Maternal obesity affects neurogenesis in the lateral hypothalamic area

Abstract

Many human epidemiological studies have reported maternal obesity confers an increased risk for obesity and metabolic disorders within the offspring. Additionally this effect has been observed in numerous animal models of maternal obesity. The hypothalamus is the central regulator of body weight and energy homeostasis. Previous research has demonstrated that the orexigenic RNAs, pro-melanin concentrating hormone (Pmch) and orexin (Hcrt), have increased expression in the lateral hypothalamic area (LHA) in rodent offspring from animal models of obese mothers. This increase in orexigenic RNA in the offspring of obese dams may explain, at least in part, the increased orexigenic drive and hence increased likelihood of obesity in these offspring. Understanding the timing and regulation of the genesis of the cells that express these RNAs, Melanin Concentrating Hormone (MCH) and Orexin neurons is thus critical to understanding prenatal programming of obesity risk in the offspring of obese dams.

This research presents novel data characterising the relationship between the time of genesis and anatomical positioning of MCH neurons in the wild-type mouse. Spatial organisation of MCH cells in the wild-type mouse did not appear to correlate with timing of genesis, which is a novel finding due to its contrast to prior observations made in the rat.

Using a mouse model of maternal high fat diet (HFD)-induced obesity, postnatal day 0 (P0) offspring of HFD mothers were found to have increased numbers of MCH neurons, however the population appeared to normalise to control levels by P4. Orexin neuron numbers appeared unchanged in HFD offspring at P4. BrdU pulse-labeling and immunohistochemistry for orexigenic cell markers revealed that the genesis of MCH neurons was altered in HFD offspring, with a greater proportion of post-mitotic MCH cells produced at E12.5.

Despite no net change in the total MCH or Orexin population, the normal genesis of these cells was altered in HFD offspring. This may affect the composition of MCH neuron subtypes, and therefore functionality of the MCH populations of the LHA. A change to the composition of the orexigenic cell population in the LHA could contribute to imbalanced energy homeostasis, predisposing offspring to obesity.