Prenatal fat-rich diet exposure alters responses of embryonic neurons to the chemokine, CCL2, in the hypothalamus

Abstract

Maternal consumption of a high fat diet (HFD) during pregnancy is found to stimulate the genesis of hypothalamic orexigenic peptide neurons in the offspring, while HFD intake in adult animals produces a systemic low-grade inflammation which increases neuroimmune factors that may affect neurogenesis and neuronal migration. Building on this evidence and our recent study showing that the inflammatory chemokine, CCL2, stimulates the migration of hypothalamic neurons and expression of orexigenic neuropeptides, we tested here the possibility that prenatal exposure to a HFD affects this chemokine system, both CCL2 and its receptors, CCR2 and CCR4, and alters its actions on hypothalamic neurons, specifically those expressing the neuropeptides, enkephalin (ENK) and galanin (GAL). Using primary dissociated hypothalamic neurons extracted from embryos on embryonic day 19, we found that prenatal HFD exposure compared to chow control actually reduces the expression of CCL2 in these hypothalamic neurons, while increasing CCR2 and CCR4 expression, and also reduces the sensitivity of hypothalamic neurons to CCL2. The HFD abolished the dose-dependent, stimulatory effect of CCL2 on the number of migrated neurons and even shifted its normal stimulatory effect on migrational velocity and distance traveled by control neurons to an inhibition of migration. Further, it abolished the dose-dependent, stimulatory effect of CCL2 on neuronal expression of ENK and GAL. These results demonstrate that prenatal HFD exposure greatly disturbs the functioning of the CCL2 chemokine system in embryonic hypothalamic neurons, reducing its endogenous levels and ability to promote the migration of neurons and their expression of orexigenic peptides.

“Hypothalamic Microinflammation” Paradigm in Aging and Metabolic Diseases

“…Some chemokines could also be involved in the embryonic development of certain hypothalamic neurons, which are important for energy balance. Recently, it was shown that prenatal HFD feeding can alter gene expression of chemokines such as CXCL12 and CCL2 in the hypothalamus and thus affect the development of hypothalamic orexigenic neurons in the offspring (Poon et al, 2016a(Poon et al, , 2017. Also, CCL5 deficiency was shown to affect hypothalamic insulin signaling in a genetic mouse model (Chou et al, 2016).…”

Maternal Diet, Metabolic State, and Inflammatory Response Exert Unique and Long-Lasting Influences on Offspring Behavior in Non-Human Primates

“…Preclinical animal models have demonstrated fetal exposure to diet-induced obesity results in neural reprogramming in multiple brain regions and neuroendocrine systems ( 12 – 15 ). Importantly, these diet-induced neurodevelopmental and behavioral aberrations are associated with altered neuroinflammatory response ( 16 – 18 ). Inflammation is believed to be crucial to perinatal behavioral programming ( 19 , 20 ), and human studies support a link between increased inflammatory factors and neurodevelopmental disorders ( 21 – 23 ).…”

Maternal Metabolic Programming of the Developing Central Nervous System: Unified Pathways to Metabolic and Psychiatric Disorders

“…Furthermore, Kim and colleagues identified increased proliferation in astrocytes, suggesting overall changes in proliferative capacity in different cellular populations of the CNS (62). In addition to the changes in generation and proliferation of cells, Poon and colleagues also show a decreased migratory ability of neurons, specifically hypothalamic neurons, in response to increasing concentrations of the potent chemokine, CCL2 (63). Overall, alterations in neurogenesis and proper cell migration are associated with maternal highfat diet intake.…”