Publications by authors named "Gunes Parlakgul"

8 Publications

  • Page 1 of 1

Brown adipose tissue thermogenic adaptation requires Nrf1-mediated proteasomal activity.

Nat Med 2018 03 5;24(3):292-303. Epub 2018 Feb 5.

Department of Genetics and Complex Diseases and Sabri Ülker Center, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.

Adipocytes possess remarkable adaptive capacity to respond to nutrient excess, fasting or cold exposure, and they are thus an important cell type for the maintenance of proper metabolic health. Although the endoplasmic reticulum (ER) is a critical organelle for cellular homeostasis, the mechanisms that mediate adaptation of the ER to metabolic challenges in adipocytes are unclear. Here we show that brown adipose tissue (BAT) thermogenic function requires an adaptive increase in proteasomal activity to secure cellular protein quality control, and we identify the ER-localized transcription factor nuclear factor erythroid 2-like 1 (Nfe2l1, also known as Nrf1) as a critical driver of this process. We show that cold adaptation induces Nrf1 in BAT to increase proteasomal activity and that this is crucial for maintaining ER homeostasis and cellular integrity, specifically when the cells are in a state of high thermogenic activity. In mice, under thermogenic conditions, brown-adipocyte-specific deletion of Nfe2l1 (Nrf1) resulted in ER stress, tissue inflammation, markedly diminished mitochondrial function and whitening of the BAT. In mouse models of both genetic and dietary obesity, stimulation of proteasomal activity by exogenously expressing Nrf1 or by treatment with the proteasome activator PA28α in BAT resulted in improved insulin sensitivity. In conclusion, Nrf1 emerges as a novel guardian of brown adipocyte function, providing increased proteometabolic quality control for adapting to cold or to obesity.
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http://dx.doi.org/10.1038/nm.4481DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5839993PMC
March 2018

Defective STIM-mediated store operated Ca entry in hepatocytes leads to metabolic dysfunction in obesity.

Elife 2017 12 15;6. Epub 2017 Dec 15.

Department of Genetics and Complex Diseases, Sabri Ülker Center, Harvard TH Chan School of Public Health, Boston, United States.

Defective Ca handling is a key mechanism underlying hepatic endoplasmic reticulum (ER) dysfunction in obesity. ER Ca level is in part monitored by the store-operated Ca entry (SOCE) system, an adaptive mechanism that senses ER luminal Ca concentrations through the STIM proteins and facilitates import of the ion from the extracellular space. Here, we show that hepatocytes from obese mice displayed significantly diminished SOCE as a result of impaired STIM1 translocation, which was associated with aberrant STIM1 O-GlycNAcylation. Primary hepatocytes deficient in STIM1 exhibited elevated cellular stress as well as impaired insulin action, increased glucose production and lipid droplet accumulation. Additionally, mice with acute liver deletion of STIM1 displayed systemic glucose intolerance. Conversely, over-expression of STIM1 in obese mice led to increased SOCE, which was sufficient to improve systemic glucose tolerance. These findings demonstrate that SOCE is an important mechanism for healthy hepatic Ca balance and systemic metabolic control.
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http://dx.doi.org/10.7554/eLife.29968DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5777820PMC
December 2017

Type I Interferons Interfere with Liver Glucose Metabolism.

Cell Metab 2017 06;25(6):1211-1212

Department of Genetics and Complex Diseases and Sabri Ülker Center, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. Electronic address:

The specific immunological components linking metabolic stresses to liver inflammation and systemic metabolic pathologies in obesity are not entirely known. A recent study (Ghazarian et al., 2017) reveals that obesity-induced type I interferon signaling drives the accumulation and activation of intrahepatic CD8 T cells, leading to systemic metabolic deterioration.
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http://dx.doi.org/10.1016/j.cmet.2017.05.009DOI Listing
June 2017

A 3 Year-Old Male Child Ingested Approximately 750 Grams of Elemental Mercury.

Balkan Med J 2016 Jul 1;33(4):467-9. Epub 2016 Jul 1.

Department of Pediatrics, İstanbul University İstanbul School of Medicine, İstanbul, Turkey.

Background: The oral ingestion of elemental mercury is unlikely to cause systemic toxicity, as it is poorly absorbed through the gastrointestinal system. However, abnormal gastrointestinal function or anatomy may allow elemental mercury into the bloodstream and the peritoneal space. Systemic effects of massive oral intake of mercury have rarely been reported.

Case Report: In this paper, we are presenting the highest single oral intake of elemental mercury by a child aged 3 years. A Libyan boy aged 3 years ingested approximately 750 grams of elemental mercury and was still asymptomatic.

Conclusion: The patient had no existing disease or abnormal gastrointestinal function or anatomy. The physical examination was normal. His serum mercury level was 91 µg/L (normal: <5 µg/L), and he showed no clinical manifestations. Exposure to mercury in children through different circumstances remains a likely occurrence.
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http://dx.doi.org/10.5152/balkanmedj.2016.15197DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5001828PMC
July 2016

Chronic enrichment of hepatic endoplasmic reticulum-mitochondria contact leads to mitochondrial dysfunction in obesity.

Nat Med 2014 Dec 24;20(12):1427-35. Epub 2014 Nov 24.

Department of Genetics and Complex Diseases and Sabri Ülker Center, Harvard School of Public Health and Broad Institute of Harvard and MIT, Boston, Massachusetts, USA.

Proper function of the endoplasmic reticulum (ER) and mitochondria is crucial for cellular homeostasis, and dysfunction at either site has been linked to pathophysiological states, including metabolic diseases. Although the ER and mitochondria play distinct cellular roles, these organelles also form physical interactions with each other at sites defined as mitochondria-associated ER membranes (MAMs), which are essential for calcium, lipid and metabolite exchange. Here we show that in the liver, obesity leads to a marked reorganization of MAMs resulting in mitochondrial calcium overload, compromised mitochondrial oxidative capacity and augmented oxidative stress. Experimental induction of ER-mitochondria interactions results in oxidative stress and impaired metabolic homeostasis, whereas downregulation of PACS-2 or IP3R1, proteins important for ER-mitochondria tethering or calcium transport, respectively, improves mitochondrial oxidative capacity and glucose metabolism in obese animals. These findings establish excessive ER-mitochondrial coupling as an essential component of organelle dysfunction in obesity that may contribute to the development of metabolic pathologies such as insulin resistance and diabetes.
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http://dx.doi.org/10.1038/nm.3735DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4412031PMC
December 2014

Serum level of vitamin D and trace elements in children with recurrent wheezing: a cross-sectional study.

BMC Pediatr 2014 Oct 16;14:270. Epub 2014 Oct 16.

Department of Pediatrics, Istanbul University, Istanbul Faculty of Medicine, Capa, 34390 Istanbul, Turkey.

Background: We aimed to show the relationship between recurrence of wheezing and serum levels of vitamin D, zinc, and copper in wheezy children compared with a healthy group.

Methods: In this cross sectional study, seventy-three children with wheezing and seventy-five controls were included without a follow-up period. The clinical characteristics of the children were assessed, the asthma predictive index and temporal pattern of wheeze were determined. The serum levels of vitamin D, zinc, and copper were measured. Pearson correlation analysis was used to evaluate the relationship between homogeneously distributed variables.

Results: Thirty-two of the seventy-three children (43.8%) had more than three wheezing attacks (recurrent wheezing). The Asthma Predictive Index index was positive in 26 patients (35.6%). When classified to temporal pattern of wheeze, fifty-three of the study group (72.6%) had episodic wheezing and the remainder (27.4%) was classified as multiple-trigger wheezing. We found no overall significant difference between the study and control group in terms of vitamin D and trace elements . The vitamin D and zinc levels were significantly lower and serum copper and copper/zinc ratio was significantly higher in patients with recurrent wheezing (p =0.03, p <0.01, p =0.013, p <0.01, respectively) positive Asthma Predictive Index and multiple-trigger temporal pattern of wheeze compared with patients with non- recurrent wheezing, negative Asthma Predictive Index and episodic temporal pattern of wheeze.

Conclusion: It may be postulated that for the determination of asthma risk in patients with recurrent wheezing, the serum level of vitamin D, copper and zinc can be used as a routine biomarker alongside the Asthma Predictive Index and temporal pattern of wheeze.
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http://dx.doi.org/10.1186/1471-2431-14-270DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4286924PMC
October 2014

Expression of regulatory receptors on γδ T cells and their cytokine production in Behcet's disease.

Arthritis Res Ther 2013 Jan 21;15(1):R15. Epub 2013 Jan 21.

Introduction: Behcet's disease (BD) is a multi-systemic disorder with muco-cutaneous, ocular, arthritic, vascular or central nervous system involvement. The role of γδ T cells is implicated in BD. The activation status of γδ T cells and their cytokine secretion against phosphoantigens are evaluated in BD.

Methods: NKG2A, NKG2C, NKG2D, CD16 and CCR7 molecules on γδ T cells were analyzed in 70 BD, 27 tuberculosis (TB) patients and 26 healthy controls (HC). Peripheral γδ T cells were expanded with a phosphoantigen (BrHPP) and IL-2, restimulated with BrHPP and a TLR3 ligand, and cytokine production was measured.

Results: γδ T cells were not increased in both BD and TB patients, but the proportions of TCRVδ2+ T cells were lower (58.9 and 50.7 vs. 71.7%, P=0.04 and P=0.005) compared to HC. Higher proportion of TCRVδ2+ T cells were CD16+ (26.2 and 33.9 vs. 16.6%, P=0.02 and P=0.001) and CCR7- (32.2 and 27.9 vs. 17.7%, P<0.0001 and P=0.014) in BD and TB patients compared to HC. NKG2C+ γδ+ T cells were relatively increased (0.5 and 0.6 vs. 0.3%, P=0.008 and 0.018), whereas NKG2D positivity was decreased in patients with BD and TB (77.7 and 75.8 vs. 87.5%, P=0.001 and 0.004). Expansion capacity of γδ T cells in BD and TB as well as production of IL-13, IFN-γ, granulocyte monocyte colony stimulating factor (GM-CSF), TNF-α, CCL4 and CCL5 in BD was lower compared to HC, when restimulated by TLR3 ligand and BrHPP.

Conclusion: The changes on γδ T cells of BD as well as TB patients implicate that γδ T cells have already been exposed to regulatory effects, which changed their activity. Lower cytokine response of γδ T cells implicates down modulation of these cells in BD.
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http://dx.doi.org/10.1186/ar4147DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3672743PMC
January 2013

Simple precision creation of digitally specified, spatially heterogeneous, engineered tissue architectures.

Adv Mater 2013 Feb 27;25(8):1192-8. Epub 2012 Nov 27.

Bio-Acoustic-MEMS in Medicine-BAMM Laboratory, Division of Biomedical Engineering at Brigham and Women's Hospital, Harvard-MIT Health Sciences & Technology, Harvard Medical School, 65 Landsdowne St. PRB 252, Cambridge, MA 02139, USA.

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http://dx.doi.org/10.1002/adma.201203261DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3842103PMC
February 2013
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