Maternal obesity predisposes offspring to obesity; understanding the role for elevated Interleukin-6

Obesity has quickly become an epidemic, and there has been a concomitant increase in the prevalence of obesity during pregnancy. Together human and animal studies have revealed that over-nutrition is a high risk factor for the development of obesity in offspring. The arcuate nucleus of the hypothalmus is located near a leaky brain-blood barrier, allowing neurons to receive blood-borne signals from the body, such as insulin, leptin and glucose, about energy expenditure. There are two populations of neurons within the arcuate nucleus that are specific for modulating weight regulation; neuropeptide Y (NPY) and proopiomelanocortin (POMC) neurons. The early development of the NPY and POMC-containing neurons places these peptidergic systems as likely targets for maternal obesity influenced disruption during embryonic and fetal development. Inflammation can be caused by the secretion of pro-inflammatory cytokines from adipose tissue macrophages, and there is evidence of elevated low-level chronic inflammation in obese individuals. A high fat diet (HFD) has also been shown to stimulate a local pro-inflammatory condition in the hypothalamus, resulting in changes in the hypothalamic regulation of energy homeostasis. Previous studies have shown that one of these cytokines, specifically Interleukin 6 (IL-6) is elevated in the maternal and placental circulation of obese mothers, in comparison to mothers of a normal weight. As elevated pro-inflammatory cytokines are a hallmark of maternal obesity, it is proposed that IL-6 may be involved in the mechanism influencing the development of weight regulation centres within the fetal brain, predisposing offspring to obesity throughout life. Therefore we hypothesised that cells within the arcuate nucleus of the fetal brain are responsive to IL-6. In vitro organotypic slice culture experiments were carried out to test this hypothesis. Fetal brains were sectioned on a Vibratome and the response of IL-6 was tested at different concentrations on the arcuate nucleus. The phosphorylation and translocation of Signal Transducer and Activator of Transcription 3 (STAT3) to the nucleus is a marker for IL-6 receptor signalling. Thus single-label immunocytochemistry detected immuno-positive phosphorylated STAT3 cells and bilateral cell counts of the fetal arcuate nucleus were performed. These studies revealed that there was no increase in the number of immuno-positive pSTAT3 cells under stimulation of IL-6 in the arcuate nucleus. Results did show a reduction in the number of immuno-positive pSTAT3 cells seen in higher concentrations of IL-6 (10 ng/ml and 100 ng/ml) in the fetal arcuate nucleus. Therefore, we conclude that cells within the fetal arcuate nucleus are responsive to IL-6 at concentrations of 10 ng/ml and 100 ng/ml IL-6