Dopamine D2 receptor overexpression in the nucleus accumbens core induces robust weight loss during scheduled fasting selectively in female mice

Abstract

Anorexia nervosa (AN) is an eating disorder observed predominantly in women and girls that is characterized by a low body-mass index, hypophagia, and hyperactivity. Activity-based anorexia (ABA), which refers to the weight loss, hypophagia, and hyperactivity exhibited by rodents exposed to both running wheels and scheduled fasting, provides a model for aspects of AN. Increased dopamine D2/D3 receptor binding in the anteroventral striatum has been reported in AN patients. We virally overexpressed D2Rs on nucleus accumbens core (D2R-OE Nac ) neurons that endogenously express D2Rs, and tested mice of both sexes in the open field test, ABA paradigm, and intraperitoneal glucose tolerance test (IGTT). D2R-OE Nac did not alter baseline body weight, but increased locomotor activity in the open field across both sexes. During constant access to food and running wheels, D2R-OE Nac mice of both sexes increased food intake and ran more than controls. However, when food was available only 7 hours a day, only female D2R-OE Nac mice rapidly lost 25% of their initial body weight, reduced food intake, and substantially increased wheel running. Surprisingly, female D2R-OE Nac mice also rapidly lost 25% of their initial body weight during scheduled fasting without wheel access and showed no changes in food intake. In contrast, male D2R-OE Nac mice maintained body weight during scheduled fasting. D2R-OE Nac mice of both sexes also showed glucose intolerance in the IGTT. In conclusion, D2R-OE Nac alters glucose metabolism in both sexes but drives robust weight loss only in females during scheduled fasting, implicating metabolic mechanisms in this sexually dimorphic effect.

Animal Models for Anorexia Nervosa—A Systematic Review

“…Welch et al investigated mice that overexpressed dopamine-2 receptors on nucleus accumbens core (D2R-OENA mice) neurons that endogenously express D2 receptors, and tested mice of both sexes in the open field test, ABA paradigm and the ip glucose tolerance test (Welch et al, 2019 ). D2R-OENAc did not alter baseline body weight but increased locomotor activity in the open field across both sexes.…”

“…During constant access to food and running wheels, D2R-OENAc mice of both sexes increased food intake and ran more than controls. However, when food was available only 7 h a day, only female D2R-OENAc mice rapidly lost 25% of their initial body weight, reduced food intake, and substantially increased wheel running (Welch et al, 2019 ). Surprisingly, female D2R-OENAc mice also rapidly lost 25% of their initial body weight during scheduled fasting without wheel access and showed no changes in food intake.…”

“…Surprisingly, female D2R-OENAc mice also rapidly lost 25% of their initial body weight during scheduled fasting without wheel access and showed no changes in food intake. In contrast, male D2R-OENAc mice maintained body weight during scheduled fasting (Welch et al, 2019 ). D2R-OENAc mice of both sexes also showed glucose intolerance in the IGTT.…”

Nucleus Accumbens Functional Connectivity with the Frontoparietal Network Predicts Subsequent Change in Body Mass Index for American Children

“…Future work is needed on various social, behaviors, and brain mechanisms that can explain how baseline NAc function predicts future obesity, and how these paths may differ for various groups of American children. As the NAc is not only responsive to food but also other categories of rewards such as alcohol [ 65 ] and sex [ 86 , 87 ], future research should replicate this result for other cue-induced behaviors. Research should also investigate how food environment and past behaviors modulate the food cue-induced behaviors that regulate eating through a change in the NAc activity.…”

GPCR-Based Dopamine Sensors—A Detailed Guide to Inform Sensor Choice for In Vivo Imaging

“…The DA system is best known for its roles in reward behavior [ 15 , 16 , 17 , 18 ], action learning [ 19 ] and motor function [ 20 ] but its effects extend to many other functional domains. For instance, DA has been extensively shown to regulate cognitive function [ 21 , 22 ], aversive processing [ 17 , 23 ], social interaction [ 24 ], feeding behavior [ 25 , 26 , 27 , 28 ], physical activity [ 29 , 30 , 31 ] or metabolic and hormonal homeostasis [ 32 , 33 , 34 ]. These many functions are modulated by a broad network of DA projection neurons, arising from nine major DAergic cell groups labeled A8 to A16 [ 35 ], as originally introduced by Dahlström and Fuxe in 1964 [ 36 ].…”