Systemic autophagy insufficiency compromises adaptation to metabolic stress and facilitates progression from obesity to diabetes

Lim, Yaeji; Lim, Hyejin; Hur, Kyu Yeon; Quan, Wenying; Lee, Hae Youn; Cheon, Hwanju; Ryu, Dongryeol; Koo, Seung Hoi; Kim, Hong Lim; Kim, Jin; Komatsu, Masaaki; Lee, Myung-Shik

doi:10.1038/ncomms5934

Cited by 159 publications

(138 citation statements)

References 70 publications

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“…Hence, reduced hepatic macro autophagy due to excess lipid overload -for example, in obesity -exacerbates lipid accumulation in vivo and creates a vicious cycle that promotes hepatic ER stress and insulin resistance 63 . In support of this, reduced lipophagy in Atg7 haploinsufficient mice is a possible cause of progression from obesity to diabetes because increased lipid toxicity promotes insulin resistance 64 .…”

Section: β-Oxidationmentioning

confidence: 94%

Autophagy at the crossroads of catabolism and anabolism

Kaur

Debnath

2015

Nat Rev Mol Cell Biol

826

801

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Section: β-Oxidationmentioning

confidence: 94%

Autophagy at the crossroads of catabolism and anabolism

Kaur

Debnath

2015

Nat Rev Mol Cell Biol

826

801

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“…The reduced capacity of autophagy with aging generates an inflammatory condition via activation of the NLRP3 inflammasome and such disturbed interplay between autophagy and inflammaosomes is linked to the pathogenesis of T2DM, obesity, and atherosclerosis 119 . Systemic impairment of autophagy by haploinsufficiency of the essential autophagy gene (Atg7 +/-) in ob/ob mice aggravated insulin resistance with increased lipid contents and inflammatory changes 120 . Furthermore, mice with a Lyz2-Cre-mediated knockout of Atg5 in macrophages fed a HFD and administered LPS demonstrated systemic and hepatic inflammation 121 .…”

Section: [H3] Autophagymentioning

confidence: 99%

Innate immunity in diabetes and diabetic nephropathy

2015

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Abstract:The innate immune system consists of several classes of pattern recognition receptors (PRRs), including membrane-bound Toll-like receptors (TLRs) and nucleotide-binding domain leucine-rich oligomerization domain (NOD)-like receptors (NLRs).These receptors detect pathogen-associated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPs) in the extracellular and intracellular space. Intracellular NLRs constitute inflammasomes, which activate and release caspase-1, IL1β, and IL18 and thus initiate an inflammatory response. Systemic and local low-grade inflammation and release of proinflammatory cytokines are implicated in the development and progression of diabetes mellitus and diabetic nephropathy. TLR2, TLR4, and the NLRP3 inflammasome are critically involved in the inflammatory responses in pancreatic islets, adipose, liver and kidney tissues. This Review discusses how innate immune system-driven inflammatory processes can lead to apoptosis, tissue fibrosis, and organ dysfunction to cause insulin resistance, impaired insulin secretion, and renal failure. We propose that careful targeting of TLR2, TLR4, and NLRP3 signalling pathways may be beneficial for the treatment of diabetes mellitus and diabetic nephropathy. 2 Key points The innate immune system consists of several classes of pattern recognition receptors, including TLRs and NLRs, which detect pathogen-associated and danger-associated molecular patterns and initiate an inflammatory response  TLR2 and TLR4 are the predominant toll-like receptors expressed on pancreatic β cells that trigger an inflammatory response in insulitis during type 1 diabetes mellitus  TLR2 and TLR4 signaling, and activation of NLRP3 inflammasomes results in production of various proinflammatory cytokines that can induce insulin resistance in type 2 diabetes mellitus (T2DM) and obesity  Innate immune responses in T2DM and obesity are modulated by the status of the gut microbiota, autophagy, and adipokines  TLR2, TLR4, NOD2, and NLRP3 inflammasome-mediated inflammation are involved in the perpetuation of inflammation in diabetic nephropathy  The activation of TLRs and NLRs stimulates the expression of MCP-1, which is associated with the progression of diabetic nephropathy [H1] IntroductionThe prevalence of diabetes mellitus is estimated to be 8.3%, affecting ~387 million people as of 2014. The number of patients living with diabetes mellitus is expected to increase to ~592 million by 2035, as reported by the International Diabetes Federation 1 . The incidence of end-stage renal disease (ESRD) is also rapidly increasing worldwide but varies up to 15-fold by country. In 2012, the number of new diagnoses of ESRD worldwide ranged from 25 to 467 patients per million. The proportion of new cases of ESRD with diabetes mellitus as the primary cause also differs by country, with 66% cases reported in Singapore and 12-16% cases reported in Ukraine, Romania, and the Netherlands 2 . Although intensified multifactorial intervention in patients with type 2 diabete...

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“…6B and C). 32 With the i.c.v. injection of Ab into the 2-to 3-mo-old-Atg7 C/C and Atg7 C/¡ mice for 2 wk, increased autophagy (represented by an increase in LC3-II levels) in the brains of Atg7 C/C mice, but not Atg7 C/¡ mice were detected (Fig.…”

Section: Autophagy-insufficient Mouse Brains Show Decreased Ide Levelmentioning

confidence: 99%

“…Atg7 C/¡ and Atg7 C/C mice (N D 12 each group) were kindly provided by Dr. Myung-Shik Lee (Sungkyunkwan University School of Medicine, Korea). 32 Ab or phosphate-buffered saline (PBS) was administered via i.c.v. injections into 2-to 3-moold-Atg7 C/¡ and Atg7 C/C mice as previously described with some modification.…”

Section: Animalsmentioning

confidence: 99%

Insulin-degrading enzyme secretion from astrocytes is mediated by an autophagy-based unconventional secretory pathway in Alzheimer disease

et al. 2016

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The secretion of proteins that lack a signal sequence to the extracellular milieu is regulated by their transition through the unconventional secretory pathway. IDE (insulin-degrading enzyme) is one of the major proteases of amyloid beta peptide (Ab), a presumed causative molecule in Alzheimer disease (AD) pathogenesis. IDE acts in the extracellular space despite having no signal sequence, but the underlying mechanism of IDE secretion extracellularly is still unknown. In this study, we found that IDE levels were reduced in the cerebrospinal fluid (CSF) of patients with AD and in pathology-bearing AD-model mice. Since astrocytes are the main cell types for IDE secretion, astrocytes were treated with Ab. Ab increased the IDE levels in a time-and concentration-dependent manner. Moreover, IDE secretion was associated with an autophagy-based unconventional secretory pathway, and depended on the activity of RAB8A and GORASP (Golgi reassembly stacking protein). Finally, mice with global haploinsufficiency of an essential autophagy gene, showed decreased IDE levels in the CSF in response to an intracerebroventricular (i.c.v.) injection of Ab. These results indicate that IDE is secreted from astrocytes through an autophagy-based unconventional secretory pathway in AD conditions, and that the regulation of autophagy is a potential therapeutic target in addressing Ab pathology.

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Systemic autophagy insufficiency compromises adaptation to metabolic stress and facilitates progression from obesity to diabetes

Cited by 159 publications

References 70 publications

Autophagy at the crossroads of catabolism and anabolism

Autophagy at the crossroads of catabolism and anabolism

Innate immunity in diabetes and diabetic nephropathy

Insulin-degrading enzyme secretion from astrocytes is mediated by an autophagy-based unconventional secretory pathway in Alzheimer disease

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