Liver Steatosis in Obese Prepubertal Children: A Possible Role of Insulin Resistance

Obesity ◽  
2008 ◽  
Vol 16 (3) ◽  
pp. 677-683 ◽  
Author(s):  
Ebe D'Adamo ◽  
Mario Impicciatore ◽  
Rita Capanna ◽  
M. Loredana Marcovecchio ◽  
Fabio G. Masuccio ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Liver Steatosis ◽  
Prepubertal Children

scholarly journals Inflammatory Mediators and Insulin Resistance in Obesity: Role of Nuclear Receptor Signaling in Macrophages

2010 ◽  
Vol 2010 ◽  
pp. 1-10 ◽  
Author(s):  
Lucía Fuentes ◽  
Tamás Rőszer ◽  
Mercedes Ricote
Keyword(s):  
Insulin Resistance ◽  
Nuclear Receptor ◽  
Cytokine Production ◽  
Current Knowledge ◽  
Liver Steatosis ◽  
Visceral Obesity ◽  
M2 Macrophage ◽  
Low Grade ◽  
The Impact

Visceral obesity is coupled to a general low-grade chronic inflammatory state characterized by macrophage activation and inflammatory cytokine production, leading to insulin resistance (IR). The balance between proinflammatory M1 and antiinflammatory M2 macrophage phenotypes within visceral adipose tissue appears to be crucially involved in the development of obesity-associated IR and consequent metabolic abnormalities. The ligand-dependent transcription factors peroxisome proliferator activated receptors (PPARs) have recently been implicated in the determination of the M1/M2 phenotype. Liver X receptors (LXRs), which form another subgroup of the nuclear receptor superfamily, are also important regulators of proinflammatory cytokine production in macrophages. Disregulation of macrophage-mediated inflammation by PPARs and LXRs therefore underlies the development of IR. This review summarizes the role of PPAR and LXR signaling in macrophages and current knowledge about the impact of these actions in the manifestation of IR and obesity comorbidities such as liver steatosis and diabetic osteopenia.

scholarly journals A Synthetic Peptide Designed to Neutralize Lipopolysaccharides Attenuates Metaflammation and Diet-Induced Metabolic Derangements in Mice

2021 ◽  
Vol 12 ◽  
Author(s):  
Shireen Mohammad ◽  
Sura Al Zoubi ◽  
Debora Collotta ◽  
Nadine Krieg ◽  
Bianka Wissuwa ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Liver Steatosis ◽  
Scavenger Receptor ◽  
Pyrin Domain ◽  
Extracellular Signal ◽  
Enhanced Expression ◽  
Severity Of The Disease ◽  
Cluster Of Differentiation ◽  
Metabolic Endotoxemia

Metabolic endotoxemia has been suggested to play a role in the pathophysiology of metaflammation, insulin-resistance and ultimately type-2 diabetes mellitus (T2DM). The role of endogenous antimicrobial peptides (AMPs), such as the cathelicidin LL-37, in T2DM is unknown. We report here for the first time that patients with T2DM compared to healthy volunteers have elevated plasma levels of LL-37. In a reverse-translational approach, we have investigated the effects of the AMP, peptide 19-2.5, in a murine model of high-fat diet (HFD)-induced insulin-resistance, steatohepatitis and T2DM. HFD-fed mice for 12 weeks caused obesity, an impairment in glycemic regulations, hypercholesterolemia, microalbuminuria and steatohepatitis, all of which were attenuated by Peptide 19-2.5. The liver steatosis caused by feeding mice a HFD resulted in the activation of nuclear factor kappa light chain enhancer of activated B cells (NF-ĸB) (phosphorylation of inhibitor of kappa beta kinase (IKK)α/β, IκBα, translocation of p65 to the nucleus), expression of NF-ĸB-dependent protein inducible nitric oxide synthase (iNOS) and activation of the NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome, all of which were reduced by Peptide 19-2.5. Feeding mice, a HFD also resulted in an enhanced expression of the lipid scavenger receptor cluster of differentiation 36 (CD36) secondary to activation of extracellular signal-regulated kinases (ERK)1/2, both of which were abolished by Peptide 19-2.5. Taken together, these results demonstrate that the AMP, Peptide 19-2.5 reduces insulin-resistance, steatohepatitis and proteinuria. These effects are, at least in part, due to prevention of the expression of CD36 and may provide further evidence for a role of metabolic endotoxemia in the pathogenesis of metaflammation and ultimately T2DM. The observed increase in the levels of the endogenous AMP LL-37 in patients with T2DM may serve to limit the severity of the disease.

Impact of PPAR-α induction on glucose homoeostasis in alcohol-fed mice

2013 ◽  
Vol 125 (11) ◽  
pp. 501-511 ◽  
Author(s):  
Valérie Lebrun ◽  
Olivier Molendi-Coste ◽  
Nicolas Lanthier ◽  
Christine Sempoux ◽  
Patrice D. Cani ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Liver Disease ◽  
Insulin Sensitivity ◽  
Alcohol Consumption ◽  
Insulin Signalling ◽  
Liver Steatosis ◽  
Hepatic Insulin Resistance ◽  
Alcoholic Fatty Liver ◽  
Glucose Homoeostasis

Alcohol consumption is a major cause of liver disease. It also associates with increased cardiovascular risk and Type 2 diabetes. ALD (alcoholic liver disease) and NAFLD (non-alcoholic fatty liver disease) share pathological features, pathogenic mechanisms and pattern of disease progression. In NAFLD, steatosis, lipotoxicity and liver inflammation participate to hepatic insulin resistance. The aim of the present study was to verify the effect of alcohol on hepatic insulin sensitivity and to evaluate the role of alcohol-induced steatosis and inflammation on glucose homoeostasis. C57BL/6J mice were fed for 20 days a modified Lieber–DeCarli diet in which the alcohol concentration was gradually increased up to 35% of daily caloric intake. OH (alcohol liquid diet)-fed mice had liver steatosis and inflammatory infiltration. In addition, these mice developed insulin resistance in the liver, but not in muscles, as demonstrated by euglycaemic–hyperinsulinaemic clamp and analysis of the insulin signalling cascade. Treatment with the PPAR-α (peroxisome-proliferator-activated receptor-α) agonist Wy14,643 protected against OH-induced steatosis and KC (Kupffer cell) activation and almost abolished OH-induced insulin resistance. As KC activation may modulate insulin sensitivity, we repeated the clamp studies in mice depleted in KC to decipher the role of macrophages. Depletion of KC using liposomes-encapsuled clodronate in OH-fed mice failed both to improve hepatic steatosis and to restore insulin sensitivity as assessed by clamp. Our study shows that chronic alcohol consumption induces steatosis, KC activation and hepatic insulin resistance in mice. PPAR-α agonist treatment that prevents steatosis and dampens hepatic inflammation also prevents alcohol-induced hepatic insulin resistance. However, KC depletion has little impact on OH-induced metabolic disturbances.

The possible role of liver steatosis in defining metabolic syndrome in prepubertal children

Metabolism ◽  
2010 ◽  
Vol 59 (5) ◽  
pp. 671-676 ◽  
Author(s):  
Ebe D'Adamo ◽  
M. Loredana Marcovecchio ◽  
Cosimo Giannini ◽  
Rita Capanna ◽  
Mario Impicciatore ◽  
...  
Keyword(s):  
Metabolic Syndrome ◽  
Liver Steatosis ◽  
Prepubertal Children

scholarly journals Role of Hepatic Glucocorticoid Receptor in Metabolism in Models of 5αR1 Deficiency in Male Mice

Endocrinology ◽  
2019 ◽  
Vol 160 (9) ◽  
pp. 2061-2073 ◽  
Author(s):  
Tracy C S Mak ◽  
Dawn E W Livingstone ◽  
Mark Nixon ◽  
Brian R Walker ◽  
Ruth Andrew
Keyword(s):  
Insulin Resistance ◽  
Glucocorticoid Receptor ◽  
High Fat Diet ◽  
Liver Steatosis ◽  
Area Under The Curve ◽  
High Fat ◽  
Glucose Challenge ◽  
Glucocorticoid Metabolism ◽  
Challenge Area

Abstract Inhibition of 5α-reductases impairs androgen and glucocorticoid metabolism and induces insulin resistance in humans and rodents. The contribution of hepatic glucocorticoids to these adverse metabolic changes was assessed using a liver-selective glucocorticoid receptor (GR) antagonist, A-348441. Mice lacking 5α-reductase 1 (5αR1-KO) and their littermate controls were studied during consumption of a high-fat diet, with or without A-348441(120 mg/kg/d). Male C57BL/6 mice (age, 12 weeks) receiving dutasteride (1.8 mg/kg/d)) or vehicle with consumption of a high-fat diet, with or without A-348441, were also studied. In the 5αR1-KO mice, hepatic GR antagonism improved diet-induced insulin resistance but not more than that of the controls. Liver steatosis was not affected by hepatic GR antagonism in either 5αR1KO mice or littermate controls. In a second model of 5α-reductase inhibition using dutasteride and hepatic GR antagonism with A-348441 attenuated the excess weight gain resulting from dutasteride (mean ± SEM, 7.03 ± 0.5 vs 2.13 ± 0.4 g; dutasteride vs dutasteride plus A-348441; P < 0.05) and normalized the associated hyperinsulinemia after glucose challenge (area under the curve, 235.9 ± 17 vs 329.3 ± 16 vs 198.4 ± 25 ng/mL/min; high fat vs high fat plus dutasteride vs high fat plus dutasteride plus A-348441, respectively; P < 0.05). However, A-348441 again did not reverse dutasteride-induced liver steatosis. Thus, overall hepatic GR antagonism improved the insulin resistance but not the steatosis induced by a high-fat diet. Moreover, it attenuated the excessive insulin resistance caused by pharmacological inhibition of 5α-reductases but not genetic disruption of 5αR1. The use of dutasteride might increase the risk of type 2 diabetes mellitus and reduced exposure to glucocorticoids might be beneficial.

scholarly journals 4-Hydroxyisoleucine Alleviates Macrophage-Related Chronic Inflammation and Metabolic Syndrome in Mice Fed a High-Fat Diet

2021 ◽  
Vol 11 ◽  
Author(s):  
Jiali Yang ◽  
Yunhui Ran ◽  
Yonghui Yang ◽  
Shuyi Song ◽  
Yahong Wu ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Insulin Sensitivity ◽  
Chronic Inflammation ◽  
Immune Cells ◽  
High Fat Diet ◽  
Liver Steatosis ◽  
High Fat ◽  
Protein Amino Acid

In obesity, macrophages and other immune cells accumulate in organs affected by insulin, leading to chronic inflammation and insulin resistance. 4-Hydroxyisoleucine (4-HIL) is a non-protein amino acid found in fenugreek seeds. 4-HIL enhances insulin sensitivity, but its mechanism is still unclear. In this study, 4-HIL intervention reduced weight gain, liver steatosis, and dyslipidemia; moreover, it increased systemic insulin sensitivity and improved insulin resistance in mice. Importantly, after administration, the accumulation of M1 like CD11c+ macrophages and inflammation in the liver and adipose tissue were reduced in the mice. 4-HIL also reduced the proportion of CD11c+ macrophages among bone marrow-derived macrophages, which were induced in vitro. These observations demonstrate a new role of 4-HIL in insulin resistance in hepatocytes and adipocytes. 4-HIL inhibits obesity-related insulin resistance by reducing inflammation and regulating the state of M1/M2 macrophages.

scholarly journals Sex-Specific Mediating Role of Insulin Resistance and Inflammation in the Effect of Adiposity on Blood Pressure of Prepubertal Children

PLoS ONE ◽  
2015 ◽  
Vol 10 (6) ◽  
pp. e0132097 ◽  
Author(s):  
Liane Correia-Costa ◽  
Ana Cristina Santos ◽  
Milton Severo ◽  
António Guerra ◽  
Franz Schaefer ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Blood Pressure ◽  
Prepubertal Children ◽  
Mediating Role

The role of metabolic syndrome components and adipokines in insulin resistance in prepubertal children

2011 ◽  
Vol 24 (5-6) ◽  
Author(s):  
Isabel Rey Madeira ◽  
Maria Alice Neves Bordallo ◽  
Cecilia Noronha Miranda Carvalho ◽  
Fernanda Mussi Gazolla ◽  
Flavio Moutinho de Souza ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Metabolic Syndrome ◽  
Prepubertal Children ◽  
Metabolic Syndrome Components

scholarly journals miR-188 promotes liver steatosis and insulin resistance via the autophagy pathway

2020 ◽  
Vol 245 (3) ◽  
pp. 411-423 ◽  
Author(s):  
Ya Liu ◽  
Xiaoqing Zhou ◽  
Ye Xiao ◽  
Changjun Li ◽  
Yan Huang ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Lipid Metabolism ◽  
Liver Disease ◽  
Liver Steatosis ◽  
Negative Regulator ◽  
Obese Mice ◽  
Nonalcoholic Fatty Liver ◽  
Glucose And Lipid Metabolism ◽  
Autophagy Pathway

Nonalcoholic fatty liver disease (NAFLD) is becoming the most prevalent liver disease worldwide, is characterized by liver steatosis and is often accompanied with other pathological features such as insulin resistance. However, the underlying mechanisms are not fully understood, and specific pharmacological agents need to be developed. Here, we investigated the role of microRNA-188 (miR-188) as a negative regulator in hepatic glucose and lipid metabolism. miR-188 was upregulated in the liver of obese mice. Loss of miR-188 alleviated diet-induced hepatosteatosis and insulin resistance. In contrast, liver-specific overexpression of miR-188 aggravated hepatic steatosis and insulin resistance during high-fat diet feeding. Mechanistically, we found that the negative effects of miR-188 on lipid and glucose metabolism were mediated by the autophagy pathway via targeting autophagy-related gene 12 (Atg12). Furthermore, suppressing miR-188 in the liver of obese mice improved liver steatosis and insulin resistance. Taken together, our findings reveal a new regulatory role of miR-188 in glucose and lipid metabolism through the autophagy pathway, and provide a therapeutic insight for NAFLD.

Therapeutic Effect of Metformin and Vitamin E Versus Prescriptive Diet in Obese Adolescents with Fatty Liver

2011 ◽  
Vol 81 (6) ◽  
pp. 398-406 ◽  
Author(s):  
Akcam ◽  
Boyaci ◽  
Pirgon ◽  
Kaya ◽  
Uysal ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Vitamin E ◽  
Fatty Liver ◽  
Liver Steatosis ◽  
Tnf Alpha ◽  
Dietary Advice ◽  
Model Assessment ◽  
Fasting Insulin ◽  
Alcoholic Fatty Liver ◽  
Obese Adolescents

Objective: The aim of the study was to determine whether metformin or vitamin E treatment for six months is effective in reducing body weight, blood pressure, and also ameliorating insulin resistance, adiponectin, and tumor necrosis factor (TNF)-alpha in obese adolescents with non-alcoholic fatty liver disease (NAFLD). Methods: Sixty-seven obese adolescents with liver steatosis (age range, 9 - 17 years) were included in the study. The metformin group received an 850-mg dose of metformin daily and the vitamin E group received 400 U vitamin E /daily, in capsule form for 6 months, plus an individually tailored diet, exercise, and behavioral therapy. Results: After 6 months later, there was a significant decline in body mass index, and fasting insulin and homeostatic model assessment (HOMA) values in all three groups. Moreover, in comparingson of changes in HOMA among the groups, the metformin- treated group showed significantly improved metabolic control and insulin sensitivity (HOMA) at the end of the study. There were no significant differences for changes of adiponectin, TNF-alpha, in all three groups after 6 months study. Conclusion: These data suggest that metformin treatment is more effective than dietary advice and vitamin E treatment in reducing insulin resistance, and also in ameliorating metabolic parameters such as fasting insulin and lipid levels, in obese adolescents having NAFLD.

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