Blocking dopamine D2 receptors by haloperidol curtails the beneficial impact of calorie restriction on the metabolic phenotype of high fat diet induced obese mice

Publication Type:

Journal Article


J Neuroendocrinol, Volume 23, Number 2, p.158-167 (2011)


1365-2826 (Electronic)09

DOI Name (links to online publication)



Calorie restriction is the most effective way of expanding life-span and decreasing morbidity. It improves insulin sensitivity and delays the age-related loss of dopamine receptor D2 (DRD2) expression in the brain. Conversely, high fat feeding is associated with obesity, insulin resistance and a reduced number of DRD2 binding sites. We hypothesized that the metabolic benefit of calorie restriction involves preservation of appropriate DRD2 transmission. The food intake of wild type C57Bl6 male mice was restricted to 60% of ad libitum intake while they were treated with the DRD2 antagonist haloperidol or vehicle using subcutaneously implanted pellets. Mice with ad libitum access to food receiving vehicle treatment served as controls. All mice received high fat food throughout the experiment. After 10 weeks an intraperitoneal glucose tolerance test was performed and after 12 weeks a hyperinsulinaemic euglycaemic clamp. Hypothalamic DRD2 binding was also determined after 12 weeks of treatment. Calorie restricted (CR) vehicle mice were glucose tolerant and insulin sensitive compared to ad libitum (AL) fed vehicle mice. CR mice treated with haloperidol were slightly heavier than vehicle treated CR mice. Haloperidol completely abolished the beneficial impact of calorie restriction on glucose tolerance and partly reduced the insulin sensitivity observed in CR vehicle mice. The metabolic differences between AL and CR vehicle mice were not accompanied by alterations in hypothalamic DRD2 binding. In conclusion, blocking DRD2 curtails the metabolic effects of calorie restriction. Although this suggests that the dopaminergic system could be involved in the metabolic benefits of calorie restriction, restricting access to high fat food does not increase (hypothalamic) DRD2 binding capacity, which argues against this inference.