TonEBP/NFAT5 haploinsufficiency attenuates hippocampal inflammation in high-fat diet/streptozotocin-induced diabetic mice

Jong Youl Lee,H Moo Kwon,Soo Youn Choi,Gu Seob Roh,Kyung Eun Kim,Gyeong Jae Cho,Sang Soo Kang,Dong Hoon Lee,Zhen Jin,Jung Eun Lee,Hyun Joon Kim,Eun Ae Jeong,Wan Sung Choi,Chin-Ok Yi

doi:10.1038/s41598-017-08319-w

Abstract

Recent studies have shown that overexpression of tonicity-responsive enhancer binding protein (TonEBP) is associated with many inflammatory diseases, including diabetes mellitus, which causes neuroinflammation in the hippocampus as well as hepatic steatosis. However, the exact mechanism in diabetic neuroinflammation is unknown. We report that haploinsufficiency of TonEBP inhibits hepatic and hippocampal high-mobility group box-1 (HMGB1) expression in diabetic mice. Here, mice were fed a high-fat diet (HFD) for 16 weeks and received an intraperitoneal injection of 100 mg/kg streptozotocin (STZ) and followed by continued HFD feeding for an additional 4 weeks to induce hyperglycemia and hepatic steatosis. Compared with wild-type diabetic mice, diabetic TonEBP+/− mice showed decreased body weight, fat mass, hepatic steatosis, and macrophage infiltration. We also found that adipogenesis and HMGB1 expression in the liver and hippocampus were lower in diabetic TonEBP+/− mice compared with the wild type. Furthermore, iba-1 immunoreactivity in the hippocampus was decreased in diabetic TonEBP+/− mice compared with that in the wild type. Our findings suggest that TonEBP haploinsufficiency suppresses diabetes-associated hepatic steatosis and neuroinflammation.

Highlights

Diabetes mellitus (DM) is a common chronic inflammatory disease that causes many complications, such as myocardial infarction, retinopathy, and nephropathy[1, 2], and is considered an important risk factor for mild cognitive impairment and Alzheimer’s disease[3]
We found that high-fat diet (HFD)/STZ treatment increased the hepatic expression of these factors in WT and tonicity-responsive enhancer binding protein (TonEBP)+/− mice, while the increases in liver X receptor β (LXRβ) and peroxisome proliferator-activated receptor α (PPARα) were significantly attenuated by TonEBP haploinsufficiency (Fig. 2d–f)
Studies suggest that TonEBP upregulation is associated with many inflammatory diseases, including rheumatoid arthritis, atherosclerosis, seizures, lipopolysaccharide-injected brain injury, and diabetes[18, 24,25,26]

Summary

Introduction

Diabetes mellitus (DM) is a common chronic inflammatory disease that causes many complications, such as myocardial infarction, retinopathy, and nephropathy[1, 2], and is considered an important risk factor for mild cognitive impairment and Alzheimer’s disease[3]. Diabetes-related obesity leads to the recruitment of large numbers of macrophages and T cells to excess adipose tissue, producing proinflammatory cytokines, as well as advanced glycation end-products, and resulting in vascular damage[4, 5] This low-grade chronic inflammation is an important risk factor for systemic insulin resistance and neuroinflammation[6, 7]. Memory impairment in aged rats with diabetes is exacerbated by inhibiting the signaling of the transcription factor nuclear factor-kappa B (NF-κB) in the hippocampus[9] Downregulation of another member of the Rel family of transcription factors, the tonicity-responsive enhancer binding protein (TonEBP, known as nuclear factor of activated T cells 5)[10], prevents neuronal death in animal models of streptozotocin (STZ)-induced diabetic retinopathy[11, 12]. We identified TonEBP as a critical regulator in both hepatic steatosis and neuroinflammation in diabetes and showed that reducing TonEBP expression protects against diabetes-induced complications

Methods

Results

Conclusion