Maternal HFD consumption and central DA signaling

Abnormalities in the development of the DA system may contribute to this increased intake of palatable, energy‐dense food. Offspring from mothers consuming a HFD displayed decreased amount of DA fiber projections to the PFC, which was primarily due to a decrease in density suggesting a reduced complexity of DA fiber projections, not a change in DA synthesis. Changes were apparent in the superficial layer indicating decreased cortico‐cortical communication of DA fibers. Deterioration of cortico‐cortical communication observed here may lead to problems with integration (27), such as sensory information from food, with motor onset to obtain more food. In contrast to our findings, a rodent study observed no impairments in the abundance of PFC‐TH proteins in offspring from HFD‐fed mothers (17). Differences between these results could be attributed to the NHP PFC being more complex (18) or due to different diet composition.

The amount of D1 and D2, receptors involved in palatable food intake (28-30), was also examined. Offspring from mothers consuming a HFD displayed a decrease in the abundance of D1 protein. This change was mediated by a decrease in the area expressing D1‐positive cells and in the percent of total cells stained with D1. Decreased abundance of D2 was attributed to a decrease in the percent of total cells stained with D2 combined with an increase in total number of cells. Proliferation of non‐D2‐positive cells appears to have diluted the population of D2‐positive cells. Decreased amount of D1 and D2 proteins in medial and deep layers may alter signaling to subcortical brain regions.

Impairments in DA neurocircuitry could be attributed to increased production of maternal obesity‐associated inflammatory factors. Circulating levels of pro‐inflammatory cytokines, such as interleukins and tumor necrosis factor α, are elevated in NHP HFD offspring (12) leading to an increase in interleukins in the brain (e.g., hypothalamus) (13). Furthermore, cytokine treatment has been shown to decrease survival of DA neurons (31). Therefore, laminar‐specific impairments may be a result of a higher concentration of cytokine receptors exerting their influence on TH fibers and D1 and D2 in these layers.

Our present findings support the fetal origins of disease hypothesis (32). Our laboratory found that maternal HFD consumption programs the risk for food‐related impulsivity in offspring. Impulsivity is a heightened drive for reward, associated with poor decision‐making (33). Food‐related impulsivity is a problem due to increased availability of palatable food. Previous research examined whether hedonic neural circuitry differs between obese and healthy individuals. Women with obesity (BMI > 30) were more anhedonic as compared to overweight women (BMI 25‐30) (34). In a functional MRI study, adolescent girls with obesity exhibited increased neural activation of the insula in response to the anticipation of food but weaker activation of the striatum during actual intake of palatable food (35). Lastly, Volkow et al. reported an inverted‐U relationship between D2 levels and hedonic responses to methylphenidate (36), where individuals with high D2 levels perceived a small dose of the drug as pleasant, whereas individuals with low D2 levels required more drug to perceive a similar pleasant experience (36). This finding is in agreement with our present finding where low levels of D2 protein were observed in offspring from HFD‐fed mothers, suggesting they perceive palatable food as less rewarding.

An important limitation to the present study is that it addresses intake of palatable food, not food addiction. Food addiction would be better targeted by examining operant responses to palatable food. An additional limitation is that only the impact of maternal HFD was examined on PFC‐DA signaling, whereas both maternal HFD and maternal obesity were assessed in the preference test. Ongoing experiments with larger sample sizes will examine the impact of maternal obesity on PFC‐DA signaling. Another limitation is the differences in developmental ages between our two experiments may contribute to changes in DA immunosignal. However, this is unlikely given that striatal‐TH immunosignal was similar at 6 and 12 months of age (37). Another caveat is intensity of DA immunosignal was measured in the present study, which provides an indirect measure of DA synthesis. DA synthesis would be more directly measured using microdialysis. A final caveat is desensitization of dopamine receptors could contribute to overeating of palatable food in HFD offspring.

In summary, our research identifies maternal HFD consumption and maternal obesity as risk factors in programming increased weight and intake of palatable, energy‐dense food in offspring. Furthermore, these behavioral changes may be mediated by reduced PFC‐DA signaling. Future work will determine whether CNS impairments extend to other neural components, such as the ventral tegmentum and nucleus accumbens. Our finding that maternal obesity drives offspring to overconsume palatable, energy‐dense food agrees with evidence in humans that maternal obesity increases a child's intake of palatable food (38). Considering the persistent influence of exposure to a poor perinatal diet and maternal obesity on offspring behavior and physiology, public health policy should focus on improving maternal nutrition and metabolic health before and during pregnancy. Such interventions minimize the risk of childhood obesity and associated long‐term health complications.