scholarly journals Mechanism of glucose intolerance in mice with dominant negative mutation of CEACAM1

2006 ◽  
Vol 291 (3) ◽  
pp. E517-E524 ◽  
Author(s):  
So-Young Park ◽  
You-Ree Cho ◽  
Hyo-Jeong Kim ◽  
Eun-Gyoung Hong ◽  
Takamasa Higashimori ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Lipid Metabolism ◽  
Glucose Intolerance ◽  
Fatty Acid Synthase ◽  
Visceral Obesity ◽  
Dominant Negative ◽  
Whole Body ◽  
Peripheral Tissues ◽  
Dominant Negative Mutation ◽  
Altered Glucose

Mice with liver-specific overexpression of dominant negative phosphorylation-defective S503A-CEACAM1 mutant (L-SACC1) developed chronic hyperinsulinemia resulting from blunted hepatic clearance of insulin, visceral obesity, and glucose intolerance. To determine the underlying mechanism of altered glucose homeostasis, a 2-h hyperinsulinemic euglycemic clamp was performed, and tissue-specific glucose and lipid metabolism was assessed in awake L-SACC1 and wild-type mice. Inactivation of carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) caused insulin resistance in liver that was mostly due to increased expression of fatty acid synthase and lipid metabolism, resulting in elevated intrahepatic levels of triglyceride and long-chain acyl-CoAs. Whole body insulin resistance in the L-SACC1 mice was further attributed to defects in insulin-stimulated glucose uptake in skeletal muscle and adipose tissue. Insulin resistance in peripheral tissues was associated with significantly elevated intramuscular fat contents that may be secondary to increased whole body adiposity (assessed by 1H-MRS) in the L-SACC1 mice. Overall, these results demonstrate that L-SACC1 is a mouse model in which chronic hyperinsulinemia acts as a cause, and not a consequence, of insulin resistance. Our findings further indicate the important role of CEACAM1 and hepatic insulin clearance in the pathogenesis of obesity and insulin resistance.

scholarly journals The Liver as an Endocrine Organ—Linking NAFLD and Insulin Resistance

2019 ◽  
Vol 40 (5) ◽  
pp. 1367-1393 ◽  
Author(s):  
Matthew J Watt ◽  
Paula M Miotto ◽  
William De Nardo ◽  
Magdalene K Montgomery
Keyword(s):  
Insulin Resistance ◽  
Lipid Metabolism ◽  
Liver Disorder ◽  
The Body ◽  
Limited Information ◽  
Peripheral Tissues ◽  
Nonalcoholic Fatty Liver ◽  
Induce Insulin Resistance ◽  
Glucose And Lipid Metabolism ◽  
Physiological Processes

AbstractThe liver is a dynamic organ that plays critical roles in many physiological processes, including the regulation of systemic glucose and lipid metabolism. Dysfunctional hepatic lipid metabolism is a cause of nonalcoholic fatty liver disease (NAFLD), the most common chronic liver disorder worldwide, and is closely associated with insulin resistance and type 2 diabetes. Through the use of advanced mass spectrometry “omics” approaches and detailed experimentation in cells, mice, and humans, we now understand that the liver secretes a wide array of proteins, metabolites, and noncoding RNAs (miRNAs) and that many of these secreted factors exert powerful effects on metabolic processes both in the liver and in peripheral tissues. In this review, we summarize the rapidly evolving field of “hepatokine” biology with a particular focus on delineating previously unappreciated communication between the liver and other tissues in the body. We describe the NAFLD-induced changes in secretion of liver proteins, lipids, other metabolites, and miRNAs, and how these molecules alter metabolism in liver, muscle, adipose tissue, and pancreas to induce insulin resistance. We also synthesize the limited information that indicates that extracellular vesicles, and in particular exosomes, may be an important mechanism for intertissue communication in normal physiology and in promoting metabolic dysregulation in NAFLD.

PPARγ regulates the function of human dendritic cells primarily by altering lipid metabolism

Blood ◽  
2007 ◽  
Vol 110 (9) ◽  
pp. 3271-3280 ◽  
Author(s):  
Istvan Szatmari ◽  
Daniel Töröcsik ◽  
Maura Agostini ◽  
Tibor Nagy ◽  
Mark Gurnell ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Lipid Metabolism ◽  
Receptor Activation ◽  
Dominant Negative ◽  
Transcriptional Level ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Positive Effects ◽  
Dominant Negative Mutation ◽  
Human Dendritic Cells

Abstract Activation of the lipid-regulated nuclear receptor peroxisome proliferator-activated receptor gamma (PPARγ) modifies the immunophenotype of monocyte-derived dendritic cells (DCs). However it has not been analyzed in a systematic manner how lipid metabolism and immune regulation are connected at the transcriptional level via this receptor. Here we present the genome-wide expression analyses of PPARγ-instructed human DCs. Receptor activation was achieved by exogenous, synthetic as well as endogenous, natural means. More than 1000 transcripts are regulated during DC development by activation of PPARγ; half of the changes are positive effects. These changes appear to enhance and modulate the robust gene expression alterations associated with monocyte to DC transition. Strikingly, only genes related to lipid metabolism are overrepresented among early induced genes. As a net consequence, lipid accumulation appears to be diminished in these cells. In contrast, genes related to immune response are regulated after 24 hours, implying the existence of indirect mechanisms of modulation. Receptor dependence was established by using DCs of patients harboring a dominant-negative mutation of PPARγ. Our data show that PPARγ acts as a mostly positive transcriptional regulator in human developing DCs, acting primarily through controlling genes involved in lipid metabolism and via this, indirectly modifying the immune phenotype.

scholarly journals Effects of different diets used in diet-induced obesity models on insulin resistance and vascular dysfunction in C57BL/6 mice

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Philipp Lang ◽  
Solveig Hasselwander ◽  
Huige Li ◽  
Ning Xia
Keyword(s):  
Insulin Resistance ◽  
Glucose Intolerance ◽  
Vascular Dysfunction ◽  
Visceral Obesity ◽  
Chow Diet ◽  
Coagulation Activity ◽  
Perivascular Adipose Tissue ◽  
Standard Chow Diet ◽  
Oxide Synthase ◽  
Endothelial Nitric Oxide

AbstractThe aim of the present study was to compare different diets used to induce obesity in a head-to-head manner with a focus on insulin resistance and vascular dysfunction. Male C57BL/6J mice were put on standard chow diet (SCD), normal-fat diet (NFD), cafeteria diet (CAF) or high-fat diet (HFD) for 12 weeks starting at the age of 6 weeks. Both CAF and HFD led to obesity (weight gain of 179% and 194%, respectively), glucose intolerance and insulin resistance to a comparable extent. In aortas containing perivascular adipose tissue (PVAT), acetylcholine-induced vasodilation was best in the NFD group and worst in the CAF group. Reduced phosphorylation of endothelial nitric oxide synthase at serine 1177 was observed in both CAF and HFD groups. Plasma coagulation activity was highest in the HFD group and lowest in the SCD group. Even the NFD group had significantly higher coagulation activity than the SCD group. In conclusions, CAF and HFD are both reliable mouse diets in inducing visceral obesity, glucose intolerance and insulin resistance. CAF is more effective than HFD in causing PVAT dysfunction and vascular dysfunction, whereas hypercoagulability was mostly evident in the HFD group. Coagulation activity was higher in NFD than NCD group.

scholarly journals Effects on Liver Lipid Metabolism of the Naturally Occurring Dietary Flavone Luteolin-7-glucoside

2015 ◽  
Vol 2015 ◽  
pp. 1-9 ◽  
Author(s):  
Carla Sá ◽  
Ana Rita Oliveira ◽  
Cátia Machado ◽  
Marisa Azevedo ◽  
Cristina Pereira-Wilson
Keyword(s):  
Lipid Metabolism ◽  
Fatty Acid Synthase ◽  
Molecular Mechanisms ◽  
Metabolic Diseases ◽  
Regulatory Element ◽  
Lipid Lowering ◽  
Whole Body ◽  
Mrna Levels ◽  
Dependent Manner ◽  
Hepatic Expression

Disruptions in whole-body lipid metabolism can lead to the onset of several pathologies such as nonalcoholic fatty liver disease (NAFLD) and cardiovascular diseases (CVDs). The present study aimed at elucidating the molecular mechanisms behind the lipid-lowering effects of the flavone luteolin-7-glucoside (L7G) which we previously showed to improve plasma lipid profile in rats. L7G is abundant in plant foods of Mediterranean diet such as aromatic plants used as herbs. Results show that dietary supplementation with L7G for one week induced the expression of peroxisome proliferator-activated receptor-alpha (PPAR-α) and of its target gene carnitine palmitoyl transferase 1 (CPT-1) in rat liver. L7G showed a tendency to decrease the hepatic expression of sterol regulatory element-binding protein-1 (SREBP-1), without affecting fatty acid synthase (FAS) protein levels. Although SREBP-2 and LDLr mRNA levels did not change, the expression of HMG CoA reductase (HMGCR) was significantly repressed by L7G. L7G also inhibited this enzyme’sin vitroactivity in a dose dependent manner, but only at high and not physiologically relevant concentrations. These results add new evidence that the flavone luteolin-7-glucoside may help in preventing metabolic diseases and clarify the mechanisms underlying the beneficial health effects of diets rich in fruits and vegetables.

scholarly journals Rapid development of systemic insulin resistance with overeating is not accompanied by robust changes in skeletal muscle glucose and lipid metabolism

2013 ◽  
Vol 38 (5) ◽  
pp. 512-519 ◽  
Author(s):  
Andrea S. Cornford ◽  
Alexander Hinko ◽  
Rachael K. Nelson ◽  
Ariel L. Barkan ◽  
Jeffrey F. Horowitz
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Lipid Metabolism ◽  
Insulin Sensitivity ◽  
Lipid Accumulation ◽  
Rapid Development ◽  
Insulin Response ◽  
Whole Body ◽  
Muscle Lipid ◽  
Wet Weight

Prolonged overeating and the resultant weight gain are clearly linked with the development of insulin resistance and other cardiometabolic abnormalities, but adaptations that occur after relatively short periods of overeating are not completely understood. The purpose of this study was to characterize metabolic adaptations that may accompany the development of insulin resistance after 2 weeks of overeating. Healthy, nonobese subjects (n = 9) were admitted to the hospital for 2 weeks, during which time they ate ∼4000 kcals·day−1 (70 kcal·kg−1 fat free mass·day−1). Insulin sensitivity was estimated during a meal tolerance test, and a muscle biopsy was obtained to assess muscle lipid accumulation and protein markers associated with insulin resistance, inflammation, and the regulation of lipid metabolism. Whole-body insulin sensitivity declined markedly after 2 weeks of overeating (Matsuda composite index: 8.3 ± 1.3 vs. 4.6 ± 0.7, p < 0.05). However, muscle markers of insulin resistance and inflammation (i.e., phosphorylation of IRS-1-Ser312, Akt-Ser473, and c-Jun N-terminal kinase) were not altered by overeating. Intramyocellular lipids tended to increase after 2 weeks of overeating (triacylglyceride: 7.6 ± 1.6 vs. 10.0 ± 1.8 nmol·mg−1 wet weight; diacylglyceride: 104 ± 10 vs. 142 ± 23 pmol·mg−1 wet weight) but these changes did not reach statistical significance. Overeating induced a 2-fold increase in 24-h insulin response (area under the curve (AUC); p < 0.05), with a resultant ∼35% reduction in 24-h plasma fatty acid AUC (p < 0.05). This chronic reduction in circulating fatty acids may help explain the lack of a robust increase in muscle lipid accumulation. In summary, our findings suggest alterations in skeletal muscle metabolism may not contribute meaningfully to the marked whole-body insulin resistance observed after 2 weeks of overeating.

scholarly journals Ketogenic Diets Induced Glucose Intolerance and Lipid Accumulation in Mice with Alterations in Gut Microbiota and Metabolites

mBio ◽  
2021 ◽  
Vol 12 (2) ◽  
Author(s):  
Yue Li ◽  
Xin Yang ◽  
Jing Zhang ◽  
Tianyi Jiang ◽  
Ziyi Zhang ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Lipid Metabolism ◽  
Gut Microbiota ◽  
Neurodegenerative Diseases ◽  
Ketogenic Diet ◽  
Glucose Intolerance ◽  
Lipid Accumulation ◽  
Fat Accumulation ◽  
Glucose And Lipid Metabolism ◽  
Ketogenic Diets

ABSTRACT The ketogenic diet (KD), which can induce changes in gut microbiota, has shown benefits for epilepsy and several neurodegenerative diseases. However, the effects of a KD on glucose and lipid metabolism remain inconclusive. Using two formulas of ketogenic diets (KDR with 89.5% fat and KDH with 91.3% fat), which are commonly used in mouse trials, we found that KDR but not KDH induced insulin resistance and damaged glucose homeostasis, while KDH induced more fat accumulation in mice. Further study showed that KD impacted glucose metabolism, which was related to the sources of fat, while both the sources and proportions of fat affected lipid metabolism. And the KD widely used in human studies still induced insulin resistance and fat accumulation in mice. Moreover, KDs changed the gut microbiota and metabolites in mice, and the sources and proportions of fat in the diets respectively changed the abundance of specific bacteria and metabolites which were correlated with parameters related to glucose intolerance and lipid accumulation. Overall, our study demonstrated that the metabolic disorders induced by KDs are closely related to the source and proportion of fat in the diet, which may be associated with the changes of the gut microbiota and metabolites. IMPORTANCE The ketogenic diet with extremely high fat and very low carbohydrate levels is very popular in society today. Although it has beneficial effects on epilepsy and neurodegenerative diseases, how ketogenic diets impact host glucose and lipid metabolism and gut microbiota still needs further investigation. Here, we surveyed the effects of two ketogenic diets which are commonly used in mouse trials on metabolic phenotypes, gut microbiota, and metabolites in mice. We found that both ketogenic diets impaired glucose and lipid metabolism in mice, and this may be due to the sources and proportions of fat in the diets. This work highlights the potential risk of glucose and lipid metabolism disorders and the importance of evaluating the sources and proportions of fat in the diets, when using ketogenic diets for weight loss and the treatment of diseases.

scholarly journals Jiao-Tai-Wan Ameliorates the Insulin Resistance and Lipid Metabolism in T2DM Rats by Regulating Neurotransmitters

2021 ◽  
Author(s):  
Jianhua Chen ◽  
Ziqi Jing ◽  
Xue Wang ◽  
Chu Li ◽  
Yanyi Li ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Lipid Metabolism ◽  
Protein Expression ◽  
Serum Insulin ◽  
Fasting Blood Glucose ◽  
Sprague Dawley ◽  
Lipid Metabolism Disorder ◽  
Peripheral Tissues ◽  
Mrna And Protein Expression ◽  
The Brain

Abstract Background: Type 2 diabetes mellitus (T2DM) is a metabolic disease characterized by insulin resistance and β-cell dysfunction, and accompanied by neuroendocrine disorders. Recently, Jiao-Tai-Wan (JTW) has been reported to exert hypoglycemic effects against diabetes. However, its mechanism has not been clarified. Therefore, we attempted to explore the effect of JTW on alleviating insulin resistance and lipid metabolism disorder in T2DM rats by regulating the level of neurotransmitters. Methods: Sprague-Dawley (SD) rats were treated with a high-fat diet/streptozotocin to induce T2DM and then gavaged with JTW for 4 weeks. Afterwards, endpoints including body weight, fasting blood glucose, glucose tolerance, serum insulin, and lipid index were determined, and we analyzed pathological changes in the liver and kidney. Meanwhile, the level of neurotransmitter neurotransmitters in the central nervous system and peripheral tissues was measured by UPLC-MS/MS. Furthermore, the expression of neurotransmitter transporter mRNA and protein levels in the brain and kidney of T2DM rats was analyzed by qRT-PCR and WB. Results: The results showed that JTW ameliorated glucose homeostasis, insulin resistance, and lipid metabolism in T2DM rats by regulating the disorder of neurotransmitter distribution in the brain, kidney, intestine, adrenal gland, blood, and urine of T2DM rats. Mechanically, JTW may improve neurotransmitter disturbance by reducing mRNA and protein expression of SERT, DAT, and GAT-1 and increasing mRNA and protein expression of NET in the brain and kidney of T2DM rats.Conclusion: Our findings confirm that JTW can play a hypoglycemic role by regulating the disorder level of neurotransmitter distribution in T2DM rats, which may have potential therapeutic implications for the treatment of T2DM.

Overproduction of inter-α-trypsin inhibitor heavy chain 1 after loss of Gα13 in liver exacerbates systemic insulin resistance in mice

2019 ◽  
Vol 11 (513) ◽  
pp. eaan4735 ◽  
Author(s):  
Tae Hyun Kim ◽  
Ja Hyun Koo ◽  
Mi Jeong Heo ◽  
Chang Yeob Han ◽  
Yong-In Kim ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Glucose Intolerance ◽  
Heavy Chain ◽  
Trypsin Inhibitor ◽  
Metabolic Stress ◽  
Whole Body ◽  
Secretory Proteins ◽  
Systemic Insulin Resistance ◽  
Glcnac Transferase ◽  
The Impact

The impact of liver disease on whole-body glucose homeostasis is largely attributed to dysregulated release of secretory proteins in response to metabolic stress. The molecular cues linking liver to whole-body glucose metabolism remain elusive. We found that expression of G protein α-13 (Gα13) was decreased in the liver of mice and humans with diabetes. Liver-specific deletion of the Gna13 gene in mice resulted in systemic glucose intolerance. Comparative secretome analysis identified inter-α-trypsin inhibitor heavy chain 1 (ITIH1) as a protein secreted by liver that was responsible for systemic insulin resistance in Gna13-deficient mice. Liver expression of ITIH1 positively correlated with surrogate markers for diabetes in patients with impaired glucose tolerance or overt diabetes. Mechanistically, a decrease in hepatic Gα13 caused ITIH1 oversecretion by liver through induction of O-GlcNAc transferase expression, facilitating ITIH1 deposition on the hyaluronan surrounding mouse adipose tissue and skeletal muscle. Neutralization of secreted ITIH1 ameliorated glucose intolerance in obese mice. Our findings demonstrate systemic insulin resistance in mice resulting from liver-secreted ITIH1 downstream of Gα13 and its reversal by ITIH1 neutralization.

scholarly journals Rat amylin-(8—37) enhances insulin action and alters lipid metabolism in normal and insulin-resistant rats

1997 ◽  
Vol 273 (5) ◽  
pp. E859-E867 ◽  
Author(s):  
M. Hettiarachchi ◽  
S. Chalkley ◽  
S. M. Furler ◽  
Y.-S. Choong ◽  
M. Heller ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Lipid Metabolism ◽  
Insulin Sensitivity ◽  
Insulin Action ◽  
Glycogen Synthesis ◽  
Human Growth ◽  
Whole Body ◽  
Nonesterified Fatty Acids ◽  
Insulin Resistant

To clarify roles of amylin, we investigated metabolic responses to rat amylin-(8—37), a specific amylin antagonist, in normal and insulin-resistant, human growth hormone (hGH)-infused rats. Fasting conscious rats were infused with saline or hGH, each with and without amylin-(8—37) (0.125 μmol/h), over 5.75 h. At 3.75 h, a hyperinsulinemic (100 mU/l) clamp with bolus 2-deoxy-d-[3H]glucose and [14C]glucose was started. hGH infusion led to prompt (2- to 3-fold) basal hyperamylinemia ( P < 0.02) and hyperinsulinemia. Amylin-(8—37) reduced plasma insulin ( P < 0.001) and enhanced several measures of whole body and muscle insulin sensitivity ( P < 0.05) in both saline- and hGH-infused rats. Amylin-(8—37) corrected hGH-induced liver insulin resistance, increased basal plasma triglycerides and lowered plasma nonesterified fatty acids in both groups, and reduced muscle triglyceride and total long-chain acyl-CoA content in saline-treated rats ( P < 0.05). In isolated soleus muscle, amylin-(8—37) blocked amylin-induced inhibition of glycogen synthesis but had no effect in the absence of amylin. Thus 1) hyperamylinemia accompanies insulin resistance induced by hGH infusion; 2) amylin-(8—37) increases whole body and muscle insulin sensitivity and consistently reduces basal insulin levels in normal and hGH-induced insulin-resistant rats; and 3) amylin-(8—37) elicits a significant alteration of in vivo lipid metabolism. These findings support a role of amylin in modulating insulin action and suggest that this could be mediated by effects on lipid metabolism.

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