Reversibility of the metabolic derangement and inflammation induced by nutritional obesity
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we measured the rate of fusion between mitochondria. Fatty acids strongly impaired the fusion between mitochondria and decreased the levels of Mitofusin2 (Mfn2), a mitochondrial fusion protein, by half. Similarly, islets isolated from corpses of type-2 diabetic patients, showed a decrease of 50% in Mfn2 levels. To determine the role of Mfn2 decrease in fatty acid-induced toxicity, we generated Mfn2 conditional KO mice. Mice lacking Mfn2 in their beta-cells showed a striking obese phenotype along with impaired glucose tolerance that led to diabetes. Two hours after glucose challenge, the mice lacking Mfn2 showed a glucose blood level twice that of control (304 mg/dl versus 148 mg/dl). Also, similarly to INS1 cells exposed to fatty acids, Mfn2 KO mice, showed accumulation of fragmented damaged mitochondria. To determine why those mito- chondria are not cleared from the cytoplasm, we examined autophagy upon exposure to palmitate. Interestingly, the number of autophago- somes (including those containing mitochondria) was increased by palmitate. Yet, protein degradation via autophagy as measured by pulse- chase experiments was strongly suppressed, and lysosomes acidity was reduced. We conclude that palmitate induces mitochondrial fragmen- tation but prevents mitochondrial clearance from beta-cells by impairing lysosomal acidification. REVERSIBILITY OF THE METABOLIC DERANGEMENT AND INFLAMMATION INDUCED BY NUTRITIONAL OBESITY Maayan Vatarescu a , Noa Slutsky a , Tal Pecht a , Ori Nov a , Hagit Shapiro b , Tanya Tarnovcki b , Nava Bashan a , Assaf Rudich a a Department of Clinical Biochemistry and Pharmacology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel; b Weizmann Institute of Science, Rehovot, Israel Introduction: Reversal of dys-regulated metabolism in obesity is achievable, but the dynamics and mechanisms for reversal of inflammation, adipose tissue stress, and insulin resistance remain poorly characterized. Aim: To characterize reversibility dynamics of obesity-induced metabolic and inflammatory processes in fat and liver. Methods: Mice were fed normal chow (NC-10% fat) or a high-fat (HFF-60% fat) diet for 8 w after which the reversibility group (REV) was switched back to NC for 2 w. Results: Whole-body and fat tissues weights were w60% reversed in REV, while the liver weight fully reversed. Fasting glucose, insulin, and insulin-tolerance-test were fully reversed (ITT AUC : 12509 1160, 6873 652 and 7889 924 for HFF, NC and REV, respectively). Glucose-toler- ance-test showed near complete reversibility (GTT AUC : 43594 2728,17955 1558, and 22461 1032, respectively, P < 0.05). In response to intra-peritoneal insulin, HFF displayed impaired insulin responsiveness compared to NC. Interestingly, insulin signaling improved to greater extent in livers than in the fat tissues, which remained significantly insulin resistant. Correspondingly, adipose tissue macrophage infiltration (increased 3.5-fold by HFF) was 3-fold higher in REV than NC, though macrophages' lipid content reversed by w50%. Adipose tissue stress signaling showed near-significant improvement. Ex-vivo, liver-derived Hepa-1 cells exhibited no improvement in insulin-stimulated Akt phosphorylation when cultured with adipose explants from REV compared to fat tissue explants from HFF. Conclusion: Reversibility of insulin resistance, adipose inflammation and hepatic steatosis may occur through pathways distinct from their patho- genesis in obesity: While adipose tissue inflammation causally links obe- sogenic diet to insulin resistance and hepatic steatosis, these parameters reverse before a significant change in adipose tissue macrophage infiltra- tion, or endocrine function of adipose tissue with hepatocytes, are apparent. Keywords: HFF diet, “Insulin resistance”, “Metabolic inflammation”, Fat tissue-liver crosstalk Abstracts / Atherosclerosis 233 (2014) 326–330 330
Transcript of Reversibility of the metabolic derangement and inflammation induced by nutritional obesity
Abstracts / Atherosclerosis 233 (2014) 326–330330
we measured the rate of fusion between mitochondria. Fatty acidsstrongly impaired the fusion between mitochondria and decreased thelevels of Mitofusin2 (Mfn2), a mitochondrial fusion protein, by half.Similarly, islets isolated from corpses of type-2 diabetic patients, showeda decrease of 50% in Mfn2 levels. To determine the role of Mfn2 decreasein fatty acid-induced toxicity, we generated Mfn2 conditional KO mice.Mice lacking Mfn2 in their beta-cells showed a striking obese phenotypealong with impaired glucose tolerance that led to diabetes. Two hoursafter glucose challenge, the mice lacking Mfn2 showed a glucose bloodlevel twice that of control (304 mg/dl versus 148 mg/dl). Also, similarlyto INS1 cells exposed to fatty acids, Mfn2 KO mice, showed accumulationof fragmented damaged mitochondria. To determine why those mito-chondria are not cleared from the cytoplasm, we examined autophagyupon exposure to palmitate. Interestingly, the number of autophago-somes (including those containing mitochondria) was increased bypalmitate. Yet, protein degradation via autophagy as measured by pulse-chase experiments was strongly suppressed, and lysosomes acidity wasreduced. We conclude that palmitate induces mitochondrial fragmen-tation but prevents mitochondrial clearance from beta-cells by impairinglysosomal acidification.
REVERSIBILITY OF THE METABOLIC DERANGEMENT ANDINFLAMMATION INDUCED BY NUTRITIONAL OBESITY
Maayan Vatarescu a, Noa Slutsky a, Tal Pecht a, Ori Nov a, HagitShapiro b, Tanya Tarnovcki b, Nava Bashan a, Assaf Rudich a
aDepartment of Clinical Biochemistry and Pharmacology, Faculty of HealthSciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel;bWeizmann Institute of Science, Rehovot, Israel
Introduction: Reversal of dys-regulated metabolism in obesity isachievable, but the dynamics and mechanisms for reversal of
inflammation, adipose tissue stress, and insulin resistance remainpoorly characterized.Aim: To characterize reversibility dynamics of obesity-induced metabolicand inflammatory processes in fat and liver.Methods: Mice were fed normal chow (NC-10% fat) or a high-fat (HFF-60%fat) diet for 8 w after which the reversibility group (REV) was switchedback to NC for 2 w.Results: Whole-body and fat tissues weights were w60% reversed inREV, while the liver weight fully reversed. Fasting glucose, insulin, andinsulin-tolerance-test were fully reversed (ITTAUC: 12509 � 1160, 6873 �652 and 7889 � 924 for HFF, NC and REV, respectively). Glucose-toler-ance-test showed near complete reversibility (GTTAUC: 43594 �2728,17955 � 1558, and 22461 � 1032, respectively, P < 0.05). Inresponse to intra-peritoneal insulin, HFF displayed impaired insulinresponsiveness compared to NC. Interestingly, insulin signalingimproved to greater extent in livers than in the fat tissues, whichremained significantly insulin resistant. Correspondingly, adiposetissue macrophage infiltration (increased 3.5-fold by HFF) was 3-foldhigher in REV than NC, though macrophages' lipid content reversedby w50%. Adipose tissue stress signaling showed near-significantimprovement. Ex-vivo, liver-derived Hepa-1 cells exhibited noimprovement in insulin-stimulated Akt phosphorylation when culturedwith adipose explants from REV compared to fat tissue explants fromHFF.Conclusion: Reversibility of insulin resistance, adipose inflammation andhepatic steatosis may occur through pathways distinct from their patho-genesis in obesity: While adipose tissue inflammation causally links obe-sogenic diet to insulin resistance and hepatic steatosis, these parametersreverse before a significant change in adipose tissue macrophage infiltra-tion, or endocrine function of adipose tissue with hepatocytes, areapparent.
Keywords: HFF diet, “Insulin resistance”, “Metabolic inflammation”, Fattissue-liver crosstalk
