Abstract
BackgroundDiabetic individuals have increased circulating inflammatory mediators which are implicated as underlying causes of neuroinflammation and memory deficits. Tonicity-responsive enhancer-binding protein (TonEBP) promotes diabetic neuroinflammation. However, the precise role of TonEBP in the diabetic brain is not fully understood.MethodsWe employed a high-fat diet (HFD)-only fed mice or HFD/streptozotocin (STZ)-treated mice in our diabetic mouse models. Circulating TonEBP and lipocalin-2 (LCN2) levels were measured in type 2 diabetic subjects. TonEBP haploinsufficient mice were used to investigate the role of TonEBP in HFD/STZ-induced diabetic mice. In addition, RAW 264.7 macrophages were given a lipopolysaccharide (LPS)/high glucose (HG) treatment. Using a siRNA, we examined the effects of TonEBP knockdown on RAW264 cell’ medium/HG-treated mouse hippocampal HT22 cells.ResultsCirculating TonEBP and LCN2 levels were higher in experimental diabetic mice or type 2 diabetic patients with cognitive impairment. TonEBP haploinsufficiency ameliorated the diabetic phenotypes including adipose tissue macrophage infiltrations, neuroinflammation, blood–brain barrier leakage, and memory deficits. Systemic and hippocampal LCN2 proteins were reduced in diabetic mice by TonEBP haploinsufficiency. TonEBP (+ / −) mice had a reduction of hippocampal heme oxygenase-1 (HO-1) expression compared to diabetic wild-type mice. In particular, we found that TonEBP bound to the LCN2 promoter in the diabetic hippocampus, and this binding was abolished by TonEBP haploinsufficiency. Furthermore, TonEBP knockdown attenuated LCN2 expression in lipopolysaccharide/high glucose-treated mouse hippocampal HT22 cells.ConclusionsThese findings indicate that TonEBP may promote neuroinflammation and cognitive impairment via upregulation of LCN2 in diabetic mice.
Highlights
Type 2 diabetes mellitus (T2DM) is accompanied by chronic low-grade inflammation, which in combination with hyperglycemia, leads to severe co-morbidities such as cardiovascular and neurodegenerative diseases [1, 2]
Many cells positive for macrophage marker (F4/80 and CD68) and neutrophil markers [neutrophil elastase (NE) and Ly6G], which were arranged in Crown like structures (CLSs) around necrotic perilipin1-free adipocytes were observed in epididymal adipose tissues of two diabetic mouse models compared to normal diet (ND)-fed mice (Fig. 1c, d)
The expressions of receptor for advanced glycation end products (RAGE), nuclear NF-κBp65, and heme oxygenase-1 (HO-1) were dramatically increased in high-fat diet (HFD)/STZ-treated diabetic mice compared to ND-fed mice (Fig. 1e–g)
Summary
Type 2 diabetes mellitus (T2DM) is accompanied by chronic low-grade inflammation, which in combination with hyperglycemia, leads to severe co-morbidities such as cardiovascular and neurodegenerative diseases [1, 2]. The hippocampus is impacted by the active mediators TNF-α and IL-6 through the breakdown of the blood–brain barrier (BBB) [7,8,9]. These evidences suggest that the increased adipocytokines under chronic diabetic conditions could be functionally associated with other inflammatory mediators in the diabetic brain, but the underlying molecular mechanisms responsible for diabetic encephalopathy remain unclear. Diabetic individuals have increased circulating inflammatory mediators which are implicated as underlying causes of neuroinflammation and memory deficits. Tonicity-responsive enhancer-binding protein (TonEBP) promotes diabetic neuroinflammation. The precise role of TonEBP in the diabetic brain is not fully understood
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