Obesity during pregnancy in the mouse alters the Netrin-1 responsiveness of fetal arcuate nucleus NPY neurons

Abstract

When individuals undergo gestation in an obese dam, they are at increased risk for impairments in the brain's ability to regulate body weight. In rodents, gestation in an obese dam leads to a number of changes to the development of the hypothalamic neurons that regulate body weight, including reduced neuronal connectivity at birth. Here, we sought to gain a clearer picture of how this neural circuitry develops normally, and to explore the mechanism underpinning the deficiency in connectivity seen in fetuses developing in obese dams. We firstly developed an in vitro model for observing and manipulating the axonal growth of fetal arcuate nucleus (ARN) NPY neurons. We then used this model to test two hypotheses: (i) ARN NPY neurons respond to Netrin-1, one of a small number of axon growth and guidance factors that regulate neural circuit formation throughout the developing brain; and (ii) Netrin-1 responsiveness would be lost upon exposure to the inflammatory cytokine interleukin 6 (IL-6), which is elevated in fetuses developing in obese dams. We observed that ARN NPY neurons responded to Netrin-1 with a significant expansion of their growth cones, the terminal apparatus that neurons use to navigate. Unexpectedly, we found further that NPY neurons from obese pregnancies had reduced responsiveness to Netrin-1, raising the possibility that ARN NPY neurons from fetuses developing in obese dams were phenotypically different from normal NPY neurons. Finally, we observed that IL-6 treatment of normal NPY neurons in vitro led to reduced growth cone responsiveness to Netrin-1, essentially causing them to behave similarly to NPY neurons from obese pregnancies. These results support the hypothesis that IL-6 can disrupt the normal process of axon growth from NPY neurons, and suggest one possible mechanism for how the body weight regulating circuitry fails to develop properly in the offspring of obese dams.

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