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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

Increased electrically-stimulated DA release in VTA projection targets during MC4R-deficiency. (A) Body weight of sedentary WT and HOM rats at time of amperometry studies. (B) Representative amperometric traces of electrical stimulation-evoked DA release in the dorsal striatum, nucleus accumbens shell (NAc) and medial prefrontal cortex (mPFC) from coronal slices of sedentary HOM rats (top) and WT littermate controls (bottom; electrical stimulation is indicated by vertical line). (C) Mean number of molecules released per stimulation, (D) mean evoked DA-event amplitude, and (E) DA-event peak width from the dorsal striatum, NAc and mPFC were significantly higher in brain slices from HOM rats (n = 34, 28 and 18 slices for each region, respectively, from 6 animals) than from WT littermate controls (n = 33, 25, and 22 slices for each region, respectively, from 6 animals). Peak width in the dorsal striatum of HOM rats trended to be higher (p = 0.06). (F) T1/2 (duration of the signal at 50% of its amplitude) did not differ among genotypes in any of the tested brain regions. *p < 0.05, **p < 0.01, ***p < 0.0005, WT versus HOM, n.s., not significant.
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fig1: Increased electrically-stimulated DA release in VTA projection targets during MC4R-deficiency. (A) Body weight of sedentary WT and HOM rats at time of amperometry studies. (B) Representative amperometric traces of electrical stimulation-evoked DA release in the dorsal striatum, nucleus accumbens shell (NAc) and medial prefrontal cortex (mPFC) from coronal slices of sedentary HOM rats (top) and WT littermate controls (bottom; electrical stimulation is indicated by vertical line). (C) Mean number of molecules released per stimulation, (D) mean evoked DA-event amplitude, and (E) DA-event peak width from the dorsal striatum, NAc and mPFC were significantly higher in brain slices from HOM rats (n = 34, 28 and 18 slices for each region, respectively, from 6 animals) than from WT littermate controls (n = 33, 25, and 22 slices for each region, respectively, from 6 animals). Peak width in the dorsal striatum of HOM rats trended to be higher (p = 0.06). (F) T1/2 (duration of the signal at 50% of its amplitude) did not differ among genotypes in any of the tested brain regions. *p < 0.05, **p < 0.01, ***p < 0.0005, WT versus HOM, n.s., not significant.

Mentions: Based on the evidence that melanocortinergic and DAergic circuitries functionally interact to regulate molecular and behavioral responses to natural reinforcers and drugs of abuse [4,17–21,25–28,31–35,42], we hypothesized that compromised MC4R function alters DAergic neurotransmission. To test this hypothesis we directly assessed DA release by examining ex vivo electrically-evoked DA release in acute coronal slices of sedentary WT and HOM rats. At the time of the amperometry studies, HOM rats were significantly heavier than WT controls (Figure 1A). The mean number of molecules released per stimulation, the mean evoked DA event amplitude, and the mean DA-event peak width from the dorsal striatum, NAc and mPFC of HOM rats were increased compared to brain slices from WT littermates (Figure 1B–E). In contrast, T1/2 (duration of the signal at 50% of its amplitude) did not differ between genotypes in any of the tested brain regions, suggesting normal DA reuptake dynamics (Figure 1F). Finally, catecholamine quantal release from the adrenal glands of sedentary HOM rats was also higher than in WT rats (Figure S1A–C in Supplement 1). Taken together, these data reveal for the first time that MC4R deficiency results in significant aberrations in catecholamine release and dysregulation of the mesolimbic DA system characterized by high levels of evoked DA release and normal DA reuptake.


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)

Increased electrically-stimulated DA release in VTA projection targets during MC4R-deficiency. (A) Body weight of sedentary WT and HOM rats at time of amperometry studies. (B) Representative amperometric traces of electrical stimulation-evoked DA release in the dorsal striatum, nucleus accumbens shell (NAc) and medial prefrontal cortex (mPFC) from coronal slices of sedentary HOM rats (top) and WT littermate controls (bottom; electrical stimulation is indicated by vertical line). (C) Mean number of molecules released per stimulation, (D) mean evoked DA-event amplitude, and (E) DA-event peak width from the dorsal striatum, NAc and mPFC were significantly higher in brain slices from HOM rats (n = 34, 28 and 18 slices for each region, respectively, from 6 animals) than from WT littermate controls (n = 33, 25, and 22 slices for each region, respectively, from 6 animals). Peak width in the dorsal striatum of HOM rats trended to be higher (p = 0.06). (F) T1/2 (duration of the signal at 50% of its amplitude) did not differ among genotypes in any of the tested brain regions. *p < 0.05, **p < 0.01, ***p < 0.0005, WT versus HOM, n.s., not significant.
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fig1: Increased electrically-stimulated DA release in VTA projection targets during MC4R-deficiency. (A) Body weight of sedentary WT and HOM rats at time of amperometry studies. (B) Representative amperometric traces of electrical stimulation-evoked DA release in the dorsal striatum, nucleus accumbens shell (NAc) and medial prefrontal cortex (mPFC) from coronal slices of sedentary HOM rats (top) and WT littermate controls (bottom; electrical stimulation is indicated by vertical line). (C) Mean number of molecules released per stimulation, (D) mean evoked DA-event amplitude, and (E) DA-event peak width from the dorsal striatum, NAc and mPFC were significantly higher in brain slices from HOM rats (n = 34, 28 and 18 slices for each region, respectively, from 6 animals) than from WT littermate controls (n = 33, 25, and 22 slices for each region, respectively, from 6 animals). Peak width in the dorsal striatum of HOM rats trended to be higher (p = 0.06). (F) T1/2 (duration of the signal at 50% of its amplitude) did not differ among genotypes in any of the tested brain regions. *p < 0.05, **p < 0.01, ***p < 0.0005, WT versus HOM, n.s., not significant.
Mentions: Based on the evidence that melanocortinergic and DAergic circuitries functionally interact to regulate molecular and behavioral responses to natural reinforcers and drugs of abuse [4,17–21,25–28,31–35,42], we hypothesized that compromised MC4R function alters DAergic neurotransmission. To test this hypothesis we directly assessed DA release by examining ex vivo electrically-evoked DA release in acute coronal slices of sedentary WT and HOM rats. At the time of the amperometry studies, HOM rats were significantly heavier than WT controls (Figure 1A). The mean number of molecules released per stimulation, the mean evoked DA event amplitude, and the mean DA-event peak width from the dorsal striatum, NAc and mPFC of HOM rats were increased compared to brain slices from WT littermates (Figure 1B–E). In contrast, T1/2 (duration of the signal at 50% of its amplitude) did not differ between genotypes in any of the tested brain regions, suggesting normal DA reuptake dynamics (Figure 1F). Finally, catecholamine quantal release from the adrenal glands of sedentary HOM rats was also higher than in WT rats (Figure S1A–C in Supplement 1). Taken together, these data reveal for the first time that MC4R deficiency results in significant aberrations in catecholamine release and dysregulation of the mesolimbic DA system characterized by high levels of evoked DA release and normal DA reuptake.

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