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. 2017 Feb 7;25(2):312-321.
doi: 10.1016/j.cmet.2016.12.001. Epub 2016 Dec 29.

Basal Ganglia Dysfunction Contributes to Physical Inactivity in Obesity

Free PMC article

Basal Ganglia Dysfunction Contributes to Physical Inactivity in Obesity

Danielle M Friend et al. Cell Metab. .
Free PMC article


Obesity is associated with physical inactivity, which exacerbates the health consequences of weight gain. However, the mechanisms that mediate this association are unknown. We hypothesized that deficits in dopamine signaling contribute to physical inactivity in obesity. To investigate this, we quantified multiple aspects of dopamine signaling in lean and obese mice. We found that D2-type receptor (D2R) binding in the striatum, but not D1-type receptor binding or dopamine levels, was reduced in obese mice. Genetically removing D2Rs from striatal medium spiny neurons was sufficient to reduce motor activity in lean mice, whereas restoring Gi signaling in these neurons increased activity in obese mice. Surprisingly, although mice with low D2Rs were less active, they were not more vulnerable to diet-induced weight gain than control mice. We conclude that deficits in striatal D2R signaling contribute to physical inactivity in obesity, but inactivity is more a consequence than a cause of obesity.

Keywords: D2; dopamine; exercise; obese; obesity; physical activity; striatum; weight loss.


Figure 1
Figure 1. Chronic high-fat diet led to physical inactivity
(a) Mice fed a high-fat diet weighed more than mice fed standard chow beginning at week 2 and continuing to week 18 (F(18, 252) = 62.43, p < 0.0001). (b, c) Obese mice have reduced physical activity compared to lean mice beginning at week 4 and continuing until week 18 (F(10, 140) = 4.83, p < 0.0001). (d) After 18 weeks on high-fat diet, obese mice had decreased time spent moving (t(14) = 3.32, p = 0.005), decreased frequency of movement (t(14) =4.74, p = 0.0003), and speed while moving (t(14) = 4.69, p = 0.0002) relative to lean controls. Obese mice also showed a trend for decreased rearing (p = 0.07). (e) When given access to a running wheel in the home cage, obese mice had fewer wheel turns relative to lean mice (t(14) = 4.55, p = 0.0005). (f–h) Energy intake over the course of the experiment (r = 0.74, p = 0.04), but not energy expenditure (r = 0.52, p = 0.19) nor open field speed (r = 0.19, p = 0.65), formed a significant correlation with total weight gain. (i–k) Average energy intake during the first week (r = 0.88, p = 0.004), but not energy expenditure (r = −0.19, p = 0.66), nor open field speed (r = 0.36, p = 0.38), formed a significant correlation with total weight gain. (a, c) two-way repeated measures ANOVA followed by posthoc t-test with Benjamini Hochberg false discovery rate; (d–e) unpaired student’s t-test; (f–h) linear regression; *p < 0.05, **p < 0.01, ***p <0.0001 vs. lean. (i–k) linear regression; ***p < 0.001 vs. lean mice.
Figure 2
Figure 2. High-fat diet impaired striatal dopamine D2R binding
(a) Images of striatal D2R binding as measured via 3H-spiperone autoradiography. (b) Striatal D2R binding was decreased in obese relative to lean mice (t(25) = 5.02, p < 0.0001). (c) Striatal D2R binding was not correlated with body fat percentage in lean (p = 0.95) or obese mice (p = 0.56). (d–f) Striatal D1R binding (t(24) = 1.31, p = 0.20), total dopamine content (DA; t(13) = 0.85, p = 0.41), and tyrosine hydroxylase (TH) density (t(14) = 0.48, p = 0.64) were not different between diet groups. Mean with individual mice; n = 8–19 mice/group; student’s t-test (b, d–f) or linear regression (c); *p < 0.01.
Figure 3
Figure 3. Movement-related firing in the striatum was disrupted in obese mice
(a) Movement events had similar velocity in lean and obese mice (b) Examples of movement-activated and non-responsive firing in striatal neurons. (c) Prevalence of movement-activated neurons was lower in obese mice (p = 0.002). (d, e) Movement-related firing of all recorded neurons was significantly lower following diet exposure (diet × movement interaction, F(1, 171) = 14.77, p < 0.0002). (f) Schematic (adapted from (Franklin and Paxinos, 1997)) illustrating electrode array placement in lean and obese recording mice (n = 3 each). (c) Fisher’s exact test (d–e) two-way repeated measures ANOVA.
Figure 4
Figure 4. DREADD mediated inhibition of iMSNs restored physical activity in obese mice
(a) Photograph of KOR-DREADD expression, and schematic (adapted from (Franklin and Paxinos, 1997)) illustrating viral injection sites of all KOR-DREADD in A2A-Cre mice; opacity indicates number of mice expressing virus in a given location. (b) Obese mice moved more when injected with SalB compared to DMSO (t(7) =3.056, p = 0.02). (c–g) After SalB administration, obese mice increased their frequency of rearing (t(7) = 3.116, p = 0.02), and trended towards an increase in frequency of movements (t(7) =1.64, p = 0.12) relative to when administered DMSO. (h) Lean mice moved more when injected with SalB compared to DMSO (t(9) =3.3, p = 0.01). (i) SalB did not affect movement in wildtype mice that did not express the KOR-DREADD (p=0.77). (b–i) Paired student’s t-tests; mean with individual mice; n = 6–10 mice/group.
Figure 5
Figure 5. Basal D2R binding did not predict future weight gain
(a) Example D2R microPET availability curves in the striatum and cerebellum using 18F-fallypride. (b–c) D2R binding potential correlated with basal open field movement (r = 0.56, p = 0.045), and trended towards a positive relationship with high-fat diet-induced weight gain (r = 0.50, p = 0.10, n = 12–14 mice). (d) Representative D2R autoradiography in mice with intact D2Rs (top) and iMSN-Drd2-KO mice (bottom). (e–f) iMSN-Drd2-KO mice had decreased physical activity in an open field (t(8) = 2.99, p = 0.02) and on home-cage running wheels (p = 0.01, n = 5–19 mice/group). (g) iMSN-Drd2-KO mice and Drd2-floxed littermate controls gained similar amounts of weight on high-fat diet (F(5, 70) = 1.417, p = 0.23; n = 6–10 mice/group). (h–j) There were no difference in normalized energy intake (p = 0.60), energy expenditure (p = 0.47), or RER (p = 0.17) between iMSN-D2R-KO mice and littermate controls.(b–c) linear regression; (e–f, h–j) unpaired Student’s t-test, (g) two-way repeated measures ANOVA, *p < 0.05.

Comment in

  • A weighty problem.
    Stanley SA. Stanley SA. Sci Transl Med. 2017 Jan 11;9(372):eaal4991. doi: 10.1126/scitranslmed.aal4991. Sci Transl Med. 2017. PMID: 28077682

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