Abstract 12189: Molecular Mechanisms Underlying Fasting Modulated Liver Insulin Sensitivity and Metabolism in Male Lipodystrophic Bscl2/Seipin-Deficient Mice

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Weiqin Chen ◽  
Hongyi Zhou ◽  
Pradip Saha ◽  
Luge Li ◽  
Lawrence Chan
Keyword(s):  
Insulin Resistance ◽  
Insulin Sensitivity ◽  
Hepatic Steatosis ◽  
Insulin Signaling ◽  
Molecular Mechanisms ◽  
De Novo ◽  
Liver Lipid ◽  
De Novo Lipogenesis ◽  
Hepatic Insulin Signaling ◽  
A Cell

Bscl2–/– mice recapitulate many of the major metabolic manifestations in Berardinelli-Seip Congenital Lipodystrophy type 2 (BSCL2) individuals, including lipodystrophy, hepatomegly, hepatic steatosis and insulin resistance. The mechanisms that underlie hepatic steatosis and insulin resistance in Bscl2–/– mice are poorly understood. To address this issue, we performed hyperinsulinemic-euglycemic clamp on Bscl2–/– and wild-type mice after an overnight (16-h) fast, and found that Bscl2–/– actually displayed increased hepatic insulin sensitivity. Interestingly, liver in Bscl2–/– mice after a short term (4-h) fast had impaired acute insulin signaling, a defect that disappeared after a 16-h fast. Notably, fasting dependent hepatic insulin signaling in Bscl2–/– mice was not associated with liver diacylglyceride and ceramide contents, but could be attributable in part to the expression of hepatic insulin signaling receptor and substrates. Meanwhile, increased de novo lipogenesis and decreased β-oxidation led to severe hepatic steatosis in fed or short fasted Bscl2–/– mice while liver lipid accumulation and metabolism in Bscl2–/– mice was markedly impacted by prolonged fasting. Furthermore, mice with liver-specific inactivation of Bscl2 manifested no hepatic steatosis even under high fat diet, suggesting Bscl2 does not play a cell autonomous role in regulating liver lipid homeostasis. Overall, our results offered new insights into the metabolic adaptations of liver in response to fasting and uncovered a novel fasting-dependent regulation of hepatic insulin signaling in a mouse model of human BSCL2.

scholarly journals Molecular Mechanisms Underlying Fasting Modulated Liver Insulin Sensitivity and Metabolism in Male Lipodystrophic Bscl2/Seipin-Deficient Mice

Endocrinology ◽  
2014 ◽  
Vol 155 (11) ◽  
pp. 4215-4225 ◽  
Author(s):  
Weiqin Chen ◽  
Hongyi Zhou ◽  
Pradip Saha ◽  
Luge Li ◽  
Lawrence Chan
Keyword(s):  
Insulin Resistance ◽  
Insulin Sensitivity ◽  
Hepatic Steatosis ◽  
Insulin Signaling ◽  
Molecular Mechanisms ◽  
De Novo ◽  
Liver Lipid ◽  
De Novo Lipogenesis ◽  
Hepatic Insulin Signaling ◽  
A Cell

Abstract Bscl2 −/− mice recapitulate many of the major metabolic manifestations in Berardinelli-Seip congenital lipodystrophy type 2 (BSCL2) individuals, including lipodystrophy, hepatomegly, hepatic steatosis, and insulin resistance. The mechanisms that underlie hepatic steatosis and insulin resistance in Bscl2−/− mice are poorly understood. To address this issue, we performed hyperinsulinemic-euglycemic clamp on Bscl2−/− and wild-type mice after an overnight (16-h) fast, and found that Bscl2−/− actually displayed increased hepatic insulin sensitivity. Interestingly, liver in Bscl2−/− mice after a short term (4-h) fast had impaired acute insulin signaling, a defect that disappeared after a 16-hour fast. Notably, fasting-dependent hepatic insulin signaling in Bscl2−/− mice was not associated with liver diacylglyceride and ceramide contents, but could be attributable in part to the expression of hepatic insulin signaling receptor and substrates. Meanwhile, increased de novo lipogenesis and decreased β-oxidation led to severe hepatic steatosis in fed or short-fasted Bscl2−/− mice whereas liver lipid accumulation and metabolism in Bscl2−/− mice was markedly affected by prolonged fasting. Furthermore, mice with liver-specific inactivation of Bscl2 manifested no hepatic steatosis even under high-fat diet, suggesting Bscl2 does not play a cell autonomous role in regulating liver lipid homeostasis. Overall, our results offered new insights into the metabolic adaptations of liver in response to fasting and uncovered a novel fasting-dependent regulation of hepatic insulin signaling in a mouse model of human BSCL2.

scholarly journals OR17-01 Leptin Decreases De Novo Lipogenesis in Lipodystrophic Patients

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Annah Petek Baykal ◽  
Elizabeth J Parks ◽  
Robert Shamburek ◽  
Stephanie Chung ◽  
Majid M Syed-Abdul ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Insulin Sensitivity ◽  
Hepatic Steatosis ◽  
De Novo ◽  
De Novo Lipogenesis ◽  
Mass Spectrometry Analysis ◽  
Alcoholic Fatty Liver ◽  
Peripheral Tissues ◽  
Hepatic Insulin Sensitivity ◽  
Total Body

Abstract De novo lipogenesis (DNL) plays a role in the development of hepatic steatosis and non-alcoholic fatty liver disease (NAFLD). In rodent models of both health and lipodystrophy (LD), leptin decreases DNL. In human patients with LD, reduced adipose tissue results in adipokine deficiencies, including lower plasma leptin, which contributes to insulin resistance, dyslipidemia and ectopic accumulation of triglycerides (TG). The mechanisms by which leptin regulates serum and hepatic-TG are not well elucidated. Studying patients with LD before and after leptin therapy provides an important clinical model for understanding leptin’s effect on DNL. We hypothesized that leptin treatment in lipodystrophic patients would decrease DNL by decreasing insulin resistance and glycemia, resulting in reduced circulating and hepatic-TG. Leptin-naïve patients with LD (n=11) were treated with recombinant leptin (metreleptin) for 6 months. All measurements were performed after an 8–12 hr fast. The % of TG in TG-rich lipoproteins (TRLP-TG) derived from DNL (% DNL) was measured using body water labeling (oral D2O) of TG and mass spectrometry analysis. Absolute DNL was calculated as the product of TRLP-TG and % DNL. HbA1c and serum-TG were measured biochemically, hepatic-TG by MRI, and total body and hepatic insulin sensitivity measured during a hyperinsulinemic-euglycemic clamp. DNL decreased after metreleptin: % DNL from 22.8±6.8 to 9.1±5.1% (p=0.0008) and absolute DNL from 54.2±32.1 to 8.6±6.5 mg/dl (p=0.003). TRLP-TG decreased from (median [interquartile range]) 160 [107, 280] to 98 [66, 147] mg/dl (p=0.01). Total body and hepatic insulin sensitivity increased from 3.7 [3.0, 7.3] to 8.4 [5.1,10.6] mg/kgFFM/min (p=0.03) and from 61.0 [48.5, 69.3] to 84.7 [75.2, 107.6] % (p =0.01), respectively. HbA1c decreased from 8.6±1.8 to 7.1±1.4% (p=0.04), hepatic-TG decreased from 17.6±11.9 to 10.3±9.1% (p=0.02), and serum-TG from 386 [216, 686] to 223 [118, 497] mg/dl (p=0.06). DNL correlated negatively with insulin sensitivity both before (r=-0.73, p=0.03) and after (r=-0.85, p=0.004) metreleptin. DNL correlated positively with hepatic-TG before (r=0.70 p=0.03) and tended to correlate after metreleptin (r=0.65, p=0.06). The change in DNL correlated with change in serum-TG (r=0.77, p=0.04) but not the change in hepatic-TG (p=0.80). We show here for the first time that 6 months of metreleptin treatment in humans with LD decreased DNL by 84% and was associated with reductions in glycemia and improved peripheral and hepatic insulin sensitivity. These data indicate a strong link between metreleptin’s effects to increase clearance of blood glucose by peripheral tissues and reduce hepatic carbohydrate flux, resulting in DNL reductions. This led to lowered hepatic steatosis and dyslipidemia and suggests treatments that target multi-organ insulin resistance may lead to decreased NAFLD and cardiovascular risk.

scholarly journals Comprehensive functional screening of miRNAs involved in fat cell insulin sensitivity among women

2017 ◽  
Vol 312 (6) ◽  
pp. E482-E494 ◽  
Author(s):  
Ingrid Dahlman ◽  
Yasmina Belarbi ◽  
Jurga Laurencikiene ◽  
Annie M. Pettersson ◽  
Peter Arner ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Insulin Sensitivity ◽  
Differential Expression ◽  
Insulin Signaling ◽  
Molecular Mechanisms ◽  
Functional Screening ◽  
Fat Cell ◽  
Subcutaneous White Adipose Tissue ◽  
Micro Rnas

The key pathological link between obesity and type 2 diabetes is insulin resistance, but the molecular mechanisms are not entirely identified. micro-RNAs (miRNA) are dysregulated in obesity and may contribute to insulin resistance. Our objective was to detect and functionally investigate miRNAs linked to insulin sensitivity in human subcutaneous white adipose tissue (scWAT). Subjects were selected based on the insulin-stimulated lipogenesis response of subcutaneous adipocytes. Global miRNA profiling was performed in abdominal scWAT of 18 obese insulin-resistance (OIR), 21 obese insulin-sensitive (OIS), and 9 lean women. miRNAs demonstrating differential expression between OIR and OIS women were overexpressed in human in vitro-differentiated adipocytes followed by assessment of lipogenesis and identification of miRNA targets by measuring mRNA/protein expression and 3′-untranslated region analysis. Eleven miRNAs displayed differential expression between OIR and OIS states. Overexpression of miR-143-3p and miR-652-3p increased insulin-stimulated lipogenesis in human in vitro differentiated adipocytes and directly or indirectly affected several genes/proteins involved in insulin signaling at transcriptional or posttranscriptional levels. Adipose expression of miR-143-3p and miR-652-3p was positively associated with insulin-stimulated lipogenesis in scWAT independent of body mass index. In conclusion, miR-143-3p and miR-652-3p are linked to scWAT insulin resistance independent of obesity and influence insulin-stimulated lipogenesis by interacting at different steps with insulin-signaling pathways.

scholarly journals Role of inhibitory κB kinase and c-Jun NH2-terminal kinase in the development of hepatic insulin resistance in critical illness diabetes

2011 ◽  
Vol 301 (3) ◽  
pp. G454-G463 ◽  
Author(s):  
Shaoning Jiang ◽  
Joseph L. Messina
Keyword(s):  
Insulin Resistance ◽  
Critical Illness ◽  
Insulin Signaling ◽  
Molecular Mechanisms ◽  
Adenovirus Vector ◽  
Dominant Negative ◽  
Serine Phosphorylation ◽  
Hepatic Insulin Resistance ◽  
Mortality And Morbidity ◽  
Hepatic Insulin Signaling

Hyperglycemia and insulin resistance induced by acute injuries or critical illness are associated with increased mortality and morbidity, as well as later development of type 2 diabetes. The molecular mechanisms underlying the acute onset of insulin resistance following critical illness remain poorly understood. In the present studies, the roles of serine kinases, inhibitory κB kinase (IKK) and c-Jun NH2-terminal kinase (JNK), in the acute development of hepatic insulin resistance were investigated. In our animal model of critical illness diabetes, activation of hepatic IKK and JNK was observed as early as 15 min, concomitant with the rapid impairment of hepatic insulin signaling and increased serine phosphorylation of insulin receptor substrate 1. Inhibition of IKKα or IKKβ, or both, by adenovirus vector-mediated expression of dominant-negative IKKα or IKKβ in liver partially restored insulin signaling. Similarly, inhibition of JNK1 kinase by expression of dominant-negative JNK1 also resulted in improved hepatic insulin signaling, indicating that IKK and JNK1 kinases contribute to critical illness-induced insulin resistance in liver.

scholarly journals Adipocyte JAK2 Regulates Hepatic Insulin Sensitivity Independently of Body Composition, Liver Lipid Content, and Hepatic Insulin Signaling

Diabetes ◽  
2017 ◽  
Vol 67 (2) ◽  
pp. 208-221 ◽  
Author(s):  
Kevin C. Corbit ◽  
João Paulo G. Camporez ◽  
Lia R. Edmunds ◽  
Jennifer L. Tran ◽  
Nicholas B. Vera ◽  
...  
Keyword(s):  
Body Composition ◽  
Insulin Sensitivity ◽  
Lipid Content ◽  
Insulin Signaling ◽  
Liver Lipid ◽  
Hepatic Insulin Sensitivity ◽  
Liver Lipid Content ◽  
Hepatic Insulin Signaling

scholarly journals The Molecular Mechanisms Underlying Mitochondria-Associated Endoplasmic Reticulum Membrane-Induced Insulin Resistance

2020 ◽  
Vol 11 ◽  
Author(s):  
Han Cheng ◽  
Xiaokun Gang ◽  
Guangyu He ◽  
Yujia Liu ◽  
Yingxuan Wang ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Insulin Signaling ◽  
Stress Responses ◽  
Molecular Mechanisms ◽  
Glucose Sensing ◽  
Hepatic Insulin Resistance ◽  
Endoplasmic Reticulum Membrane ◽  
Hepatic Insulin Signaling

Mitochondria and the endoplasmic reticulum (ER) are connected at multiple sites via what are known as mitochondria-associated ER membranes (MAMs). These associations are known to play an important role in maintaining cellular homeostasis. Impaired MAM signaling has wide-ranging effects in many diseases, such as obesity, diabetes, and neurodegenerative disorders. Accumulating evidence has suggested that MAMs influence insulin signaling through different pathways, including those associated with Ca2+ signaling, lipid metabolism, mitochondrial function, ER stress responses, and inflammation. Altered MAM signaling is a common feature of insulin resistance in different tissues, including the liver, muscle, and even the brain. In the liver, MAMs are key glucose-sensing regulators and have been proposed to be a hub for insulin signaling. Impaired MAM integrity has been reported to disrupt hepatic responses to changes in glucose availability during nutritional transition and to induce hepatic insulin resistance. Meanwhile, these effects can be rescued by the reinforcement of MAM interactions. In contrast, several studies have proposed that enhanced ER-mitochondria connections are detrimental to hepatic insulin signaling and can lead to mitochondrial dysfunction. Thus, given these contradictory results, the role played by the MAM in the regulation of hepatic insulin signaling remains elusive. Similarly, in skeletal muscle, enhanced MAM formation may be beneficial in the early stage of diabetes, whereas continuous MAM enhancement aggravates insulin resistance. Furthermore, recent studies have suggested that ER stress may be the primary pathway through which MAMs induce brain insulin resistance, especially in the hypothalamus. This review will discuss the possible mechanisms underlying MAM-associated insulin resistance as well as the therapeutic potential of targeting the MAM in the treatment of type 2 diabetes.

scholarly journals Hepatic Steatosis is Common in Adolescents with Obesity and PCOS and Relates to De Novo Lipogenesis but not Insulin Resistance

Obesity ◽  
2016 ◽  
Vol 24 (11) ◽  
pp. 2399-2406 ◽  
Author(s):  
Melanie Cree-Green ◽  
Bryan C. Bergman ◽  
Gregory V. Coe ◽  
Lindsey Newnes ◽  
Amy D. Baumgartner ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Hepatic Steatosis ◽  
De Novo ◽  
De Novo Lipogenesis

scholarly journals Flavonoids and Insulin-Resistance: From Molecular Evidences to Clinical Trials

2019 ◽  
Vol 20 (9) ◽  
pp. 2061 ◽  
Author(s):  
Benedetta Russo ◽  
Fabiana Picconi ◽  
Ilaria Malandrucco ◽  
Simona Frontoni
Keyword(s):  
Insulin Resistance ◽  
Metabolic Syndrome ◽  
Clinical Trials ◽  
Insulin Sensitivity ◽  
Insulin Signaling ◽  
Molecular Mechanisms ◽  
Food Sources ◽  
Main Factors

Insulin-resistance is one of the main factors responsible for the onset and progression of Metabolic Syndrome (MetS). Among all polyphenols, the effects of flavonoids and their main food sources on insulin sensitivity have been widely evaluated in molecular and clinical studies. The aim of this review is to analyse the data observed in vitro, in vivo and in clinical trials concerning the effects of flavonoids on insulin resistance and to determine the molecular mechanisms with which flavonoids interact with insulin signaling.

scholarly journals miR-146a regulates insulin sensitivity via NPR3

2020 ◽  
Author(s):  
Julian Roos ◽  
Meike Dahlhaus ◽  
Jan-Bernd Funcke ◽  
Monika Kustermann ◽  
Gudrun Strauss ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Insulin Sensitivity ◽  
Glucose Uptake ◽  
High Fat Diet ◽  
Metabolic Diseases ◽  
De Novo ◽  
Liver Steatosis ◽  
De Novo Lipogenesis ◽  
Loss Of Function ◽  
High Fat

AbstractThe pathogenesis of obesity-related metabolic diseases has been linked to the inflammation of white adipose tissue (WAT), but the molecular interconnections are still not fully understood. MiR-146a controls inflammatory processes by suppressing pro-inflammatory signaling pathways. The aim of this study was to characterize the role of miR-146a in obesity and insulin resistance. MiR-146a−/− mice were subjected to a high-fat diet followed by metabolic tests and WAT transcriptomics. Gain- and loss-of-function studies were performed using human Simpson–Golabi–Behmel syndrome (SGBS) adipocytes. Compared to controls, miR-146a−/− mice gained significantly more body weight on a high-fat diet with increased fat mass and adipocyte hypertrophy. This was accompanied by exacerbated liver steatosis, insulin resistance, and glucose intolerance. Likewise, adipocytes transfected with an inhibitor of miR-146a displayed a decrease in insulin-stimulated glucose uptake, while transfecting miR-146a mimics caused the opposite effect. Natriuretic peptide receptor 3 (NPR3) was identified as a direct target gene of miR-146a in adipocytes and CRISPR/Cas9-mediated knockout of NPR3 increased insulin-stimulated glucose uptake and enhanced de novo lipogenesis. In summary, miR-146a regulates systemic and adipocyte insulin sensitivity via downregulation of NPR3.

scholarly journals Dietary Glycotoxins Impair Hepatic Lipidemic Profile in Diet-Induced Obese Rats Causing Hepatic Oxidative Stress and Insulin Resistance

2019 ◽  
Vol 2019 ◽  
pp. 1-14 ◽  
Author(s):  
C. Neves ◽  
T. Rodrigues ◽  
J. Sereno ◽  
C. Simões ◽  
J. Castelhano ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Insulin Resistance ◽  
Fatty Acid ◽  
High Fat Diet ◽  
De Novo ◽  
Liver Lipid ◽  
Lipid Fraction ◽  
De Novo Lipogenesis ◽  
High Fat ◽  
Obese Rats

Nonalcoholic fatty liver disease (NAFLD) is caused by excessive liver lipid accumulation, but insulin resistance is specifically associated with impaired lipid saturation, oxidation, and storage (esterification), besides increased de novo lipogenesis. We hypothesized that dietary glycotoxins could impair hepatic lipid metabolism in obesity contributing to lipotoxicity-driven insulin resistance and thus to the onset of nonalcoholic steatohepatitis (NASH). In diet-induced obese rats with methylglyoxal-induced glycation, magnetic resonance spectroscopy, mass spectrometry, and gas chromatography were used to assess liver composition in fatty acyl chains and phospholipids. High-fat diet-induced obesity increased liver lipid fraction and suppressed de novo lipogenesis but did not change fatty acid esterification and saturation or insulin sensitivity. Despite a similar increase in total lipid fraction when supplementing the high-fat diet with dietary glycotoxins, impairment in the suppression of de novo lipogenesis and decreased fatty acid unsaturation and esterification were observed. Moreover, glycotoxins also decreased polyunsaturated cardiolipins and caused oxidative stress, portal inflammation, and insulin resistance in high-fat diet-induced obese rats. Dietary glycated products do not change total lipid levels in the liver of obese rats but dramatically modify the lipidemic profile, leading to oxidative stress, hepatic lipotoxicity, and insulin resistance in obesity and thus contribute to the onset of NASH.

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