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

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.

A Pathophysiological Intersection of Diabetes and Alzheimer’s Disease

“…With respect to diabetes, Dusp8, which codes for a dual-specificity phosphatase involved in MAPK signaling and is predominantly expressed in the brain, was implicated by genome-wide association studies as a type 2 diabetes risk gene. There is evidence that Dusp8 can have sex-specific effects in mice and men on hypothalamic insulin resistance, hippocampal size, and cognitive, emotional, and hedonic behaviors [ 68 , 69 , 70 ]. The second insulin receptor signaling pathway, the Akt pathway—which is responsible for cell growth and survival, protein synthesis, and inhibition of the glycogen synthase kinase-3β (GSK-3β) enzyme [ 71 , 72 , 73 , 74 , 75 ]—is also affected by both AD and type 2 diabetes [ 76 ].…”