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Moderate voluntary exercise attenuates the metabolic syndrome in melanocortin-4 receptor-deficient rats showing central dopaminergic dysregulation.

Obici S, Magrisso IJ, Ghazarian AS, Shirazian A, Miller JR, Loyd CM, Begg DP, Krawczewski Carhuatanta KA, Haas MK, Davis JF, Woods SC, Sandoval DA, Seeley RJ, Goodyear LJ, Pothos EN, Mul JD - Mol Metab (2015)

Bottom Line: Voluntary wheel running (VWR) induces adaptations in the mesolimbic dopamine system and has a myriad of long-term beneficial effects on health.VWR improved metabolic parameters in wild-type wheel-runners.The data also suggest that exercise can be a successful lifestyle intervention in MC4R-haploinsufficient individuals despite reduced positive reinforcement during exercise training.

View Article: PubMed Central - PubMed

Affiliation: Metabolic Diseases Institute, University of Cincinnati, Cincinnati, OH, USA.

ABSTRACT

Objective: Melanocortin-4 receptors (MC4Rs) are highly expressed by dopamine-secreting neurons of the mesolimbic tract, but their functional role has not been fully resolved. Voluntary wheel running (VWR) induces adaptations in the mesolimbic dopamine system and has a myriad of long-term beneficial effects on health. In the present experiments we asked whether MC4R function regulates the effects of VWR, and whether VWR ameliorates MC4R-associated symptoms of the metabolic syndrome.

Methods: Electrically evoked dopamine release was measured in slice preparations from sedentary wild-type and MC4R-deficient Mc4r (K314X) (HOM) rats. VWR was assessed in wild-type and HOM rats, and in MC4R-deficient loxTB (Mc4r) mice, wild-type mice body weight-matched to loxTB (Mc4r) mice, and wild-type mice with intracerebroventricular administration of the MC4R antagonist SHU9119. Mesolimbic dopamine system function (gene/protein expression) and metabolic parameters were examined in wheel-running and sedentary wild-type and HOM rats.

Results: Sedentary obese HOM rats had increased electrically evoked dopamine release in several ventral tegmental area (VTA) projection sites compared to wild-type controls. MC4R loss-of-function decreased VWR, and this was partially independent of body weight. HOM wheel-runners had attenuated markers of intracellular D1-type dopamine receptor signaling despite increased dopamine flux in the VTA. VWR increased and decreased ΔFosB levels in the nucleus accumbens (NAc) of wild-type and HOM runners, respectively. VWR improved metabolic parameters in wild-type wheel-runners. Finally, moderate voluntary exercise corrected many aspects of the metabolic syndrome in HOM runners.

Conclusions: Central dopamine dysregulation during VWR reinforces the link between MC4R function and molecular and behavioral responding to rewards. The data also suggest that exercise can be a successful lifestyle intervention in MC4R-haploinsufficient individuals despite reduced positive reinforcement during exercise training.

No MeSH data available.


Related in: MedlinePlus

Indices of increased dopaminergic regulators in the VTA of HOM wheel-runners. (A) ObRb, (B) Drd1a, (C) Drd2, (D) Th, (E), Slc6a3, and (F) Oprk1 gene expression in the ventral tegmental area of WT and HOM littermate rats without (sedentary) or with (runner) free access to running wheels for 5 wk (n = 5–6/group). All data are represented relative to WT sedentary controls. Different letters indicate significant difference as following: a,bp < 0.05, genotype × treatment interaction.
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fig3: Indices of increased dopaminergic regulators in the VTA of HOM wheel-runners. (A) ObRb, (B) Drd1a, (C) Drd2, (D) Th, (E), Slc6a3, and (F) Oprk1 gene expression in the ventral tegmental area of WT and HOM littermate rats without (sedentary) or with (runner) free access to running wheels for 5 wk (n = 5–6/group). All data are represented relative to WT sedentary controls. Different letters indicate significant difference as following: a,bp < 0.05, genotype × treatment interaction.

Mentions: Within the mesolimbic DA system, the VTA innervates the NAc, among other regions, and VWR can induce neuronal plasticity in the VTA [44]. Therefore, we measured expression of genes capable of modulating DAergic neurotransmission in the VTA after 5 wk of VWR (Figure 3A–F). Leptin receptor (ObRb) expression was higher in HOM wheel-runners than sedentary HOM rats, but did not differ among the other groups. Drd1a (D1R) mRNA expression was lower in WT wheel-runners and sedentary HOM rats compared to sedentary WT rats but did not differ significantly from HOM wheel-runners. Drd2 (D2R), Th (tyrosine hydroxylase), Slc6a3 (dopamine transporter; DAT), and Oprk1 (κ-opioid receptor) expression were each elevated in HOM wheel-runners by 2–4 fold compared to all other experimental groups. Presynaptic D2Rs, TH, and DAT exert counter-regulatory roles for DA release. Thus, these data indirectly indicate that HOM wheel-runners may have increased DAergic flux originating from the VTA compared to controls. Bdnf (brain-derived neurotrophic factor), Oprm1 (μ-opioid receptor 1), and Ox1r (orexin receptor type 1) expression in the VTA did not differ among any of the experimental groups (Figure S4A–C in Supplement 1).


Moderate voluntary exercise attenuates the metabolic syndrome in melanocortin-4 receptor-deficient rats showing central dopaminergic dysregulation.

Obici S, Magrisso IJ, Ghazarian AS, Shirazian A, Miller JR, Loyd CM, Begg DP, Krawczewski Carhuatanta KA, Haas MK, Davis JF, Woods SC, Sandoval DA, Seeley RJ, Goodyear LJ, Pothos EN, Mul JD - Mol Metab (2015)

Indices of increased dopaminergic regulators in the VTA of HOM wheel-runners. (A) ObRb, (B) Drd1a, (C) Drd2, (D) Th, (E), Slc6a3, and (F) Oprk1 gene expression in the ventral tegmental area of WT and HOM littermate rats without (sedentary) or with (runner) free access to running wheels for 5 wk (n = 5–6/group). All data are represented relative to WT sedentary controls. Different letters indicate significant difference as following: a,bp < 0.05, genotype × treatment interaction.
© Copyright Policy - CC BY-NC-ND
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4588435&req=5

fig3: Indices of increased dopaminergic regulators in the VTA of HOM wheel-runners. (A) ObRb, (B) Drd1a, (C) Drd2, (D) Th, (E), Slc6a3, and (F) Oprk1 gene expression in the ventral tegmental area of WT and HOM littermate rats without (sedentary) or with (runner) free access to running wheels for 5 wk (n = 5–6/group). All data are represented relative to WT sedentary controls. Different letters indicate significant difference as following: a,bp < 0.05, genotype × treatment interaction.
Mentions: Within the mesolimbic DA system, the VTA innervates the NAc, among other regions, and VWR can induce neuronal plasticity in the VTA [44]. Therefore, we measured expression of genes capable of modulating DAergic neurotransmission in the VTA after 5 wk of VWR (Figure 3A–F). Leptin receptor (ObRb) expression was higher in HOM wheel-runners than sedentary HOM rats, but did not differ among the other groups. Drd1a (D1R) mRNA expression was lower in WT wheel-runners and sedentary HOM rats compared to sedentary WT rats but did not differ significantly from HOM wheel-runners. Drd2 (D2R), Th (tyrosine hydroxylase), Slc6a3 (dopamine transporter; DAT), and Oprk1 (κ-opioid receptor) expression were each elevated in HOM wheel-runners by 2–4 fold compared to all other experimental groups. Presynaptic D2Rs, TH, and DAT exert counter-regulatory roles for DA release. Thus, these data indirectly indicate that HOM wheel-runners may have increased DAergic flux originating from the VTA compared to controls. Bdnf (brain-derived neurotrophic factor), Oprm1 (μ-opioid receptor 1), and Ox1r (orexin receptor type 1) expression in the VTA did not differ among any of the experimental groups (Figure S4A–C in Supplement 1).

Bottom Line: Voluntary wheel running (VWR) induces adaptations in the mesolimbic dopamine system and has a myriad of long-term beneficial effects on health.VWR improved metabolic parameters in wild-type wheel-runners.The data also suggest that exercise can be a successful lifestyle intervention in MC4R-haploinsufficient individuals despite reduced positive reinforcement during exercise training.

View Article: PubMed Central - PubMed

Affiliation: Metabolic Diseases Institute, University of Cincinnati, Cincinnati, OH, USA.

ABSTRACT

Objective: Melanocortin-4 receptors (MC4Rs) are highly expressed by dopamine-secreting neurons of the mesolimbic tract, but their functional role has not been fully resolved. Voluntary wheel running (VWR) induces adaptations in the mesolimbic dopamine system and has a myriad of long-term beneficial effects on health. In the present experiments we asked whether MC4R function regulates the effects of VWR, and whether VWR ameliorates MC4R-associated symptoms of the metabolic syndrome.

Methods: Electrically evoked dopamine release was measured in slice preparations from sedentary wild-type and MC4R-deficient Mc4r (K314X) (HOM) rats. VWR was assessed in wild-type and HOM rats, and in MC4R-deficient loxTB (Mc4r) mice, wild-type mice body weight-matched to loxTB (Mc4r) mice, and wild-type mice with intracerebroventricular administration of the MC4R antagonist SHU9119. Mesolimbic dopamine system function (gene/protein expression) and metabolic parameters were examined in wheel-running and sedentary wild-type and HOM rats.

Results: Sedentary obese HOM rats had increased electrically evoked dopamine release in several ventral tegmental area (VTA) projection sites compared to wild-type controls. MC4R loss-of-function decreased VWR, and this was partially independent of body weight. HOM wheel-runners had attenuated markers of intracellular D1-type dopamine receptor signaling despite increased dopamine flux in the VTA. VWR increased and decreased ΔFosB levels in the nucleus accumbens (NAc) of wild-type and HOM runners, respectively. VWR improved metabolic parameters in wild-type wheel-runners. Finally, moderate voluntary exercise corrected many aspects of the metabolic syndrome in HOM runners.

Conclusions: Central dopamine dysregulation during VWR reinforces the link between MC4R function and molecular and behavioral responding to rewards. The data also suggest that exercise can be a successful lifestyle intervention in MC4R-haploinsufficient individuals despite reduced positive reinforcement during exercise training.

No MeSH data available.


Related in: MedlinePlus