scholarly journals Sugar causes obesity and metabolic syndrome in mice independently of sweet taste

2020 ◽  
Vol 319 (2) ◽  
pp. E276-E290
Author(s):  
Ana Andres-Hernando ◽  
Masanari Kuwabara ◽  
David J. Orlicky ◽  
Aurelie Vandenbeuch ◽  
Christina Cicerchi ◽  
...  
Keyword(s):  
Metabolic Syndrome ◽  
Knockout Mice ◽  
De Novo ◽  
Sweet Taste ◽  
De Novo Lipogenesis ◽  
Fibroblast Growth Factor 21 ◽  
Relative Role ◽  
Double Knockout ◽  
Metabolic Outcome

Intake of sugars, especially the fructose component, is strongly associated with the development of obesity and metabolic syndrome, but the relative role of taste versus metabolism in driving preference, intake, and metabolic outcome is not fully understood. We aimed to evaluate the preference for sweet substances and the tendency to develop metabolic syndrome in response to these sugars in mice lacking functional taste signaling [P2X2 (P2X purinoreceptor 2)/P2X3 (P2X purinoreceptor 3) double knockout mice (DKO)] and mice unable to metabolize fructose (fructokinase knockout mice). Of interest, our data indicate that despite their inability to taste sweetness, P2X2/3 DKO mice still prefer caloric sugars (including fructose and glucose) to water in long-term testing, although with diminished preference compared with control mice. Despite reduced intake of caloric sugars by P2X2/3 DKO animals, the DKO mice still show increased levels of the sugar-dependent hormone FGF21 (fibroblast growth factor 21) in plasma and liver. Despite lower sugar intake, taste-blind mice develop severe features of metabolic syndrome due to reduced sensitivity to leptin, reduced ability to mobilize and oxidize fats, and increased hepatic de novo lipogenesis. In contrast to P2X2/3 DKO and wild-type mice, fructokinase knockout mice, which cannot metabolize fructose and are protected against fructose-induced metabolic syndrome, demonstrate reduced preference and intake for all fructose-containing sugars tested but not for glucose or artificial sweeteners. Based on these observations, we conclude that sugar can induce metabolic syndrome in mice independently of its sweet properties. Furthermore, our data demonstrate that the metabolism of fructose is necessary for sugar to drive intake and preference in mice.

Adipose tissue triglyceride turnover, de novo lipogenesis, and cell proliferation in humans measured with 2H2O

2004 ◽  
Vol 286 (4) ◽  
pp. E577-E588 ◽  
Author(s):  
A. Strawford ◽  
F. Antelo ◽  
M. Christiansen ◽  
M. K. Hellerstein
Keyword(s):  
Cell Proliferation ◽  
Adipose Tissue ◽  
Half Life ◽  
De Novo ◽  
Human Subjects ◽  
De Novo Lipogenesis ◽  
Gas Chromatography Mass Spectrometry ◽  
Distribution Analysis ◽  
Mass Isotopomer Distribution Analysis

The turnover of adipose tissue components (lipids and cells) and the pathways of adipose lipid deposition have been difficult to measure in humans. We apply here a 2H2O long-term labeling technique for concurrent measurement of adipose-triglyceride (TG) turnover, cell (DNA) proliferation, and de novo lipogenesis (DNL). Healthy subjects drank 2H2O (70 ml/day) for 5-9 wk. Subcutaneous adipose tissue aspirates were taken (gluteal, thigh, and flank depots). Deuterium incorporation into TG glycerol (representing all-source TG synthesis), TG palmitate (representing DNL, by mass isotopomer distribution analysis), and DNA (representing cell proliferation) was measured by gas chromatography-mass spectrometry. Subjects tolerated the protocol well, and body 2H2O enrichments were stable. Mean TG-glycerol fractional synthesis was 0.12 (i.e., 12%) with a range of 0.03-0.32 after 5 wk and 0.20 (range 0.08-0.49) after 9 wk (TG half-life 200-270 days). Label decay measurements 5-8 mo after discontinuing 2H2O gave similar turnover estimates. Net lipolysis (TG turnover) was 50-60 g/day. DNL contribution to adipose-TG was 0.04 after 9 wk, representing ∼20% of newly deposited TG. Cell proliferation was 0.10-0.17 after 9 wk (half-life 240-425 days). In summary, long-term 2H2O administration to human subjects allows measurement of the dynamics of adipose tissue components. Turnover of all elements is slow, and DNL contributes ∼20% of new TG.

Effects of Long-term Direct Thrombin Inhibition by Dabigatran Etexilate on Progression of Atherosclerosis in ApoE-/- and LDLR-/- Double-knockout Mice

2021 ◽  
Vol 5 (2) ◽  
Author(s):  
Hyodo K ◽  
◽  
Sanda T ◽  
Yoshimura M ◽  
Yamashita T ◽  
...  
Keyword(s):  
Placebo Group ◽  
Knockout Mice ◽  
Dabigatran Etexilate ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Tissue Type ◽  
Double Knockout ◽  
Progression Of Atherosclerosis ◽  
Inhibition Of Thrombin

Background: Atherosclerosis is characterized by a hypercoagulable state, during which coagulation and fibrinolytic factors are simultaneously activated. However, details regarding the progression of atherosclerosis remain unknown. Here, we investigated the effects of direct long-term inhibition of thrombin by dabigatran etexilate on atherosclerotic progression in apolipoprotein E–/– and low-density lipoprotein receptor–/– double-knockout mice. Methods: Mice received either standard chow (placebo group) or dabigatran-supplemented chow for 22 weeks. The amount of atherosclerosis was estimated as the ratio of the atherosclerotic area to the total aortic intimal area. Immunohistochemistry was used to examine the expression of Matrix Metalloproteinase-9 (MMP-9), Vascular Endothelial Growth Factor (VEGF), Tissue-Type Plasminogen Activator (t-PA), and Endothelial Nitric Oxide Synthase (eNOS) in atherosclerotic regions. Results: The atherosclerotic area was smaller in the dabigatran group than in the placebo group. Immunohistochemistry revealed decreased expression of MMP-9 and VEGF, but increased expression of eNOS, in the dabigatran group compared with the placebo group. t-PA expression did not differ between the groups. Conclusion: Direct long-term inhibition of thrombin by dabigatran in mice led to a decrease in atherosclerosis progression via decreased expression of MMP-9 and VEGF.

scholarly journals Cardiovascular and Metabolic Consequences of Liver Transplantation: A Review

Medicina ◽  
2019 ◽  
Vol 55 (8) ◽  
pp. 489
Author(s):  
Plotogea ◽  
Ilie ◽  
Sandru ◽  
Chiotoroiu ◽  
Bratu ◽  
...  
Keyword(s):  
Metabolic Syndrome ◽  
Liver Transplantation ◽  
De Novo ◽  
Current Knowledge ◽  
Morbidity And Mortality ◽  
High Morbidity ◽  
Term Survival ◽  
The Metabolic Syndrome ◽  
Acute Liver Disease

Liver transplantation (LT) is considered the curative treatment option for selected patients who suffer from end-stage or acute liver disease or hepatic malignancy (primary). After LT, patients should be carefully monitored for complications that may appear, partially due to immunosuppressive therapy, but not entirely. Cardiovascular diseases are frequently encountered in patients with LT, being responsible for high morbidity and mortality. Patients with underlying cardiovascular and metabolic pathologies are prone to complications after the transplant, but these complications can also appear de novo, mostly associated with immunosuppressants. Metabolic syndrome, defined by obesity, hypertension, dyslipidemia, and hyperglycemia, is diagnosed among LT recipients and is aggravated after LT, influencing the long-term survival. In this review, our purpose was to summarize the current knowledge regarding cardiovascular (CV) diseases and the metabolic syndrome associated with LT and to assess their impact on short and long-term morbidity and mortality.

scholarly journals The Role of mTOR Inhibitors in Liver Transplantation: Reviewing the Evidence

2014 ◽  
Vol 2014 ◽  
pp. 1-45 ◽  
Author(s):  
Goran B. Klintmalm ◽  
Björn Nashan
Keyword(s):  
Metabolic Syndrome ◽  
Liver Transplantation ◽  
Renal Function ◽  
De Novo ◽  
Immunosuppressive Agents ◽  
Mammalian Target Of Rapamycin ◽  
Calcineurin Inhibitors ◽  
Mtor Inhibitors

Despite the success of liver transplantation, long-term complications remain, includingde novomalignancies, metabolic syndrome, and the recurrence of hepatitis C virus (HCV) and hepatocellular carcinoma (HCC). The current mainstay of treatment, calcineurin inhibitors (CNIs), can also worsen posttransplant renal dysfunction, neurotoxicity, and diabetes. Clearly there is a need for better immunosuppressive agents that maintain similar rates of efficacy and renal function whilst minimizing adverse effects. The mammalian target of rapamycin (mTOR) inhibitors with a mechanism of action that is different from other immunosuppressive agents has the potential to address some of these issues. In this review we surveyed the literature for reports of the use of mTOR inhibitors in adult liver transplantation with respect to renal function, efficacy, safety, neurological symptoms,de novotumors, and the recurrence of HCC and HCV. The results of our review indicate that mTOR inhibitors are associated with efficacy comparable to CNIs while having benefits on renal function in liver transplantation. We also consider newer dosing schedules that may limit side effects. Finally, we discuss evidence that mTOR inhibitors may have benefits in the oncology setting and in relation to HCV-related allograft fibrosis, metabolic syndrome, and neurotoxicity.

scholarly journals Hepatic PPARγ Is Not Essential for the Rapid Development of Steatosis After Loss of Hepatic GH Signaling, in Adult Male Mice

Endocrinology ◽  
2016 ◽  
Vol 157 (5) ◽  
pp. 1728-1735 ◽  
Author(s):  
Rhonda D. Kineman ◽  
Neena Majumdar ◽  
Papasani V. Subbaiah ◽  
Jose Cordoba-Chacon
Keyword(s):  
De Novo ◽  
Rapid Development ◽  
De Novo Lipogenesis ◽  
Peroxisome Proliferator ◽  
Male Mice ◽  
Double Knockout ◽  
Peroxisome Proliferator Activated Receptor ◽  
Hepatic Expression ◽  
Triglyceride Content ◽  
Pparγ Expression

Abstract Our group has previously reported de novo lipogenesis (DNL) and hepatic triglyceride content increases in chow-fed male mice within 7 days of hepatocyte-specific GH receptor knockdown (aLivGHRkd). Here, we report that these changes are associated with an increase in hepatic expression of peroxisome proliferator-activated receptor γ (PPARγ), consistent with previous reports showing steatosis is associated with an increase in PPARγ expression in mice with congenital loss of hepatic GH signaling. PPARγ is thought to be an important driver of steatosis by enhancing DNL, as well as increasing the uptake and esterification of extrahepatic fatty acids (FAs). In order to determine whether hepatic PPARγ is critical for the rapid development of steatosis in the aLivGHRkd mouse model, we have generated aLivGHRkd mice, with or without PPARγ (ie, adult-onset, hepatocyte-specific double knockout of GHR and PPARγ). Hepatic PPARγ was not required for the rapid increase in liver triglyceride content or FA indexes of DNL (16:0/18:2 and 16:1/16:0). However, loss of hepatic PPARγ blunted the rise in fatty acid translocase/CD36 and monoacylglycerol acyltransferase 1 expression induced by aLivGHRkd, and this was associated with a reduction in the hepatic content of 18:2. These results suggest that the major role of PPARγ is to enhance pathways critical in uptake and reesterification of extrahepatic FA. Because FAs have been reported to directly increase PPARγ expression, we speculate that in the aLivGHRkd mouse, the FA produced by DNL enhances the expression of PPARγ, which in turn increases extrahepatic FA uptake, thereby further enhancing PPARγ activity and exacerbating steatosis overtime.

Hippocampal mossy fiber long-term depression in Grm2/3 double knockout mice

Synapse ◽  
2011 ◽  
Vol 65 (9) ◽  
pp. 945-954 ◽  
Author(s):  
Louisa Lyon ◽  
Melodie Borel ◽  
Miriam CarriÓn ◽  
James N.C. Kew ◽  
Corrado Corti ◽  
...  
Keyword(s):  
Knockout Mice ◽  
Mossy Fiber ◽  
Double Knockout ◽  
Long Term Depression

scholarly journals Fibroblast Growth Factor 21 Corrects Obesity in Mice

Endocrinology ◽  
2008 ◽  
Vol 149 (12) ◽  
pp. 6018-6027 ◽  
Author(s):  
Tamer Coskun ◽  
Holly A. Bina ◽  
Michael A. Schneider ◽  
James D. Dunbar ◽  
Charlie C. Hu ◽  
...  
Keyword(s):  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
De Novo ◽  
Caloric Intake ◽  
De Novo Lipogenesis ◽  
Leptin Resistance ◽  
Health Concern ◽  
Fibroblast Growth Factor 21 ◽  
Fibroblast Growth ◽  
Lipid Control

Fibroblast growth factor 21 (FGF21) is a metabolic regulator that provides efficient and durable glycemic and lipid control in various animal models. However, its potential to treat obesity, a major health concern affecting over 30% of the population, has not been fully explored. Here we report that systemic administration of FGF21 for 2 wk in diet-induced obese and ob/ob mice lowered their mean body weight by 20% predominantly via a reduction in adiposity. Although no decrease in total caloric intake or effect on physical activity was observed, FGF21-treated animals exhibited increased energy expenditure, fat utilization, and lipid excretion, reduced hepatosteatosis, and ameliorated glycemia. Transcriptional and blood cytokine profiling studies revealed effects consistent with the ability of FGF21 to ameliorate insulin and leptin resistance, enhance fat oxidation and suppress de novo lipogenesis in liver as well as to activate futile cycling in adipose. Overall, these data suggest that FGF21 exhibits the therapeutic characteristics necessary for an effective treatment of obesity and fatty liver disease and provides novel insights into the metabolic determinants of these activities.

scholarly journals mGluR-Dependent Long-Term Depression Is Associated with Increased Phosphorylation of S6 and Synthesis of Elongation Factor 1A but Remains Expressed in S6K-Deficient Mice

2008 ◽  
Vol 28 (9) ◽  
pp. 2996-3007 ◽  
Author(s):  
Marcia D. Antion ◽  
Lingfei Hou ◽  
Helen Wong ◽  
Charles A. Hoeffer ◽  
Eric Klann
Keyword(s):  
Protein Synthesis ◽  
Signaling Pathways ◽  
Knockout Mice ◽  
Metabotropic Glutamate Receptor ◽  
Elongation Factor ◽  
Double Knockout ◽  
Long Term Depression ◽  
Group I ◽  
Deficient Mice

ABSTRACT Metabotropic glutamate receptor-dependent long-term depression (mGluR-LTD) in the hippocampus requires rapid protein synthesis, which suggests that mGluR activation is coupled to signaling pathways that regulate translation. Herein, we have investigated the signaling pathways that couple group I mGluRs to ribosomal S6 protein phosphorylation and 5′oligopyrimidine tract (5′TOP)-encoded protein synthesis during mGluR-LTD. We found that mGluR-LTD was associated with increased phosphorylation of p70S6 kinase (S6K1) and S6, as well as the synthesis of the 5′TOP-encoded protein elongation factor 1A (EF1A). Moreover, we found that LTD-associated increases in S6K1 phosphorylation, S6 phosphorylation, and levels of EF1A were sensitive to inhibitors of phosphoinositide 3-kinase (PI3K), mammalian target of rapamycin (mTOR), and extracellular signal-regulated kinase (ERK). However, mGluR-LTD was normal in S6K1 knockout mice and enhanced in both S6K2 knockout mice and S6K1/S6K2 double knockout mice. In addition, we observed that LTD-associated increases in S6 phosphorylation were still increased in S6K1- and S6K2-deficient mice, whereas basal levels of EF1A were abnormally elevated. Taken together, these findings indicate that mGluR-LTD is associated with PI3K-, mTOR-, and ERK-dependent alterations in the phosphorylation of S6 and S6K. Our data also suggest that S6Ks are not required for the expression of mGluR-LTD and that the synthesis of 5′TOP-encoded proteins is independent of S6Ks during mGluR-LTD.

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