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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

Moderate voluntary exercise decreases hyperleptinemia and normalizes hypercholesterolemia and hepatic steatosis in HOM rats. (A) Plasma leptin, (B) correlation analysis of final body weight and plasma leptin, (C) plasma insulin, (D) plasma triglycerides (TG), (E) plasma cholesterol, (F) liver lobe weight, (G) hepatic TG levels (n = 7/group), and hepatic (H) Scd1 mRNA expression (n = 12–14/group) of WT and HOM rats without (sedentary) or with (runner) free access to running wheels for 5 wk. Different letters indicate significant difference as following: a,b,cp < 0.05, genotype × treatment interaction; d,ep < 0.05, effect of treatment; f,gp < 0.05, effect of genotype.
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fig7: Moderate voluntary exercise decreases hyperleptinemia and normalizes hypercholesterolemia and hepatic steatosis in HOM rats. (A) Plasma leptin, (B) correlation analysis of final body weight and plasma leptin, (C) plasma insulin, (D) plasma triglycerides (TG), (E) plasma cholesterol, (F) liver lobe weight, (G) hepatic TG levels (n = 7/group), and hepatic (H) Scd1 mRNA expression (n = 12–14/group) of WT and HOM rats without (sedentary) or with (runner) free access to running wheels for 5 wk. Different letters indicate significant difference as following: a,b,cp < 0.05, genotype × treatment interaction; d,ep < 0.05, effect of treatment; f,gp < 0.05, effect of genotype.

Mentions: Finally, we also investigated several characteristic MC4R-associated metabolic complications after 5 wk of VWR. The moderate amounts of VWR drastically lowered plasma leptin and insulin levels in HOM runners compared to sedentary HOM controls, normalized plasma TG and cholesterol levels, and reduced liver TG levels to those of sedentary WT controls (Figure 7A–G). VWR decreased liver Scd1 expression in HOM wheel-runners compared to sedentary HOM controls (Figure 7H). The central melanocortin system regulates leptin-induced skeletal muscle AMPK activation and GLUT4 translocation [54,55], resulting in decreased skeletal muscle glucose uptake during MC4R deficiency [56]. Because impaired substrate utilization can decrease exercise capacity, we measured protein levels of GLUT4 and HXK2, important regulators of increased muscle glucose utilization during exercise [57], in triceps muscle after 5 wk of VWR. VWR induction of muscle GLUT4 was severely blunted in HOM wheel-runners, whereas VWR induction of HXK2 was similar in WT and HOM wheel-runners (Figure S5A–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)

Moderate voluntary exercise decreases hyperleptinemia and normalizes hypercholesterolemia and hepatic steatosis in HOM rats. (A) Plasma leptin, (B) correlation analysis of final body weight and plasma leptin, (C) plasma insulin, (D) plasma triglycerides (TG), (E) plasma cholesterol, (F) liver lobe weight, (G) hepatic TG levels (n = 7/group), and hepatic (H) Scd1 mRNA expression (n = 12–14/group) of WT and HOM rats without (sedentary) or with (runner) free access to running wheels for 5 wk. Different letters indicate significant difference as following: a,b,cp < 0.05, genotype × treatment interaction; d,ep < 0.05, effect of treatment; f,gp < 0.05, effect of genotype.
© Copyright Policy - CC BY-NC-ND
Related In: Results  -  Collection

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

fig7: Moderate voluntary exercise decreases hyperleptinemia and normalizes hypercholesterolemia and hepatic steatosis in HOM rats. (A) Plasma leptin, (B) correlation analysis of final body weight and plasma leptin, (C) plasma insulin, (D) plasma triglycerides (TG), (E) plasma cholesterol, (F) liver lobe weight, (G) hepatic TG levels (n = 7/group), and hepatic (H) Scd1 mRNA expression (n = 12–14/group) of WT and HOM rats without (sedentary) or with (runner) free access to running wheels for 5 wk. Different letters indicate significant difference as following: a,b,cp < 0.05, genotype × treatment interaction; d,ep < 0.05, effect of treatment; f,gp < 0.05, effect of genotype.
Mentions: Finally, we also investigated several characteristic MC4R-associated metabolic complications after 5 wk of VWR. The moderate amounts of VWR drastically lowered plasma leptin and insulin levels in HOM runners compared to sedentary HOM controls, normalized plasma TG and cholesterol levels, and reduced liver TG levels to those of sedentary WT controls (Figure 7A–G). VWR decreased liver Scd1 expression in HOM wheel-runners compared to sedentary HOM controls (Figure 7H). The central melanocortin system regulates leptin-induced skeletal muscle AMPK activation and GLUT4 translocation [54,55], resulting in decreased skeletal muscle glucose uptake during MC4R deficiency [56]. Because impaired substrate utilization can decrease exercise capacity, we measured protein levels of GLUT4 and HXK2, important regulators of increased muscle glucose utilization during exercise [57], in triceps muscle after 5 wk of VWR. VWR induction of muscle GLUT4 was severely blunted in HOM wheel-runners, whereas VWR induction of HXK2 was similar in WT and HOM wheel-runners (Figure S5A–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