A role for ΔFosB in calorie restriction-induced metabolic changes

Abstract

Background: Calorie restriction (CR) induces long-term changes in motivation to eat highly palatable food and, in body weight regulation, through an unknown mechanism.

Methods: After a period of CR and refeeding, mice were assessed by behavioral and metabolic studies and for levels of the transcription factor ΔFosB. The ΔFosB levels were then increased specifically in nucleus accumbens (NAc) with viral-mediated gene transfer, and behavioral and metabolic studies were conducted.

Results: We show that accumulation of ΔFosB in the NAc shell after CR in mice corresponds to a period of increased motivation for high fat reward and reduced energy expenditure. Furthermore, ΔFosB overexpression in this region increases instrumental responding for a high fat reward via an orexin-dependent mechanism while also decreasing energy expenditure and promoting adiposity.

Conclusions: These results suggest that ΔFosB signaling in NAc mediates adaptive responses to CR.

Figure 1. ΔFosB expression in NAc enhances motivation for HFD

Eight week old c57BL/6 male mice were subjected to 10 days of 60% CR. (A) Number of rewards earned by operant responding prior to reaching breakpoint in mice one week after recovering body weight (Student's t-test. *p<0.05, n=7/group). (B) Representative image of ΔFosB+ neurons in NAc. (C) ΔFosB+ neurons in NAc (Student's t-test, **P<0.01, n=5/group). (D) Number of rewards earned by operant responding prior to reaching breakpoint in mice over-expressing ΔFosB in NAc by viral injection (significant effect of orexin [F_1,28 = 7.04] by two-way ANOVA, Bonferroni post-test revealed a significant difference *P<0.05 between wild-type groups, n=12 for wild-type/GFP, n=10 for wild-type/ΔFosB and n=5 for both orexin^-/- groups,). Data are presented as mean ± SEM.

Figure 2. Metabolic parameters after calorie restriction or ΔFosB over-expression

Eight week old c57BL/6 male mice were subjected to 10 days of 60% CR and then allowed to regain body weight. Mice (n=6/group) were then allowed to recover for one week and monitored for three days in metabolic cages. (A) Oxygen consumption, (B) carbon dioxide production, (C) body weight, (D) food intake, (E) locomotor activity, and (F) body composition were determined. Eight week old c57BL/6 mice received viral injections of either AAV-GFP or AAV-ΔFosB into the NAc. Four weeks later the mice were tested for (G) Oxygen consumption, (H) carbon dioxide production, (I) body weight, (J) food intake, (K) locomotor activity, and (L) body composition (*P<0.05, **P<0.01). Data are presented as mean ± SEM.