Dopaminergic dysregulation in mice selectively bred for excessive exercise or obesity.
Dysregulation of the dopamine system is linked to various aberrant behaviors, including addiction, compulsive exercise, and hyperphagia leading to obesity. The goal of the present experiments was to determine how dopamine contributes to the expression of opposing phenotypes, excessive exercise and obesity. We hypothesized that similar alterations in dopamine and dopamine-related gene expression may underly obesity and excessive exercise, as competing traits for central reward pathways. Moreover, we hypothesized that selective breeding for high levels of exercise or obesity may have influenced genetic variation controlling these pathways, manifesting as opposing complex traits. Dopamine, dopamine-related peptide concentrations, and gene expression were evaluated in dorsal striatum (DS) and nucleus accumbens (NA) of mice from lines selectively bred for high rates of wheel running (HR) or obesity (M16), and the non-selected ICR strain from which these lines were derived. HPLC analysis showed significantly greater neurotransmitter concentrations in DS and NA of HR mice compared to M16 and ICR. Microarray analysis showed significant gene expression differences between HR and M16 compared to ICR in both brain areas, with changes revealed throughout the dopamine pathway including D1 and D2 receptors, associated G-proteins (e.g., Golf), and adenylate cyclase (e.g., Adcy5). The results suggest that similar modifications within the dopamine system may contribute to the expression of opposite phenotypes in mice, demonstrating that alterations within central reward pathways can contribute to both obesity and excessive exercise.
Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7264, USA. wfmathes@med.unc.edu
Wendy Foulds
WF
Mathes
Derrick L
DL
Nehrenberg
Ryan
R
Gordon
Kunjie
K
Hua
Theodore
T
Garland
Daniel
D
Pomp
D000262:Adenylyl Cyclases / Q000235:genetics / Q000378:metabolism; D000704:Analysis of Variance; D000818:Animals; D015306:Biogenic Monoamines / Q000378:metabolism; D001835:Body Weight / Q000502:physiology; D001947:Breeding; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D003342:Corpus Striatum / Q000378:metabolism; D004298:Dopamine / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005786:Gene Expression Regulation / Q000502:physiology*; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D008840:Microfilament Proteins / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism; D009765:Obesity / Q000235:genetics / Q000378:metabolism / Q000401:mortality*; D010805:Physical Conditioning, Animal / Q000502:physiology*; D017447:Receptors, Dopamine D1 / Q000235:genetics / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000235:genetics / Q000378:metabolism; D012641:Selection, Genetic / Q000502:physiology*; D015398:Signal Transduction / Q000235:genetics; D013045:Species Specificity; D033921:Vesicular Transport Proteins / Q000235:genetics / Q000378:metabolism
D015306:Biogenic Monoamines; D008840:Microfilament Proteins; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; C485904:SYNE2 protein, human; D033921:Vesicular Transport Proteins; D000262:Adenylyl Cyclases; D004298:Dopamine