Genetic and biochemical evidence for a functional role of BACE1 in the regulation of insulin mRNA expression

Hoffmeister, Albrecht; Tuennemann, Jan; Sommerer, Ines; Mössner, Joachim; Rittger, Andrea; Schleinitz, Dorit; Kratzsch, Jürgen; Rosendahl, Jonas; Klöting, Nora; Stahl, Tobias; Rößner, Steffen; Paroni, Federico; Maedler, Kathrin; Kovacs, Peter; Blüher, Matthias

doi:10.1002/oby.20482

Cited by 22 publications

(12 citation statements)

References 33 publications

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“…Islets of Langerhans were isolated from pooled pancreases of 12‐week‐old male C57BL/6NTac mice ( N = 4 per experiment). Pancreatic islets were prepared by fractionated collagenase digestion (Roche, Mannheim, Germany) after separation from exocrine tissue and hand‐picked as previously described . Groups of five to seven islets cultured under sterile conditions at a glucose concentration of 5.5 mmol/l were incubated in the presence or absence of 10 μg/ml recombinant AFABP (Adipogen, Seoul, South Korea) overnight.…”

Section: Methodsmentioning

confidence: 99%

Circulating adipocyte fatty acid-binding protein induces insulin resistance in micein vivo

Kralisch

Klöting

Ebert

et al. 2015

Obesity

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Objective: Circulating levels of the adipokine adipocyte fatty acid-binding protein (AFABP) are increased in obesity. However, the influence of circulating AFABP on insulin sensitivity in vivo remains unclear. Methods: C57BL/6NTac mice (10 weeks) were treated over 8 weeks i.p. with saline (control) or recombinant AFABP (0.5 mg/kg/d). A comprehensive characterization of metabolic parameters, body composition, and energy expenditure was performed. Furthermore, the effect of AFABP on pancreatic b-cell responsiveness, hepatic glycogen content, and peroxisome proliferator-activated receptor (PPAR) c protein expression was elucidated. Results: In male mice, AFABP treatment induced insulin resistance with significantly increased fasting insulin, C-peptide, and homeostasis model assessment of insulin resistance. In female animals, a similar trend was observed. In both genders, no difference in body weight, lipid parameters, body composition, or energy expenditure could be detected between AFABP-treated and control mice. Insulin resistance in male AFABP-treated mice was accompanied by decreased PPARc protein content in perigonadal adipose tissue and diminished circulating adiponectin. AFABP treatment did not affect pancreatic b-cell responsiveness and hepatic glycogen content. Conclusions: Circulating AFABP induces insulin resistance in male mice. AFABP-mediated degradation of PPARc in adipose tissue and subsequently decreased expression of insulin-sensitizing adiponectin are potential mechanisms for this effect.

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Section: Methodsmentioning

confidence: 99%

Circulating adipocyte fatty acid-binding protein induces insulin resistance in micein vivo

Kralisch

Klöting

Ebert

et al. 2015

Obesity

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“… Metabolism/fatty acid metabolism. 36 , 63 , 74 , 75 , 76 , 77 , 78 , 79 , 80 , 81 , 82 , 83 , 84 , 85 , 86 , 87 , 88 , 89 , 90 , 91 , 92 , 93 , 94 Apoptosis/proliferation/p53. 37 , 49 , 54 , 56 , 58 , 95 , 96 , 97 , 98 , 99 , 100 , 101 , 102 , 103 , 104 , 105 , 106 , 107 , 108 , 109 , 110 , 111 , 112 , 113 , 114 , 115 , 116 , 117 , 118 Migration.…”

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Fibroblasts from patients with major depressive disorder show distinct transcriptional response to metabolic stressors

et al. 2015

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Major depressive disorder (MDD) is increasingly viewed as interplay of environmental stressors and genetic predisposition, and recent data suggest that the disease affects not only the brain, but the entire body. As a result, we aimed at determining whether patients with major depression have aberrant molecular responses to stress in peripheral tissues. We examined the effects of two metabolic stressors, galactose (GAL) or reduced lipids (RL), on the transcriptome and miRNome of human fibroblasts from 16 pairs of patients with MDD and matched healthy controls (CNTR). Our results demonstrate that both MDD and CNTR fibroblasts had a robust molecular response to GAL and RL challenges. Most importantly, a significant part (messenger RNAs (mRNAs): 26–33% microRNAs (miRNAs): 81–90%) of the molecular response was only observed in MDD, but not in CNTR fibroblasts. The applied metabolic challenges uncovered mRNA and miRNA signatures, identifying responses to each stressor characteristic for the MDD fibroblasts. The distinct responses of MDD fibroblasts to GAL and RL revealed an aberrant engagement of molecular pathways, such as apoptosis, regulation of cell cycle, cell migration, metabolic control and energy production. In conclusion, the metabolic challenges evoked by GAL or RL in dermal fibroblasts exposed adaptive dysfunctions on mRNA and miRNA levels that are characteristic for MDD. This finding underscores the need to challenge biological systems to bring out disease-specific deficits, which otherwise might remain hidden under resting conditions.

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“…In addition, BACE1 finsertms to play a role in glucose and lipid homoeostasis and may be a link between Alzheimer's disease and diabetes [19,20]. Besides its well-characterized expression pattern in the brain, BACE1 mRNA was also detected in non-neuronal tissue, especially within the pancreas [21,22].…”

Section: Discussionmentioning

confidence: 99%

Loss of bace1 in mice does not alter the severity of caerulein induced pancreatitis

et al. 2014

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ContextBeta-site alpha-amyloid protein cleaving enzyme1 (BACE1) plays a key role in the pathogenesis of Alzheimer's disease. Additional to its moderate expression in the brain, high levels of BACE1 mRNA were found in the pancreas. Murine Bace1 has been immunohistochemicaly detected at the apical pole of acinar cells within the exocrine pancreas of mice and Bace1 activity was observed in pancreatic juice. In vitro experiments revealed enteropeptidase as a putative substrate for Bace1 suggesting a role in acute pancreatitis. ObjectiveThe aim of this study was to address a protective mechanism of Bace1 in acute experimental pancreatitis in mice. Methods Acute experimental pancreatitis was induced by intraperitoneal injection of caerulein in homozygote Bace1-/-mice and wild type mice. Serum and tissue analyses were carried out after 4 h, 8 h and 24 h. Measurement of plasma amylase and lipase was performed to confirm pancreatitis induction. In order to assess the severity of pancreatitis H&E stained pancreatic sections were examined regarding edema, inflammation and apoptosis. Immunohistochemical detection of myeloperoxidase (MPO) positive cells was carried out to further quantify the extent of inflammation. Expression of Bace2 within the pancreas was analyzed by immunohistochemistry and RT-qPCR. ResultsWe demonstrate that total loss of Bace1 in mice leads to no alterations in the course of acute experimental caerulein-pancreatitis. Funding: The authors have no support or funding to report.Competing Interests: The authors have declared that no competing interests exist. DiscussionWe discuss the results in the context of the applied caerulein induced edematous pancreatitis model and possible compensatory mechanisms via Bace2 that might be responsible for the observed results.

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Genetic and biochemical evidence for a functional role of BACE1 in the regulation of insulin mRNA expression

Cited by 22 publications

References 33 publications

Circulating adipocyte fatty acid-binding protein induces insulin resistance in micein vivo

Circulating adipocyte fatty acid-binding protein induces insulin resistance in micein vivo

Fibroblasts from patients with major depressive disorder show distinct transcriptional response to metabolic stressors

Loss of bace1 in mice does not alter the severity of caerulein induced pancreatitis

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