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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

MC4R loss-of-function decreases wheel running independent of body weight. (A) Experimental timeline of VWR in WT and HOM rats, with tissues collected 6 h after final night of VWR. (B) Mean daily running distance, (C) cumulative running distance, and (D) body weights at week 0 and 4 of WT and HOM littermate rats without (sedentary) or with (runner) 4-wk free access to running wheels (n = 14/group). (E) Mean daily running distance, (F) cumulative running distance, and (G) body weights at week 0 and 12 of WT and loxTBMc4r littermate mice without (sedentary) or with (runner) 12-wk free access to running wheels (n = 6–7/group). (H) Mean daily running distance, (I) cumulative running distance, and (J) body weights at week 0 and 12 of lean WT and WTBWM mice (body-weight matched to loxTBMc4r mice; values for loxTBMc4r mice are depicted in I and J for comparison) with 12-wk free access to running wheels (n = 6–7/group). (K) Mean daily running distance, and (L) cumulative running distance of WT mice with ICV administration of vehicle or SHU9119 (5 ng/day) during 7-d free access to running wheels (n = 5–6/group). *p < 0.05, **P < 0.001 versus WT wheel-runner/vehicle; †p < 0.05 versus WTBWM wheel-runner; Different letters indicate significant difference as following: a,bp < 0.05, main effect of genotype.
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fig2: MC4R loss-of-function decreases wheel running independent of body weight. (A) Experimental timeline of VWR in WT and HOM rats, with tissues collected 6 h after final night of VWR. (B) Mean daily running distance, (C) cumulative running distance, and (D) body weights at week 0 and 4 of WT and HOM littermate rats without (sedentary) or with (runner) 4-wk free access to running wheels (n = 14/group). (E) Mean daily running distance, (F) cumulative running distance, and (G) body weights at week 0 and 12 of WT and loxTBMc4r littermate mice without (sedentary) or with (runner) 12-wk free access to running wheels (n = 6–7/group). (H) Mean daily running distance, (I) cumulative running distance, and (J) body weights at week 0 and 12 of lean WT and WTBWM mice (body-weight matched to loxTBMc4r mice; values for loxTBMc4r mice are depicted in I and J for comparison) with 12-wk free access to running wheels (n = 6–7/group). (K) Mean daily running distance, and (L) cumulative running distance of WT mice with ICV administration of vehicle or SHU9119 (5 ng/day) during 7-d free access to running wheels (n = 5–6/group). *p < 0.05, **P < 0.001 versus WT wheel-runner/vehicle; †p < 0.05 versus WTBWM wheel-runner; Different letters indicate significant difference as following: a,bp < 0.05, main effect of genotype.

Mentions: Exercise increases DA levels in the NAc and dorsal striatum of mice [43], is a self-reinforcing behavior [14–16,44], and induces molecular adaptations in the mesolimbic reward pathway [36,44,45]. Because sedentary HOM rats have increased ex vivo electrically evoked DA release, we predicted that HOM rats would have decreased behavioral responding to VWR. To test this, we assessed VWR in WT and HOM rats during 5-wk voluntary access to freely moving running wheels (Figure 2A). Sedentary controls had access to blocked running wheels. WT runners increased their daily running distance to a greater extent than HOM wheel-runners (Figure 2B), which resulted in 66% less cumulative running distance traveled by HOM wheel-runners compared with WT wheel-runners (Figure 2C). Dark-phase running wheel occupancy was similar between genotypes during week 1, but was lower in HOM than in WT wheel-runners during week 4 (Figure S2A in Supplement 1). At the onset of VWR, HOM rats were 35% heavier than WT rats (552 ± 2 g vs. 407 ± 4 g; Figure 2D). VWR blunted body weight gain in both WT and HOM wheel-runners (Figure 2D). Our observations in MC4R-deficient rats contrast with previous reports that VWR is similar in WT and Mc4r mice, although VWR trended to be lower in the Mc4r mice [33,34]. Thus, to exclude species-specific differences, we also analyzed VWR parameters in WT and loxTBMc4r mice during 12-wk voluntary access to freely moving or blocked running wheels. Compared to WT wheel-runners, loxTBMc4r wheel-runners had smaller daily running distances (Figure 2E), had smaller cumulative running distances (57% reduction; Figure 2F), and were 41% heavier at the onset of VWR (36.4 ± 1.1 g vs. 25.9 ± 0.4 g; Figure 2G). VWR blunted body weight gain in both WT and loxTBMc4r wheel-runners (Figure 2G). Dark-phase running wheel occupancy was lower in loxTBMc4r runners compared to WT wheel-runners during week 1 and week 11 (Figure S2B in Supplement 1). Thus, obese MC4R-deficient mice as well as rats demonstrate decreased VWR.


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)

MC4R loss-of-function decreases wheel running independent of body weight. (A) Experimental timeline of VWR in WT and HOM rats, with tissues collected 6 h after final night of VWR. (B) Mean daily running distance, (C) cumulative running distance, and (D) body weights at week 0 and 4 of WT and HOM littermate rats without (sedentary) or with (runner) 4-wk free access to running wheels (n = 14/group). (E) Mean daily running distance, (F) cumulative running distance, and (G) body weights at week 0 and 12 of WT and loxTBMc4r littermate mice without (sedentary) or with (runner) 12-wk free access to running wheels (n = 6–7/group). (H) Mean daily running distance, (I) cumulative running distance, and (J) body weights at week 0 and 12 of lean WT and WTBWM mice (body-weight matched to loxTBMc4r mice; values for loxTBMc4r mice are depicted in I and J for comparison) with 12-wk free access to running wheels (n = 6–7/group). (K) Mean daily running distance, and (L) cumulative running distance of WT mice with ICV administration of vehicle or SHU9119 (5 ng/day) during 7-d free access to running wheels (n = 5–6/group). *p < 0.05, **P < 0.001 versus WT wheel-runner/vehicle; †p < 0.05 versus WTBWM wheel-runner; Different letters indicate significant difference as following: a,bp < 0.05, main effect of genotype.
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fig2: MC4R loss-of-function decreases wheel running independent of body weight. (A) Experimental timeline of VWR in WT and HOM rats, with tissues collected 6 h after final night of VWR. (B) Mean daily running distance, (C) cumulative running distance, and (D) body weights at week 0 and 4 of WT and HOM littermate rats without (sedentary) or with (runner) 4-wk free access to running wheels (n = 14/group). (E) Mean daily running distance, (F) cumulative running distance, and (G) body weights at week 0 and 12 of WT and loxTBMc4r littermate mice without (sedentary) or with (runner) 12-wk free access to running wheels (n = 6–7/group). (H) Mean daily running distance, (I) cumulative running distance, and (J) body weights at week 0 and 12 of lean WT and WTBWM mice (body-weight matched to loxTBMc4r mice; values for loxTBMc4r mice are depicted in I and J for comparison) with 12-wk free access to running wheels (n = 6–7/group). (K) Mean daily running distance, and (L) cumulative running distance of WT mice with ICV administration of vehicle or SHU9119 (5 ng/day) during 7-d free access to running wheels (n = 5–6/group). *p < 0.05, **P < 0.001 versus WT wheel-runner/vehicle; †p < 0.05 versus WTBWM wheel-runner; Different letters indicate significant difference as following: a,bp < 0.05, main effect of genotype.
Mentions: Exercise increases DA levels in the NAc and dorsal striatum of mice [43], is a self-reinforcing behavior [14–16,44], and induces molecular adaptations in the mesolimbic reward pathway [36,44,45]. Because sedentary HOM rats have increased ex vivo electrically evoked DA release, we predicted that HOM rats would have decreased behavioral responding to VWR. To test this, we assessed VWR in WT and HOM rats during 5-wk voluntary access to freely moving running wheels (Figure 2A). Sedentary controls had access to blocked running wheels. WT runners increased their daily running distance to a greater extent than HOM wheel-runners (Figure 2B), which resulted in 66% less cumulative running distance traveled by HOM wheel-runners compared with WT wheel-runners (Figure 2C). Dark-phase running wheel occupancy was similar between genotypes during week 1, but was lower in HOM than in WT wheel-runners during week 4 (Figure S2A in Supplement 1). At the onset of VWR, HOM rats were 35% heavier than WT rats (552 ± 2 g vs. 407 ± 4 g; Figure 2D). VWR blunted body weight gain in both WT and HOM wheel-runners (Figure 2D). Our observations in MC4R-deficient rats contrast with previous reports that VWR is similar in WT and Mc4r mice, although VWR trended to be lower in the Mc4r mice [33,34]. Thus, to exclude species-specific differences, we also analyzed VWR parameters in WT and loxTBMc4r mice during 12-wk voluntary access to freely moving or blocked running wheels. Compared to WT wheel-runners, loxTBMc4r wheel-runners had smaller daily running distances (Figure 2E), had smaller cumulative running distances (57% reduction; Figure 2F), and were 41% heavier at the onset of VWR (36.4 ± 1.1 g vs. 25.9 ± 0.4 g; Figure 2G). VWR blunted body weight gain in both WT and loxTBMc4r wheel-runners (Figure 2G). Dark-phase running wheel occupancy was lower in loxTBMc4r runners compared to WT wheel-runners during week 1 and week 11 (Figure S2B in Supplement 1). Thus, obese MC4R-deficient mice as well as rats demonstrate decreased VWR.

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