Brief exposure to obesogenic diet disrupts brain dopamine networks

Abstract

ObjectiveWe have previously demonstrated that insulin signaling, through the downstream signaling kinase Akt, is a potent modulator of dopamine transporter (DAT) activity, which fine-tunes dopamine (DA) signaling at the synapse. This suggests a mechanism by which impaired neuronal insulin receptor signaling, a hallmark of diet-induced obesity, may contribute to impaired DA transmission. We tested whether a short-term (two-week) obesogenic high-fat (HF) diet could reduce striatal Akt activity, a marker of central insulin, receptor signaling and blunt striatal and dopaminergic network responsiveness to amphetamine (AMPH).MethodsWe examined the effects of a two-week HF diet on striatal DAT activity in rats, using AMPH as a probe in a functional magnetic resonance imaging (fMRI) assay, and mapped the disruption in AMPH-evoked functional connectivity between key dopaminergic targets and their projection areas using correlation and permutation analyses. We used phosphorylation of the Akt substrate GSK3α in striatal extracts as a measure of insulin receptor signaling. Finally, we confirmed the impact of HF diet on striatal DA D2 receptor (D2R) availability using [18F]fallypride positron emission tomography (PET).ResultsWe found that rats fed a HF diet for only two weeks have reductions in striatal Akt activity, a marker of decreased striatal insulin receptor signaling and blunted striatal responsiveness to AMPH. HF feeding also reduced interactions between elements of the mesolimbic (nucleus accumbens–anterior cingulate) and sensorimotor circuits (caudate/putamen–thalamus–sensorimotor cortex) implicated in hedonic feeding. D2R availability was reduced in HF-fed animals.ConclusionThese studies support the hypothesis that central insulin signaling and dopaminergic neurotransmission are already altered after short-term HF feeding. Because AMPH induces DA efflux and brain activation, in large part via DAT, these findings suggest that blunted central nervous system insulin receptor signaling through a HF diet can impair DA homeostasis, thereby disrupting cognitive and reward circuitry involved in the regulation of hedonic feeding.

Puberty is a critical window for the impact of diet on mammary gland development in the rabbit

“…Similar results have been found in swine fed with an OD during the juvenile period; the gilts did not exhibit any signs of obesity, because they developed an adaptive response to the diet by reducing their food intake . By contrast, the feeding of rats with a high‐fat diet for 2 weeks around puberty induced significant adiposity and body weight gain . Similarly, in humans, an unbalanced dietary pattern during adolescence has been shown to cause greater adiposity and an increased metabolic risk …”

“…41 By contrast, the feeding of rats with a high-fat diet for 2 weeks around puberty induced significant adiposity and body weight gain. 42 Similarly, in humans, an unbalanced dietary pattern during adolescence has been shown to cause greater adiposity and an increased metabolic risk. 43 No differences were measured regarding the number of fetuses or fetal mortality in OD-fed females compared to CD group, suggesting that OD exposure during the peri-pubertal period did not affect reproductive performance, at least in early pregnancy.…”

Lost in Translation? On the Need for Convergence in Animal and Human Studies on the Role of Dopamine in Diet-Induced Obesity

“…Rodent models allow for the investigation of more causal links between obesity and dopamine transmission and have begun to disentangle the effects of an obesogenic diet from adiposity. Short-term and chronic high fat diets (HFDs) as well as diet-induced obesity were shown to reduce D2R-mRNA and protein expression levels ( [96][97][98][99], but see [100]) ( Table 2). An elegant study suggests that diet-induced obesity may be the cause rather than the result of reduced D2R availability [18••].…”

“…One study showed reduced D1R signalling when a diet high in saturated, but not monounsaturated fats (palm oil vs. olive oil), was administered [101]. Finally, diet-related changes in dopamine synthesis [108], release [59,102,105] and uptake (DAT) [98,99] have been observed.…”

Brain Imaging of Taste Perception in Obesity: a Review

“…Further, obesity is associated with reward circuitry dysregulations, which is reflected in brain response to fat [ 30 , 52 , 53 ]. For instance, overweight compared to healthy-weight children showed greater BOLD responses in right insula, operculum, bilateral precuneus, and posterior cingulate cortex following milkshake consumption [ 9 ].…”