title: 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.
authors: Diabetes Research Group, Division of Diabetes and Nutritional Sciences, Faculty of Life Sciences and Medicine, King's College London, London SE1 1UL, United Kingdom.
authors: H C
authors: HC
authors: Barbosa-Sampaio
authors: Diabetes Research Group, Division of Diabetes and Nutritional Sciences, Faculty of Life Sciences and Medicine, King's College London, London SE1 1UL, United Kingdom.
authors: R
authors: R
authors: Drynda
authors: Diabetes Research Group, Division of Diabetes and Nutritional Sciences, Faculty of Life Sciences and Medicine, King's College London, London SE1 1UL, United Kingdom.
authors: B
authors: B
authors: Liu
authors: Diabetes Research Group, Division of Diabetes and Nutritional Sciences, Faculty of Life Sciences and Medicine, King's College London, London SE1 1UL, United Kingdom.
authors: A M
authors: AM
authors: Rodriguez De Ledesma
authors: INSERM U1068, Centre de Recherche en Cancérologie de Marseille, Parc Scientifique de Luminy, Case 915, 13288 Marseille Cedex 9, France.
authors: C
authors: C
authors: Malicet
authors: INSERM U1068, Centre de Recherche en Cancérologie de Marseille, Parc Scientifique de Luminy, Case 915, 13288 Marseille Cedex 9, France.
authors: J L
authors: JL
authors: Iovanna
authors: Diabetes Research Group, Division of Diabetes and Nutritional Sciences, Faculty of Life Sciences and Medicine, King's College London, London SE1 1UL, United Kingdom.
authors: P M
authors: PM
authors: Jones
authors: Diabetes Research Group, Division of Diabetes and Nutritional Sciences, Faculty of Life Sciences and Medicine, King's College London, London SE1 1UL, United Kingdom.
authors: D S
authors: DS
authors: Muller
authors: Diabetes Research Group, Division of Diabetes and Nutritional Sciences, Faculty of Life Sciences and Medicine, King's College London, London SE1 1UL, United Kingdom. Electronic address: shanta.persaud@kcl.ac.uk.
authors: S J
authors: SJ
authors: Persaud
mesh_terms: D000818:Animals; D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D059305:Diet, High-Fat / Q000009:adverse effects; D015870:Gene Expression; D018149:Glucose Intolerance / Q000209:etiology / Q000235:genetics* / Q000378:metabolism; D018840:HSP70 Heat-Shock Proteins / Q000235:genetics* / Q000378:metabolism; D007150:Immunohistochemistry; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance / Q000235:genetics*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000378:metabolism; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009363:Neoplasm Proteins / Q000235:genetics* / Q000378:metabolism; D010766:Phosphorylation; D011401:Promoter Regions, Genetic / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D015854:Up-Regulation
chemical_list: D004268:DNA-Binding Proteins; D018840:HSP70 Heat-Shock Proteins; D007328:Insulin; D009363:Neoplasm Proteins; C491644:Nupr1 protein, mouse; D051057:Proto-Oncogene Proteins c-akt
keywords: Glucose homeostasis; Heat shock protein; High fat diet; Insulin resistance; Islets of Langerhans