scholarly journals Adipocytokines and the Regulation of Lipid Metabolism in Growth Hormone Transgenic and Calorie-Restricted Mice

Endocrinology ◽  
2007 ◽  
Vol 148 (6) ◽  
pp. 2845-2853 ◽  
Author(s):  
Zhihui Wang ◽  
Michal M. Masternak ◽  
Khalid A. Al-Regaiey ◽  
Andrzej Bartke
Keyword(s):  
Insulin Resistance ◽  
Lipid Metabolism ◽  
Insulin Sensitivity ◽  
Transgenic Mice ◽  
Plasma Lipid ◽  
Improve Insulin Sensitivity ◽  
Plasma Adiponectin ◽  
Protein Levels ◽  
Cholesterol Levels ◽  
Resistance To Insulin

Chronic elevation of GH induces resistance to insulin and hyperinsulinemia in both humans and animals, whereas calorie restriction (CR) improves peripheral insulin sensitivity in many species. To investigate the mechanisms that lead to insulin resistance in animals with high levels of GH as well as the mechanisms that might improve insulin sensitivity, we fed GH-overexpressing transgenic mice ad libitum or subjected them to 30% CR. We then assayed the plasma adipocytokines levels related to insulin sensitivity, plasma lipid levels, and tissue triglycerides accumulation and examined adipocyte morphology. Furthermore, we evaluated mRNA expression and protein levels of enzymes or regulators involved in regulating hepatic lipid metabolism. Our results suggest that decreased plasma adiponectin, increased plasma resistin and cholesterol, and elevated levels of TNF-α and IL-6 in adipocytes may all contribute to the insulin resistance observed in GH-Tg mice. Increased accumulation of triglycerides and impaired adipocytes differentiation in GH-transgenic mice provide plausible mechanisms for the alterations of adipocytokines. Hepatic and muscle insulin resistance in these mice is probably related to excessive accumulation of fatty acids and their metabolites. An increase in plasma adiponectin and decrease in plasma IL-6, triglycerides, and cholesterol levels in response to CR may improve insulin sensitivity.

scholarly journals Insulin resistance and liver histopathology in metabolically unhealthy subjects do not correlate with the hepatic abundance of NLRP3 inflammasome nor circulating IL-1β levels

2021 ◽  
Vol 9 (1) ◽  
pp. e001975
Author(s):  
Nicolas Quezada ◽  
Ilse Valencia ◽  
Javiera Torres ◽  
Gregorio Maturana ◽  
Jaime Cerda ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Insulin Sensitivity ◽  
Liver Damage ◽  
Nlrp3 Inflammasome ◽  
Low Grade ◽  
Model Assessment ◽  
Alcoholic Fatty Liver ◽  
Protein Levels ◽  
Liver Histopathology ◽  
Inflammatory Status

IntroductionSystemic chronic low-grade inflammation has been linked to insulin resistance (IR) and non-alcoholic steatohepatitis (NASH). NOD-like receptor protein 3 (NLRP3) inflammasome and its final product, interleukin (IL)-1β, exert detrimental effects on insulin sensitivity and promote liver inflammation in murine models. Evidence linking hepatic NLRP3 inflammasome, systemic IR and NASH has been scarcely explored in humans. Herein, we correlated the hepatic abundance of NLRP3 inflammasome components and IR and NASH in humans.Research design and methodsMetabolically healthy (MH) (n=11) and metabolically unhealthy (MUH) (metabolic syndrome, n=21, and type 2 diabetes, n=14) subjects were recruited. Insulin sensitivity (homeostatic model assessment of IR (HOMA-IR) and Oral Glucose Sensitivity (OGIS120)), glycemic (glycated hemoglobin), and lipid parameters were determined by standard methods. Plasma cytokines were quantified by Magpix. Hepatic NLRP3 inflammasome components were determined at the mRNA and protein levels by reverse transcription–quantitative PCR and western blot, respectively. Liver damage was assessed by histological analysis (Non-alcoholic Fatty Liver Disease Activity Score (NAS) and Steatosis, Inflammatory Activity, and Fibrosis (SAF) scores). IR and liver histopathology were correlated with NLRP3 inflammasome components as well as with liver and plasma IL-1β levels.ResultsBody Mass Index, waist circumference, and arterial hypertension frequency were significantly higher in MUH subjects. These patients also had increased high-sensitivity C reactive protein levels compared with MH subjects. No differences in the plasma levels of IL-1β nor the hepatic content of Nlrp3, apoptosis-associated speck-like (Asc), Caspase-1, and IL-1β were detected between MUH and MH individuals. MUH subjects had significantly higher NAS and SAF scores, indicating more severe liver damage. However, histological severity did not correlate with the hepatic content of NLRP3 inflammasome components nor IL-1β levels.ConclusionOur results suggest that NLRP3 inflammasome activation is linked neither to IR nor to the inflammatory status of the liver in MUH patients.

scholarly journals Duration of rise in free fatty acids determines salicylate's effect on hepatic insulin sensitivity

2013 ◽  
Vol 217 (1) ◽  
pp. 31-43 ◽  
Author(s):  
Sandra Pereira ◽  
Wen Qin Yu ◽  
María E Frigolet ◽  
Jacqueline L Beaudry ◽  
Yaniv Shpilberg ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Insulin Sensitivity ◽  
Muscle Protein ◽  
Hepatic Insulin Resistance ◽  
Skeletal Muscle Protein ◽  
Protein Levels ◽  
Peripheral Insulin Resistance ◽  
Plasma Ffa ◽  
A Site

We have shown in rats that sodium salicylate (SS), which inhibits IkBa kinase B (IKKB), prevents hepatic and peripheral insulin resistance caused by short-term (7 h) i.v. administration of Intralipid and heparin (IH). We wished to further determine whether this beneficial effect of SS persisted after prolonged (48 h) IH infusion, which better mimics the chronic free fatty acid (FFA) elevation of obesity. Hence, we performed hyperinsulinemic euglycemic clamps with tritiated glucose methodology to determine hepatic and peripheral insulin sensitivity in rats infused with saline, IH, IH and SS, or SS alone. SS prevented peripheral insulin resistance (P<0.05) caused by prolonged plasma FFA elevation; however, it did not prevent hepatic insulin resistance. In skeletal muscle, protein levels of phospho-IkBa were augmented by prolonged IH administration and this was prevented by SS, suggesting that IH activates while SS prevents the activation of IKKB. Markers of IKKB activation, namely protein levels of phospho-IkBa and IkBa, indicated that IKKB is not activated in the liver after prolonged FFA elevation. Phosphorylation of serine 307 at insulin receptor substrate (IRS)-1, which is a marker of proximal insulin resistance, was not altered by IH administration in the liver, suggesting that this is not a site of hepatic insulin resistance in the prolonged lipid infusion model. Our results suggest that the role of IKKB in fat-induced insulin resistance is time and tissue dependent and that hepatic insulin resistance induced by prolonged lipid elevation is not due to an IRS-1 serine 307 kinase.

Leptin, skeletal muscle lipids, and lipid-induced insulin resistance

2007 ◽  
Vol 293 (2) ◽  
pp. R642-R650 ◽  
Author(s):  
John J. Dube ◽  
Bankim A. Bhatt ◽  
Nikolas Dedousis ◽  
Arend Bonen ◽  
Robert M. O'Doherty
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Fatty Acid ◽  
Lipid Metabolism ◽  
Insulin Sensitivity ◽  
Insulin Action ◽  
Glycogen Synthase ◽  
Acid Oxidation ◽  
Fatty Acid Binding ◽  
Lipid Metabolites

Leptin-induced increases in insulin sensitivity are well established and may be related to the effects of leptin on lipid metabolism. However, the effects of leptin on the levels of lipid metabolites implicated in pathogenesis of insulin resistance and the effects of leptin on lipid-induced insulin resistance are unknown. The current study addressed in rats the effects of hyperleptinemia (HL) on insulin action and markers of skeletal muscle (SkM) lipid metabolism in the absence or presence of acute hyperlipidemia induced by an infusion of a lipid emulsion. Compared with controls (CONT), HL increased insulin sensitivity, as assessed by hyperinsulinemic-euglycemic clamp (∼15%), and increased SkM Akt (∼30%) and glycogen synthase kinase 3α (∼52%) phosphorylation. These improvements in insulin action were associated with decreased SkM triglycerides (TG; ∼61%), elevated ceramides (∼50%), and similar diacylglycerol (DAG) levels in HL compared with CONT. Acute hyperlipidemia in CONT decreased insulin sensitivity (∼25%) and increased SkM DAG (∼33%) and ceramide (∼60%) levels. However, hyperlipidemia did not induce insulin resistance or SkM DAG and ceramide accumulation in HL. SkM total fatty acid transporter CD36, plasma membrane fatty acid binding protein, acetyl Co-A carboxylase phosphorylation, and fatty acid oxidation were similar in HL compared with CONT. However, HL decreased SkM protein kinase Cθ (PKCθ), a kinase implicated in mediating the detrimental effects of lipids on insulin action. We conclude that increases in insulin sensitivity induced by HL are associated with decreased levels of SkM TG and PKCθ and increased SkM insulin signaling, but not with decreases in other lipid metabolites implicated in altering SkM insulin sensitivity (DAG and ceramide). Furthermore, insulin resistance induced by an acute lipid infusion is prevented by HL.

scholarly journals Probiotics, prebiotics, synbiotics and insulin sensitivity

2017 ◽  
Vol 31 (1) ◽  
pp. 35-51 ◽  
Author(s):  
Y. A. Kim ◽  
J. B. Keogh ◽  
P. M. Clifton
Keyword(s):  
Oxidative Stress ◽  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Insulin Sensitivity ◽  
Intestinal Permeability ◽  
Peptide Yy ◽  
Glucagon Secretion ◽  
Energy Harvest ◽  
Improve Insulin Sensitivity

AbstractAnimal studies indicate that the composition of gut microbiota may be involved in the progression of insulin resistance to type 2 diabetes. Probiotics and/or prebiotics could be a promising approach to improve insulin sensitivity by favourably modifying the composition of the gut microbial community, reducing intestinal endotoxin concentrations and decreasing energy harvest. The aim of the present review was to investigate the effects of probiotics, prebiotics and synbiotics (a combination of probiotics and prebiotics) on insulin resistance in human clinical trials and to discuss the potential mechanisms whereby probiotics and prebiotics improve glucose metabolism. The anti-diabetic effects of probiotics include reducing pro-inflammatory cytokines via a NF-κB pathway, reduced intestinal permeability, and lowered oxidative stress. SCFA play a key role in glucose homeostasis through multiple potential mechanisms of action. Activation of G-protein-coupled receptors on L-cells by SCFA promotes the release of glucagon-like peptide-1 and peptide YY resulting in increased insulin and decreased glucagon secretion, and suppressed appetite. SCFA can decrease intestinal permeability and decrease circulating endotoxins, lowering inflammation and oxidative stress. SCFA may also have anti-lipolytic activities in adipocytes and improve insulin sensitivity via GLUT4 through the up-regulation of 5'-AMP-activated protein kinase signalling in muscle and liver tissues. Resistant starch and synbiotics appear to have favourable anti-diabetic effects. However, there are few human interventions. Further well-designed human clinical studies are required to develop recommendations for the prevention of type 2 diabetes with pro- and prebiotics.

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 The ERα-PI3K Cascade in Proopiomelanocortin Progenitor Neurons Regulates Feeding and Glucose Balance in Female Mice

Endocrinology ◽  
2015 ◽  
Vol 156 (12) ◽  
pp. 4474-4491 ◽  
Author(s):  
Liangru Zhu ◽  
Pingwen Xu ◽  
Xuehong Cao ◽  
Yongjie Yang ◽  
Antentor Othrell Hinton ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Insulin Sensitivity ◽  
Food Intake ◽  
Phosphatidyl Inositol ◽  
Pi3k Pathway ◽  
Improve Insulin Sensitivity ◽  
Female Mice ◽  
Intracellular Signals ◽  
Inhibit Food Intake ◽  
Regulatory Effects

Estrogens act upon estrogen receptor (ER)α to inhibit feeding and improve glucose homeostasis in female animals. However, the intracellular signals that mediate these estrogenic actions remain unknown. Here, we report that anorexigenic effects of estrogens are blunted in female mice that lack ERα specifically in proopiomelanocortin (POMC) progenitor neurons. These mutant mice also develop insulin resistance and are insensitive to the glucose-regulatory effects of estrogens. Moreover, we showed that propyl pyrazole triol (an ERα agonist) stimulates the phosphatidyl inositol 3-kinase (PI3K) pathway specifically in POMC progenitor neurons, and that blockade of PI3K attenuates propyl pyrazole triol-induced activation of POMC neurons. Finally, we show that effects of estrogens to inhibit food intake and to improve insulin sensitivity are significantly attenuated in female mice with PI3K genetically inhibited in POMC progenitor neurons. Together, our results indicate that an ERα-PI3K cascade in POMC progenitor neurons mediates estrogenic actions to suppress food intake and improve insulin sensitivity.

scholarly journals Chronic Dietary Branched-Chain Amino Acids Induced Lipid Oxidation and Blunted Insulin-Stimulated Glucose Production in Mice With NAFLD

2021 ◽  
Vol 5 (Supplement_2) ◽  
pp. 529-529
Author(s):  
Chaitra Surugihalli ◽  
Vaishna Muralidaran ◽  
Kruti Patel ◽  
Tabitha Gregory ◽  
Nishanth Sunny
Keyword(s):  
Insulin Resistance ◽  
Amino Acids ◽  
Lipid Metabolism ◽  
Insulin Sensitivity ◽  
Lipid Oxidation ◽  
Glucose Production ◽  
Branched Chain Amino Acids ◽  
Hepatic Insulin Resistance ◽  
High Fat ◽  
Branched Chain

Abstract Objectives Elevated circulating branched-chain amino acids (BCAAs) during insulin resistance are strong predictors of type 2 diabetes mellitus onset. Defects in BCAA degradation are evident in several tissues during insulin resistance and non-alcoholic fatty liver disease (NAFLD). Furthermore, alterations in BCAA metabolism are associated with changes in several aspects lipid metabolism, including lipogenesis, ketogenesis and mitochondrial TCA cycle activity. Considering the crosstalk between BCAAs and lipid metabolism, we hypothesized that chronic supplementation of BCAAs will modulate hepatic insulin resistance and mitochondrial lipid oxidation during NAFLD. Methods Mice (C57BL/6N) were reared on either a low-fat (LF; 10% fat kcal), high-fat (HF; 60% fat kcal or high-fat diet supplemented with BCAA (HFBA; 150% BCAA) for 24 weeks. Metabolic profiling was conducted under fed or overnight fasted (14–16 hrs) conditions. A subset of overnight fasted mice from the HF and HFBA groups were subjected to hyperinsulinemic euglycemic clamps, following implantation of jugular vein catheters. Results Feeding HF and HFBA diets resulted in NAFLD. Circulating BCAAs were higher in ‘fed’ mice consuming HFBA diet (e.g., Valine, µM ± SEM; 311 ± 38 in HF, 432 ± 34 in HFBA, P ≤ 0.05). Overnight fasting significantly reduced BCAA levels in all groups, but the fasting levels of BCAAs remained similar between groups. Fed-to-fasted fold changes in blood glucose, serum insulin and c-peptide were higher in HFBA mice (P ≤ 0.05). Insulin stimulated suppression of glucose production (% ± SEM; HF = 38 ± 11, HFBA = 16 ± 16) was blunted in HFBA mice.  Furthermore, fed-to-fasted expression of hepatic genes involved in lipid oxidation, including LCAD, MCAD, PPARa and CPT1a were significantly higher (P ≤ 0.05) in the HFBA mice. Conclusions In summary, chronic BCAA supplementation induced hepatic lipid oxidation gene expression, without any apparent improvements in insulin sensitivity. In conclusion, while the induction of lipid oxidation by BCAAs could explain certain beneficial effects associated with their supplementation, the longer-term impact of the BCAAs on insulin sensitivity need to be further explored. Funding Sources National Institutes of Health (NIH) grant RO1-DK-112865

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