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

Kosacka, Joanna; Kern, Matthias; Klöting, Nora; Paeschke, Sabine; Rudich, Assaf; Haim, Yulia; Gericke, Martin; Serke, Heike; Stümvoll, Michael; Bechmann, Ingo; Nowicki, Marcin; Blüher, Matthias

doi:10.1016/j.mce.2015.03.015

Cited by 131 publications

(110 citation statements)

References 48 publications

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“…Given that FoxO1 is activated by insulin resistance 20,46,47 , the FoxO1-autophagy-FSP27 axis may promote LD and adipocyte expansion in obese insulin resistant subjects, thereby casting light on the pathological relevance of augmented autophagy in adipose tissues from obese subjects. [7][8][9][10][11][12] To the best of our knowledge, this is also the first study investigating the role of FoxO1 in the regulation of adipose autophagy.…”

Section: Discussionmentioning

confidence: 87%

“…6 Recent studies show that increased adiposity is associated with augmented autophagy in the adipose tissue from obese and type 2 diabetic humans and rodents. [7][8][9][10][11][12][13][14] Genetic suppression of autophagy by targeting autophagy related 5 (Atg5) or Atg7 in adipose tissue reduces adipocyte size, increases energy expenditure, and protects mice against diet-induced obesity. [15][16][17] Moreover, deletion of Atg5 suppresses adipogenesis (de novo formation of adipocytes).…”

Section: Introductionmentioning

confidence: 99%

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FoxO1 antagonist suppresses autophagy and lipid droplet growth in adipocytes

et al. 2016

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Obesity and related metabolic disorders constitute one of the most pressing heath concerns worldwide. Increased adiposity is linked to autophagy upregulation in adipose tissues. However, it is unknown how autophagy is upregulated and contributes to aberrant adiposity. Here we show a FoxO1-autophagy-FSP27 axis that regulates adipogenesis and lipid droplet (LD) growth in adipocytes. Adipocyte differentiation was associated with upregulation of autophagy and fat specific protein 27 (FSP27), a key regulator of adipocyte maturation and expansion by promoting LD formation and growth. However, FoxO1 specific inhibitor AS1842856 potently suppressed autophagy, FSP27 expression, and adipocyte differentiation. In terminally differentiated adipocytes, AS1842856 significantly reduced FSP27 level and LD size, which was recapitulated by autophagy inhibitors (bafilomycin-A1 and leupeptin, BL). Similarly, AS1842856 and BL dampened autophagy activity and FSP27 expression in explant cultures of white adipose tissue. To our knowledge, this is the first study addressing FoxO1 in the regulation of adipose autophagy, shedding light on the mechanism of increased autophagy and adiposity in obese individuals. Given that adipogenesis and adipocyte expansion contribute to aberrant adiposity, targeting the FoxO1-autophagy-FSP27 axis may lead to new anti-obesity options.

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Section: Discussionmentioning

confidence: 87%

Section: Introductionmentioning

confidence: 99%

FoxO1 antagonist suppresses autophagy and lipid droplet growth in adipocytes

et al. 2016

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“…The most plausible explanation as to why higher BMI and UUN were associated with a decreased APOL1 risk for adaptive forms of CKD progression is that these other non-APOL1-mediated pathways were occurring. Alternatively, an incremental deleterious effect of APOL1 risk variants on CKD progression may not have been observed among individuals with obesity or high UUN, because downstream pathways (e.g., apoptosis and autophagy) involving APOL1 may already be dysregulated in these individuals (28)(29)(30)(31). Finally, it is possible that our findings related to BMI and UUN may have been due to chance or residual confounding, because their significance did not persist in sensitivity analyses.…”

Section: Discussionmentioning

confidence: 89%

Examination of Potential Modifiers of the Association of APOL1 Alleles with CKD Progression

Chen¹,

Choi²,

Kao³

et al. 2015

Clinical Journal of the American Society of Nephrology

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Background and objectives Common apolipoprotein L1 (APOL1) variants are associated with increased risk of progressive CKD; however, not all individuals with high-risk APOL1 variants experience CKD progression. Identification of factors contributing to heterogeneity has important scientific and clinical implications.Design, setting, participants, & measurements Using multivariable Cox models, we analyzed data from 693 participants in the African American Study of Kidney Disease and Hypertension to identify factors that modify the association between APOL1 genotypes and CKD progression (doubling of serum creatinine or incident ESRD).Results Participant mean age was 54 years old, median GFR was 49 ml/min per 1.73 m 2 , and 23% had the APOL1 high-risk genotype (two copies of the high-risk allele). Over a mean follow-up of 7.8 years, 288 (42%) participants experienced CKD progression. As previously reported, the high-risk genotype was associated with higher risk of CKD progression compared with the low-risk genotype (hazard ratio [HR], 1.88; 95% confidence interval [95% CI], 1.46 to 2.41). Although we found some suggestion that obesity (HR, 1.48; 95% CI, 1.05 to 2.08 and HR, 2.44; 95% CI, 1.66 to 3.57 for body mass index $30 versus ,30 kg/m 2 ; P interaction =0.04) and increased urinary excretion of urea nitrogen (HR, 1.43; 95% CI, 0.98 to 2.09 versus HR, 2.33; 95% CI, 1.65 to 3.30 for urine urea nitrogen $8 versus ,8 g/d; P interaction =0.04) were associated with lower APOL1-associated risk for CKD progression, these findings were not robust in sensitivity analyses with alternative cut points. No other sociodemographic (e.g., education and income), clinical (e.g., systolic BP and smoking), or laboratory (e.g., net endogenous acid production, urinary sodium and potassium excretions, 25-hydroxy vitamin D, intact parathyroid hormone, or fibroblast growth factor 23) variables modified the association between APOL1 and CKD progression (P interaction .0.05 for each).Conclusions Sociodemographic factors and common risk factors for CKD progression do not seem to alter APOL1-related CKD progression. Additional investigation is needed to identify nontraditional factors that may affect the association between APOL1 and progressive CKD.

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“…Obesity is associated with increased accumulation of autophagosomes, an attenuated mTOR signaling, as well as enhanced expression of key autophagy-related proteins beclin-1, ATG5, ATG7, ATG12, and LC3B (166,167,201,268). Markers of autophagy are correlated with whole body adiposity, visceral fat distribution, and adipocyte hypertrophy (167,268).…”

Section: Biological and Morphological Changes Of White Adipose Tissuementioning

confidence: 99%

Revisiting the adipocyte: a model for integration of cytokine signaling in the regulation of energy metabolism

Rodrı́guez

Ezquerro

Méndez‐Giménez

et al. 2015

American Journal of Physiology-Endocrinology and Metabolism

242

197

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Adipose tissue constitutes an extremely active endocrine organ with a network of signaling pathways enabling the organism to adapt to a wide range of different metabolic challenges, such as starvation, stress, infection, and short periods of gross energy excess. The functional pleiotropism of adipose tissue relies on its ability to synthesize and release a huge variety of hormones, cytokines, complement and growth factors, extracellular matrix proteins, and vasoactive factors, collectively termed adipokines. Obesity is associated with adipose tissue dysfunction leading to the onset of several pathologies including type 2 diabetes, dyslipidemia, nonalcoholic fatty liver, or hypertension, among others. The mechanisms underlying the development of obesity and its associated comorbidities include the hypertrophy and/or hyperplasia of adipocytes, adipose tissue inflammation, impaired extracellular matrix remodeling, and fibrosis together with an altered secretion of adipokines. Recently, the potential role of brown and beige adipose tissue in the protection against obesity has been also recognized. In contrast to white adipocytes, which store energy in the form of fat, brown and beige fat cells display energy-dissipating capacity through the promotion of triacylglycerol clearance, glucose disposal, and generation of heat for thermogenesis. Identification of the morphological and molecular changes in white, beige, and brown adipose tissue during weight gain is of utmost relevance for the identification of pharmacological targets for the treatment of obesity and its associated metabolic diseases. white and brown adipogenesis; fat browning; adipocyte hypertrophy and hyperplasia; adipose tissue inflammation; extracellular matrix remodeling THE ADIPOSE ORGAN REPRESENTS a special loose connective tissue containing adipocytes and several cell types surrounded by capillary and innervation networks (47, 79, 82). Adipocytes comprise ϳ35-70% of adipose mass, and the other cell types found in the stroma-vascular fraction include preadipocytes, mesenchymal stem cells, macrophages and other immune cells, and endothelial and smooth muscle cells, among others (79). The classical functions of adipose tissue are the storage of energy in the form of triacylglycerols (TG) and as thermal insulator. Adipocytes were formerly classified into two main types: white adipocytes, which store energy in the form of fat, and brown adipocytes, which induce thermogenesis (82). The current classification scheme includes a third category of adipocytes, termed beige or brite (brown-in-white) adipocytes, which can be considered inducible brown-like cells with thermogenic properties (340). Since the identification of leptin in 1994 (359), adipose tissue has emerged as an extremely active endocrine organ that secretes a huge variety of hormones, cytokines, growth factors, and vasoactive factors that are collectively termed adipokines (67, 81,235,262). Over the last three decades, overwhelming evidence has proven that adipokines not only influence adipobiol...

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

Cited by 131 publications

References 48 publications

FoxO1 antagonist suppresses autophagy and lipid droplet growth in adipocytes

FoxO1 antagonist suppresses autophagy and lipid droplet growth in adipocytes

Examination of Potential Modifiers of the Association of APOL1 Alleles with CKD Progression

Revisiting the adipocyte: a model for integration of cytokine signaling in the regulation of energy metabolism

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