Mutations in PINK1 cause the mitochon‐drial‐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 RNAinterference in cell culture models. Following inactivity, the PINK1 locus had an opposing regulation pattern (PINK1 was down‐regu‐lated 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 neurodegen‐erative 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.—Scheele C., Nielsen, A. R., Walden, T. B., Sewell, D. A., Fischer, C. P., Brogan, R. J., Petrovic, N., Larsson, O., Tesch, P. A., Wennmalm, K., Hutchinson, D. S., Cannon, B., Wahlestedt C., Pedersen, B. K., Timmons J. A. Altered regulation of the PINK1 locus: a link between Type 2 diabetes and neurodegeneration? FASEB J. 21, 3653–3665 (2007)