Altered regulation of the PINKI locus: a link between type 2 diabetes and neurodegeneration?

A link between type 2 diabetes and neurodegeneration?

C Scheele, A R Nielsen, T B Walden, Dean Alan Sewell, C P Fischer, R J Brogan, N Petrovic, O Larson, P A Tesch, K Wennmalm, D Hutchison, B Cannon, C Wahlestedt, B K Pedersen, Jamie Timmons

Research output: Contribution to journalArticle

Abstract

Mutations in PINK1 cause the mitochondrial-related neurodegenerative disease Parkinson's. Here we investigate whether obesity, type 2 diabetes, or inactivity alters transcription from the PINK1 locus. We utilized a cDNA-array and quantitative real-time PCR for gene expression analysis of muscle from healthy volunteers following physical inactivity, and muscle and adipose tissue from nonobese or obese subjects with normal glucose tolerance or type 2 diabetes. Functional studies of PINK1 were performed utilizing RNA interference in cell culture models. Following inactivity, the PINK1 locus had an opposing regulation pattern (PINK1 was down-regulated while natural antisense PINK1 was up-regulated). In type 2 diabetes skeletal muscle, all transcripts from the PINK1 locus were suppressed and gene expression correlated with diabetes status. RNA interference of PINK1 in human neuronal cell lines impaired basal glucose uptake. In adipose tissue, mitochondrial gene expression correlated with PINK1 expression although remained unaltered following siRNA knockdown of Pink1 in primary cultures of brown preadipocytes. In conclusion, regulation of the PINK1 locus, previously linked to neurodegenerative disease, is altered in obesity, type 2 diabetes and inactivity, while the combination of RNAi experiments and clinical data suggests a role for PINK1 in cell energetics rather than in mitochondrial biogenesis. © FASEB.

Original languageEnglish
Pages (from-to)3653-3665
Number of pages13
JournalThe FASEB Journal
Volume21
Issue number13
DOIs
Publication statusPublished - Nov 2007

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Type 2 Diabetes Mellitus
RNA Interference
Gene Expression
Neurodegenerative Diseases
Adipose Tissue
Obesity
Glucose
Muscles
Mitochondrial Genes
Organelle Biogenesis
Oligonucleotide Array Sequence Analysis
Small Interfering RNA
Real-Time Polymerase Chain Reaction
Healthy Volunteers
Skeletal Muscle
Cell Culture Techniques
Cell Line
Mutation

Keywords

  • Altered gene regulation
  • Inactivity
  • Metabolism
  • Mitochondria

Cite this

Scheele, C., Nielsen, A. R., Walden, T. B., Sewell, D. A., Fischer, C. P., Brogan, R. J., ... Timmons, J. (2007). Altered regulation of the PINKI locus: a link between type 2 diabetes and neurodegeneration? A link between type 2 diabetes and neurodegeneration? The FASEB Journal, 21(13), 3653-3665. https://doi.org/10.1096/fj.07-8520com
Scheele, C ; Nielsen, A R ; Walden, T B ; Sewell, Dean Alan ; Fischer, C P ; Brogan, R J ; Petrovic, N ; Larson, O ; Tesch, P A ; Wennmalm, K ; Hutchison, D ; Cannon, B ; Wahlestedt, C ; Pedersen, B K ; Timmons, Jamie. / Altered regulation of the PINKI locus: a link between type 2 diabetes and neurodegeneration? A link between type 2 diabetes and neurodegeneration?. In: The FASEB Journal. 2007 ; Vol. 21, No. 13. pp. 3653-3665.
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Scheele, C, Nielsen, AR, Walden, TB, Sewell, DA, Fischer, CP, Brogan, RJ, Petrovic, N, Larson, O, Tesch, PA, Wennmalm, K, Hutchison, D, Cannon, B, Wahlestedt, C, Pedersen, BK & Timmons, J 2007, 'Altered regulation of the PINKI locus: a link between type 2 diabetes and neurodegeneration? A link between type 2 diabetes and neurodegeneration?', The FASEB Journal, vol. 21, no. 13, pp. 3653-3665. https://doi.org/10.1096/fj.07-8520com

Altered regulation of the PINKI locus: a link between type 2 diabetes and neurodegeneration? A link between type 2 diabetes and neurodegeneration? / Scheele, C; Nielsen, A R; Walden, T B; Sewell, Dean Alan; Fischer, C P; Brogan, R J; Petrovic, N; Larson, O; Tesch, P A; Wennmalm, K; Hutchison, D; Cannon, B; Wahlestedt, C; Pedersen, B K; Timmons, Jamie.

In: The FASEB Journal, Vol. 21, No. 13, 11.2007, p. 3653-3665.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Altered regulation of the PINKI locus: a link between type 2 diabetes and neurodegeneration?

T2 - A link between type 2 diabetes and neurodegeneration?

AU - Scheele, C

AU - Nielsen, A R

AU - Walden, T B

AU - Sewell, Dean Alan

AU - Fischer, C P

AU - Brogan, R J

AU - Petrovic, N

AU - Larson, O

AU - Tesch, P A

AU - Wennmalm, K

AU - Hutchison, D

AU - Cannon, B

AU - Wahlestedt, C

AU - Pedersen, B K

AU - Timmons, Jamie

PY - 2007/11

Y1 - 2007/11

N2 - Mutations in PINK1 cause the mitochondrial-related neurodegenerative disease Parkinson's. Here we investigate whether obesity, type 2 diabetes, or inactivity alters transcription from the PINK1 locus. We utilized a cDNA-array and quantitative real-time PCR for gene expression analysis of muscle from healthy volunteers following physical inactivity, and muscle and adipose tissue from nonobese or obese subjects with normal glucose tolerance or type 2 diabetes. Functional studies of PINK1 were performed utilizing RNA interference in cell culture models. Following inactivity, the PINK1 locus had an opposing regulation pattern (PINK1 was down-regulated while natural antisense PINK1 was up-regulated). In type 2 diabetes skeletal muscle, all transcripts from the PINK1 locus were suppressed and gene expression correlated with diabetes status. RNA interference of PINK1 in human neuronal cell lines impaired basal glucose uptake. In adipose tissue, mitochondrial gene expression correlated with PINK1 expression although remained unaltered following siRNA knockdown of Pink1 in primary cultures of brown preadipocytes. In conclusion, regulation of the PINK1 locus, previously linked to neurodegenerative disease, is altered in obesity, type 2 diabetes and inactivity, while the combination of RNAi experiments and clinical data suggests a role for PINK1 in cell energetics rather than in mitochondrial biogenesis. © FASEB.

AB - Mutations in PINK1 cause the mitochondrial-related neurodegenerative disease Parkinson's. Here we investigate whether obesity, type 2 diabetes, or inactivity alters transcription from the PINK1 locus. We utilized a cDNA-array and quantitative real-time PCR for gene expression analysis of muscle from healthy volunteers following physical inactivity, and muscle and adipose tissue from nonobese or obese subjects with normal glucose tolerance or type 2 diabetes. Functional studies of PINK1 were performed utilizing RNA interference in cell culture models. Following inactivity, the PINK1 locus had an opposing regulation pattern (PINK1 was down-regulated while natural antisense PINK1 was up-regulated). In type 2 diabetes skeletal muscle, all transcripts from the PINK1 locus were suppressed and gene expression correlated with diabetes status. RNA interference of PINK1 in human neuronal cell lines impaired basal glucose uptake. In adipose tissue, mitochondrial gene expression correlated with PINK1 expression although remained unaltered following siRNA knockdown of Pink1 in primary cultures of brown preadipocytes. In conclusion, regulation of the PINK1 locus, previously linked to neurodegenerative disease, is altered in obesity, type 2 diabetes and inactivity, while the combination of RNAi experiments and clinical data suggests a role for PINK1 in cell energetics rather than in mitochondrial biogenesis. © FASEB.

KW - Altered gene regulation

KW - Inactivity

KW - Metabolism

KW - Mitochondria

U2 - 10.1096/fj.07-8520com

DO - 10.1096/fj.07-8520com

M3 - Article

VL - 21

SP - 3653

EP - 3665

JO - The FASEB Journal

JF - The FASEB Journal

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