PGRN induces impaired insulin sensitivity and defective autophagy in hepatic insulin resistance.

Abstract

Progranulin (PGRN) has recently emerged as an important regulator for glucose metabolism and insulin sensitivity. However, the underlying mechanisms of PGRN in the regulation of insulin sensitivity and autophagy remain elusive. In this study, we aimed to address the direct effects of PGRN in vivo and to evaluate the potential interaction of impaired insulin sensitivity and autophagic disorders in hepatic insulin resistance. We found that mice treated with PGRN for 21 days exhibited the impaired glucose tolerance and insulin tolerance and hepatic autophagy imbalance as well as defective insulin signaling. Furthermore, treatment of mice with TNF receptor (TNFR)-1 blocking peptide-Fc, a TNFR1 blocking peptide-Fc fusion protein to competitively block the interaction of PGRN and TNFR1, resulted in the restoration of systemic insulin sensitivity and the recovery of autophagy and insulin signaling in liver. Consistent with these findings in vivo, we also observed that PGRN treatment induced defective autophagy and impaired insulin signaling in hepatocytes, with such effects being drastically nullified by the addition of TNFR1 blocking peptide -Fc or TNFR1-small interference RNA via the TNFR1-nuclear factor-κB-dependent manner, indicating the causative role of PGRN in hepatic insulin resistance. In conclusion, our findings supported the notion that PGRN is a key regulator of hepatic insulin resistance and that PGRN may mediate its effects, at least in part, by inducing defective autophagy via TNFR1/nuclear factor-κB.

• Authors: Jiali Liu, Huixia Li, Bo Zhou, Lin Xu, Xiaomin Kang, Wei Yang, Shufang Wu, Hongzhi Sun
• Journal: Molecular endocrinology (Baltimore, Md.) (Mol Endocrinol) Vol. 29 Issue 4 Pg. 528-41 (Apr 2015) ISSN: 1944-9917 [Electronic] United States
• PMID: 25664864 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Blood Glucose
• Granulins
• Grn protein, mouse
• Insulin
• Intercellular Signaling Peptides and Proteins
• NF-kappa B
• Progranulins
• RNA, Small Interfering
• Tumor Necrosis Factor-alpha
• Etanercept

Topics

• Animals
• Autophagy (drug effects)
• Blood Glucose (metabolism)
• Cells, Cultured
• Etanercept (pharmacology)
• Female
• Granulins
• Hepatocytes (drug effects, metabolism)
• Insulin (blood)
• Insulin Resistance (physiology)
• Intercellular Signaling Peptides and Proteins (blood, pharmacology)
• Lipogenesis (drug effects)
• Liver (drug effects, metabolism)
• Mice
• NF-kappa B (metabolism)
• Phosphorylation (drug effects)
• Progranulins
• RNA, Small Interfering
• Signal Transduction (drug effects)
• Tumor Necrosis Factor-alpha (antagonists & inhibitors, genetics)