, suggesting that the metabolic and inflammatory effects of estrogens can be dissociated. Eventually comparison of sham-operated with ovariectomized HFD-fed mice demonstrated that endogenous estrogens levels are sufficient to exert a full protective effect against insulin resistance and glucose intolerance. In conclusion, the regulation of the ERα pathway could represent an effective strategy to reduce the impact of high-fat diet-induced type 2 diabetes.

scholarly journals Regulation of the Bacillus subtilis bcrC Bacitracin Resistance Gene by Two Extracytoplasmic Function σ Factors

2002 ◽  
Vol 184 (22) ◽  
pp. 6123-6129 ◽  
Author(s):  
Min Cao ◽  
John D. Helmann
Keyword(s):  
Bacillus Subtilis ◽  
Resistance Gene ◽  
Mutant Strain ◽  
Stress Responses ◽  
Double Mutant ◽  
De Novo ◽  
De Novo Synthesis ◽  
Gene Encoding ◽  
Single Promoter ◽  
Higher Sensitivity

ABSTRACT Bacitracin resistance is normally conferred by either of two major mechanisms, the BcrABC transporter, which pumps out bacitracin, or BacA, an undecaprenol kinase that provides C55-isoprenyl phosphate by de novo synthesis. We demonstrate that the Bacillus subtilis bcrC (ywoA) gene, encoding a putative bacitracin transport permease, is an important bacitracin resistance determinant. A bcrC mutant strain had an eightfold-higher sensitivity to bacitracin. Expression of bcrC initiated from a single promoter site that could be recognized by either of two extracytoplasmic function (ECF) σ factors, σX or σM. Bacitracin induced expression of bcrC, and this induction was dependent on σM but not on σX. Under inducing conditions, expression was primarily dependent on σM. As a consequence, a sigM mutant was fourfold more sensitive to bacitracin, while the sigX mutant was only slightly sensitive. A sigX sigM double mutant was similar to a bcrC mutant in sensitivity. These results support the suggestion that one function of B. subtilis ECF σ factors is to coordinate antibiotic stress responses.

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