title: Circulating PGRN is significantly associated with systemic insulin sensitivity and autophagic activity in metabolic syndrome.
abstract: Progranulin (PGRN) is a secreted protein that has recently emerged as an important regulatory adipokine of glucose metabolism and insulin sensitivity. We report here that serum PGRN concentrations were significantly higher in patients with metabolic syndrome (MS) than in subjects without MS and correlated positively with body mass index, waist circumference, fasting insulin, fasting plasma glucose, glycated hemoglobin A1c, triglyceride, and homeostasis model assessment of insulin resistance, and were inversely related to high-density lipoprotein cholesterol and homeostasis model assessment of β cell function. Subgroup analysis in 32 subjects showed that elevated expression levels of PGRN were positively correlated with increased autophagy markers LC3 and Atg7 proteins in omental adipose tissue of subjects with MS. Consistent with these findings, the enhanced PGRN levels were also observed in multiple insulin-resistant cellular models, whereas PGRN-deficient adipocytes were more susceptible to insulin action and refractory to tunicamycin-induced autophagic disorders. PGRN remarkably attenuated insulin sensitivity, increased autophagic activity, and triggered endoplasmic reticulum (ER) stress in cultured human adipocytes, whereas these effects were nullified by reduction of ER stress with phenylbutyric acid chemical chaperone treatment. In addition, PGRN-induced ER stress and impaired insulin sensitivity were improved in TNFR1(-/-) cells, indicating a causative role of TNF receptor in the action of PGRN. Collectively, our findings suggest that circulating PGRN is significantly associated with systemic insulin sensitivity and autophagic activity in adipose tissue and support the notion that PGRN functions as a potential link between chronic inflammation and insulin resistance.
authors: First Affiliated Hospital of Medical School of Xi'an Jiaotong University, Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Medical School of Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, China.
authors: Huixia
authors: H
authors: Li
authors: Bo
authors: B
authors: Zhou
authors: Lin
authors: L
authors: Xu
authors: Jiali
authors: J
authors: Liu
authors: Weijin
authors: W
authors: Zang
authors: Shufang
authors: S
authors: Wu
authors: Hongzhi
authors: H
authors: Sun
mesh_terms: D017667:Adipocytes / Q000378:metabolism; D000328:Adult; D000368:Aged; D000818:Animals; D001343:Autophagy; D000071193:Autophagy-Related Protein 7; D015331:Cohort Studies; D005260:Female; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D036341:Intercellular Signaling Peptides and Proteins / Q000097:blood*; D008297:Male; D024821:Metabolic Syndrome / Q000097:blood / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism; D008875:Middle Aged; D000077153:Progranulins; D044764:Ubiquitin-Activating Enzymes / Q000235:genetics / Q000378:metabolism
chemical_list: C492314:GRN protein, human; D007328:Insulin; D036341:Intercellular Signaling Peptides and Proteins; C477012:MAP1LC3A protein, human; D008869:Microtubule-Associated Proteins; D000077153:Progranulins; C509349:ATG7 protein, human; D000071193:Autophagy-Related Protein 7; D044764:Ubiquitin-Activating Enzymes