Autophagy in adipose tissue and the beta cell: implications for obesity and diabetes

Stienstra, Rinke; Haim, Yulia; Riahi, Yael; Netea, Mihai G.; Rudich, Assaf; Leibowitz, Gil

doi:10.1007/s00125-014-3255-3

Cited by 86 publications

(68 citation statements)

References 105 publications

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“…In our study, we confirm previous findings (Cummins et al, 2014;Kovsan et al, 2011;Stienstra et al, 2014) of increased autophagy markers in visceral and SC AT of obese and T2D patients compared to lean individuals. However, we extend previous findings by visualizing numerous autophagosomes accumulated within adipocytes using electron transmission microscopy.…”

Section: Discussionsupporting

confidence: 95%

“…Our data support recent studies demonstrating that autophagy is up-regulated in visceral AT of obese patients, leptin-receptor deficient db/db mice (Cinti et al, 2005;Stienstra et al, 2014) and WOKW rats (Kosacka et al, 2013) and that predominantly visceral expression of Atg5, LC3A, and LC3B genes as well as increased autophagic flux of LC3II protein expression are associated with human obesity (Kovsan et al, 2011). Moreover, the observation that visceral AT autophagy is most strongly related to AT apoptosis in obese patients with additional T2D strengthens our previous hypothesis that activation of autophagy occurs together with insulin resistance but may precede obesity-associated disorders (Kovsan et al, 2011).…”

Section: Tablesupporting

confidence: 94%

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Autophagy in adipose tissue of patients with obesity and type 2 diabetes

Kosacka

Kern

Klöting

et al. 2015

Molecular and Cellular Endocrinology

131

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Section: Discussionsupporting

confidence: 95%

Section: Tablesupporting

confidence: 94%

Autophagy in adipose tissue of patients with obesity and type 2 diabetes

Kosacka

Kern

Klöting

et al. 2015

Molecular and Cellular Endocrinology

131

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“…Regardless, our data now suggest that suppression of CHOP would represent a beneficial adaptation to high-fat feeding, albeit one that might come at the cost of reduced insulin secretion due to disruption of lipid signalling pathways [9]. Although it is commonly assumed, based on genetic models [12,13], that modulation of ER stress explains the reciprocal relationship between autophagy and beta cell apoptosis [2,4,14], we believe our CHOP data are the first to confirm this mechanistic link in the context of high-fat feeding. Our results would also tend to counter the idea, suggested by some in vitro studies [3] that lipotoxic ER stress is actually triggered by autophagy.…”

Section: Discussionmentioning

confidence: 82%

High-fat diet increases autophagic flux in pancreatic beta cells in vivo and ex vivo in mice

et al. 2015

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Aims/hypothesis Defective beta cell function during lipid oversupply and type 2 diabetes is associated with dysregulation of lysosomal function and autophagy. Whether this dysregulation represents augmentation or inhibition is unclear because of technical limitations in assaying autophagy. The current aim was to determine the effects of high-fat feeding on true autophagic flux in beta cells in vivo in mice, and to establish the relationship between autophagy, endoplasmic reticulum (ER) stress and apoptosis. Methods Green fluorescent protein-microtubule-associated protein 1 light chain 3 (GFP-LC3) mice were fed chow or high-fat diets for 8-10 weeks and injected with 100 mg kg −1 day −1 chloroquine for 5 days, prior to being killed, to block clearance of autophagic markers. Pancreases and livers were fixed and GFP-LC3 aggregates or autophagosomes were detected by fluorescence or electron microscopy, respectively. Independently, islets isolated from chow or high-fat-fed mice were treated for 2 h with chloroquine ex vivo, and immunoblotting was performed for markers of autophagy (LC3 lipidation -LC3II and p62/SQSTM1), ER stress (C/EBP homology protein [CHOP], phosphorylated eukaryotic initiation factor 2α [p-eIFα] and inositol requiring enzyme 1α ) and apoptosis (cleaved caspase-3). Results Numbers of autophagosomes and GFP puncta were increased in beta cells by combined high-fat feeding and chloroquine injection, indicative of enhanced autophagic flux. By contrast, GFP puncta were attenuated in liver under the same conditions. Relative to chow-fed controls, islets isolated from fat-fed mice exhibited higher LC3II levels when treated ex vivo with chloroquine. The combination of high-fat feeding and acute chloroquine treatment induced CHOP, p-eIF2α and caspase-3, but not either treatment alone. Conclusions/interpretation We provide the first in vivo demonstrations that high-fat feeding increases autophagic flux in pancreatic beta cells, and that this serves to protect against induction of terminal ER stress. We also highlight an approach for monitoring dietary alterations in autophagic flux using ex vivo manipulation of isolated islets.

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“…It is likely that lack of NPC2 impairs the activation of TLR4 by LPS in adipocytes, leading to the failure of the NFB signaling pathway and autophagy activation. Further intracellular homeostasis and limiting cellular dysfunction (50). Mitophagy, a type of selective autophagy, plays an important role in mitochondrial quality control by eliminating damaged mitochondria (51,52).…”

Section: Discussionmentioning

confidence: 99%

Niemann-Pick type C2 deficiency impairs autophagy-lysosomal activity, mitochondrial function, and TLR signaling in adipocytes

Guo

Zhao

Qiu

et al. 2016

Journal of Lipid Research

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Aging is a risk factor for the development of chronic metabolic diseases such as type 2 diabetes, cardiovascular disease, neurodegenerative disease, and cancer. These aging-related diseases are known to be clustered together; aging-associated neurodegenerative disorders frequently coincide with type 2 diabetes, insulin resistance, obesity, and metabolic syndrome. This suggests that neurodegenerative disorders and type 2 diabetes share common genetic and metabolic features. Therefore, studying the role of the gene that contributes to neurodegenerative diseases in obesity and diabetes is of particular importance, as it may provide a clue for the pathological mechanism of the development of aging-related diseases. Intensive investigation on the underlying mechanisms of cellular aging has suggested that autophagy-lysosome and mitochondrial function plays an essential role in the regulation of cellular homeostasis and health (1). The autophagy-lysosome system is one of the main intracellular proteolytic systems that is responsible for the clearance of unwanted intracellular macromolecules and organelles (2). Cellular aging is associated with the disruption of this homeostatic mechanism, leading to the accumulation of oxidized/misfolded proteins, lipids, and damaged organelles (3). However, the genes and proteins that regulate autophagy-lysosomal activation and contribute to cellular aging remain largely unidentified.Autophagy is a highly regulated process that is inducible by nutrient deprivation and cellular stress. During nutrient deprivation, multiple signaling pathways cooperate to Abstract In this study, we investigated the role and mechanism of Niemann-Pick type C (NPC)2 in regulating lysosomal activity, mitophagy, and mitochondrial function in adipocytes. We found that knocking down NPC2 impaired lysosomal activity, as evidenced by the reduced mature cathepsin B, the increased accumulation of light chain 3 (LC3) and p62, and the decreased autophagic flux. In NPC2-knockdown (kd) adipocytes, the starvation-induced conversion of LC3-I to LC3-II was abolished. More interestingly, the majority of NPC2 was found in the mitochondrial fraction, and NPC2 deficiency led to impaired autophagic flux and decreased induction of LC3-II in the mitochondrial fraction during mitochondrial stress. Moreover, cellular respiration profiling revealed that NPC2-kd adipocytes had significantly decreased basal/maximal respiration and mitochondrial gene expression compared with scrambled cells, suggesting mitochondrial dysfunction. Additionally, we found that the mitochondrial recruitment of LC3-II induced by lipopolysaccharide (LPS), but not TNF, was blunted in NPC2-kd adipocytes. Most intriguingly, NPC2-kd selectively diminished LPS-induced NFB and ERK1/2 phosphorylation and the expression of pro-inflammatory genes, indicating that tolllike receptor signaling activation is impaired in the absence of NPC2. Our results suggest that NPC2 is in a mitochondrially associated autophagosome and plays an important role in regulating mitophag...

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Autophagy in adipose tissue and the beta cell: implications for obesity and diabetes

Cited by 86 publications

References 105 publications

Autophagy in adipose tissue of patients with obesity and type 2 diabetes

Autophagy in adipose tissue of patients with obesity and type 2 diabetes

High-fat diet increases autophagic flux in pancreatic beta cells in vivo and ex vivo in mice

Niemann-Pick type C2 deficiency impairs autophagy-lysosomal activity, mitochondrial function, and TLR signaling in adipocytes

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