Reduced nuclear protein 1 expression improves insulin sensitivity and protects against diet-induced glucose intolerance through up-regulation of heat shock protein 70

Abstract

We recently reported that deletion of the stress-regulated nuclear protein 1 (Nupr1) protected against obesity-associated metabolic alterations due to increased beta cell mass, but complete Nupr1 ablation was not advantageous since it led to insulin resistance on a normal diet. The current study used Nupr1 haplodeficient mice to investigate whether a partial reduction in Nupr1 expression conferred beneficial effects on glucose homeostasis. Islet number, morphology and area, assessed by immunofluorescence and morphometric analyses, were not altered in Nupr1 haplodeficient mice under normal diet conditions and nor was beta cell BrdU incorporation. Glucose and insulin tolerance tests indicated that there were no significant changes in in vivo insulin secretion and glucose clearance in Nupr1 haplodeficient mice, and beta cell function in vitro was normal. However, reduced Nupr1 expression decreased visceral fat deposition and significantly increased insulin sensitivity in vivo. In contrast to wild type animals, high fat diet-fed Nupr1 haplodeficient mice were not hyperinsulinaemic or glucose intolerant, and their sustained insulin sensitivity was demonstrated by appropriate insulin-induced Akt phosphorylation, as determined by Western blotting. At the molecular level, measurements of gene expression levels and promoter activities identified Nupr1-dependent inhibition of heat shock factor-1-induced heat shock protein 70 (Hsp70) expression as a mechanism through which Nupr1 regulates insulin sensitivity. We have shown for the first time that Nupr1 plays a central role in inhibiting Hsp70 expression in tissues regulating glucose homeostasis, and reductions in Nupr1 expression could be used to protect against the metabolic defects associated with obesity-induced insulin resistance.

Epigenetic silencing of microRNA‐874‐3p implicates in erectile dysfunction in diabetic rats by activating the Nupr1/Chop‐mediated pathway

“…Despite this, the pathogenesis of diabetes is not completely understood, and treatments are far from satisfactory. 33,34 On the contrary, because Nupr1 has an intrinsic pro-apoptotic effect, the effects of Nupr1 silencing may be due reduced apoptotic impact of CSMC that has been shown previously and in the current study. Diabetes causes a number of complications that severely affect patients' quality of life, 2 among which the erectile dysfunction affects more than half of male diabetic patients.…”

“…Although the underlying mechanisms in which how Nupr1 alleviates DMED remain unknown, it may be due to increased beta-cell mass and/or expression of heat shock protein 70. 33,34 On the contrary, because Nupr1 has an intrinsic pro-apoptotic effect, the effects of Nupr1 silencing may be due reduced apoptotic impact of CSMC that has been shown previously and in the current study. 21,22 In any case, our results provide clear evidence that Nupr1 is involved in DMED.…”

LH‐21 and abnormal cannabidiol improve β‐cell function in isolated human and mouse islets through GPR55‐dependent and ‐independent signalling

“…Forty micrograms of lysates were fractionated on 4% to 12% polyacrylamide gels (1 hour, 200 V), transferred onto 0.2 μm PVDF membranes, blocked with 5% BSA in Tris‐buffered saline, 0.1% Tween‐20 (TBST) for 1 hour at room temperature and then probed overnight at 4°C with rabbit anti‐phospho CREB, anti‐total CREB, anti‐phospho‐AKT and anti‐total‐AKT antibodies, all diluted 1:1000 in 5% BSA in TBST. The membranes were then incubated with anti‐rabbit HRP‐conjugated secondary antibody (1:10 000) for 1 hour at room temperature and exposed to X‐ray film after addition of ECL substrate …”

“…Sections of 5 μm thickness were dewaxed, then antigens were retrieved using citrate buffer ( (1:10 000) for 1 hour at room temperature and exposed to X-ray film after addition of ECL substrate. 44…”

p8 deficiency leads to elevated pancreatic beta cell mass but does not contribute to insulin resistance in mice fed with high-fat diet

“…In contrast, p8 −/− mice show mild insulin resistance compared to wild type animals but maintained normoglycemia through increase of beta cell mass and consecutive hyperinsulinemia [ 20 ]. On the other hand, p8 haplodeficiency decreases visceral fat deposition and ameliorates insulin resistance through upregulation of stress-induced protein hsp70 [ 21 ].…”