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. 2021 Jan;11(1):e01928.
doi: 10.1002/brb3.1928. Epub 2020 Nov 1.

Diabetes type 2 risk gene Dusp8 is associated with altered sucrose reward behavior in mice and humans

Peter Baumann  1   2   3   4 , Sonja C Schriever  1   2   3 , Stephanie Kullmann  3   5   6 , Annemarie Zimprich  7   8   9 , Andreas Peter  3   5   10 , Valerie Gailus-Durner  7 , Helmut Fuchs  7 , Martin Hrabe de Angelis  3   7   11 , Wolfgang Wurst  8   9   12   13 , Matthias H Tschöp  2   3   14 , Martin Heni  3   5   6   10 , Sabine M Hölter  7   8   9 , Paul T Pfluger  1   2   3   4
Affiliations

Diabetes type 2 risk gene Dusp8 is associated with altered sucrose reward behavior in mice and humans

Peter Baumann et al. Brain Behav. 2021 Jan.

Abstract

Background: Dusp8 is the first GWAS-identified gene that is predominantly expressed in the brain and has previously been linked with the development of diabetes type 2 in humans. In this study, we unravel how Dusp8 is involved in the regulation of sucrose reward behavior.

Methods: Female, chow-fed global Dusp8 WT and KO mice were tested in an observer-independent IntelliCage setup for self-administrative sucrose consumption and preference followed by a progressive ratio task with restricted sucrose access to monitor seeking and motivation behavior. Sixty-three human carriers of the major C and minor T allele of DUSP8 SNP rs2334499 were tested for their perception of food cues by collecting a rating score for sweet versus savory high caloric food.

Results: Dusp8 KO mice showed a comparable preference for sucrose, but consumed more sucrose compared to WT mice. In a progressive ratio task, Dusp8 KO females switched to a "trial and error" strategy to find sucrose while control Dusp8 WT mice kept their previously established seeking pattern. Nonetheless, the overall motivation to consume sucrose, and the levels of dopaminergic neurons in the brain areas NAcc and VTA were comparable between genotypes. Diabetes-risk allele carriers of DUSP8 SNP rs2334499 preferred sweet high caloric food compared to the major allele carriers, rating scores for savory food remained comparable between groups.

Conclusion: Our data suggest a novel role for Dusp8 in the perception of sweet high caloric food as well as in the control of sucrose consumption and foraging in mice and humans.

Keywords: Dusp8; MAP kinase; dopamine; sucrose reward.

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Conflict of interest statement

Dr. Matthias Tschöp is a member of the scientific advisory board of ERX Pharmaceuticals, Inc., Cambridge, MA. He was a member of the Research Cluster Advisory Panel (ReCAP) of the Novo Nordisk Foundation between 2017 and 2019. He attended a scientific advisory board meeting of the Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, in 2016. He received funding for his research projects by Novo Nordisk (2016–2020) and Sanofi‐Aventis (2012–2019). He was a consultant for Bionorica SE (2013–2017), Menarini Ricerche S.p.A. (2016), and Bayer Pharma AG Berlin (2016). As former Director of the Helmholtz Diabetes Center and the Institute for Diabetes and Obesity at Helmholtz Zentrum München (2011–2018) and since 2018 as CEO of Helmholtz Zentrum München he has been responsible for collaborations with a multitude of companies and institutions, worldwide. In this capacity, he discussed potential projects with and has signed/signs contracts for his institute(s) and for the staff for research funding and/or collaborations with industry and academia, worldwide, including but not limited to pharmaceutical corporations like Boehringer Ingelheim, Eli Lilly, Novo Nordisk, Medigene, Arbormed, BioSyngen, and others. In this role, he was/is further responsible for commercial technology transfer activities of his institute(s), including diabetes‐related patent portfolios of Helmholtz Zentrum München, for example, WO/2016/188932 A2 or WO/2017/194499 A1. Dr. Tschöp confirms that to the best of his knowledge none of the above funding sources were involved in the preparation of this paper.

Figures

FIGURE 1
FIGURE 1
Two‐bottle sucrose versus. water choice test of female, chow‐fed Dusp8 WT & KO mice. Preference for (a) sucrose or (b) water in the first and second dark phase, displayed as percentage of nose pokes (NPs) for sucrose or water versus total NPs, respectively. (c) Preference for NPs in incorrect corners in the first and second dark phase. (d) Total number of corner visits in the second dark phase. (e) Total consumption of water and sucrose in the second dark phase. Female WT: n = 6, female Dusp8 KO: n = 8. Means ±SEM. **p < .01
FIGURE 2
FIGURE 2
Sucrose preference was assessed in female chow‐fed Dusp8 WT and KO mice by a two‐bottle choice test for sucrose versus water with a progressive ratio schedule. Preference for nose poke (NP) performance for accessing sucrose in the (a) first and second night phase and (b) during the 8 days of testing, measured by the number of nose pokes (NPs) in the correct corner. Preference for NPs for water in the (c) first and second night phase and (d) during the 8 days of testing. Preference for NPs in the incorrect corner of the IntelliCage setup during the (e) first and second night phase and (f) over the 8 days of testing. Maximum numbers of NPs in the progressive ratio schedule (g) after the second night and (h) during the 8th dark phase of testing indicate a comparable motivation for sucrose consumption in WT and Dusp8 KO mice. Increased foraging and random investigation behaviors in Dusp8 KO mice were reflected by higher total numbers of corner visits in the second night (i) and during the 8th dark phase (j). Total liquid consumption in the second night phase remained unchanged (k). Dusp8 KO mice have a random 25% distribution in the nose poke preference for the assigned correct versus. incorrect corners during the 8th dark phase (l). Female WT: n = 6, female Dusp8 KO: n = 8. Means ± SEM. *p < .05, **p < .01, ***p < .001
FIGURE 3
FIGURE 3
Dopamine transporter (DAT) densities in the NAcc (a) and the VTA (b), two key areas for sucrose reward, were assessed by immunostaining for DAT in female mice. (c) Signal intensities of DAT‐positive projections in the NAcc and (d) the number of DAT‐positive cells in the VTA of WT and Dusp8 KO females. Arrow heads indicate examples for DAT‐positive cells. NAcc: nucleus accumbens, NAccSh: nucleus accumbens shell. Female WT: n = 4, female Dusp8 KO: n = 6. Scale bar 100 µm. Means ± SEM
FIGURE 4
FIGURE 4
Rating for sweet and savory high caloric food in humans. Hedonic (liking) rating scores of carriers of the major C and minor T allele of DUSP8 SNP rs2334499 of (a) sweet high caloric food (CC: n = 18, CT: n = 31, TT: n = 14) and (b) savory high caloric food (CC: n = 18, CT: n = 31, TT: n = 13). (c,d) show the wanting rating score for sweet and savory high caloric food, respectively. Means ± SEM. * p < .05
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