Impact of hypothalamic gliosis on appetite regulation and obesity risk in children

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ABSTRACT Pediatric obesity is a harbinger of lifelong excess weight, suggesting that neurobiological processes beginning in childhood could ultimately raise the defended level of body adiposity. Recent findings from rodent models suggest a possible mechanism for this process: an inflammatory glial cell response—called gliosis— occurs in the arcuate nucleus, plays a pathogenic role in diet-induced obesity, and involves neuronal loss and potentially permanent glial scarring. The arcuate nucleus is located in the mediobasal hypothalamus (MBH) and is the primary hypothalamic region regulating energy homeostasis; thus, neuronal damage or tissue remodeling in this brain area could significantly impact regulation of body weight and appetite. Importantly, gliosis is detectable in brain tissue in humans by magnetic resonance imaging (MRI). Using MRI, the investigators discovered the first evidence of MBH gliosis in obese adults. The investigators' new findings show that gliosis negatively impacts brain regulation of appetite in adults and that MBH gliosis is also present in children with greater adiposity. Our overarching hypothesis is that the presence of MBH gliosis contributes to reduced satiety responsiveness and poor intake regulation in children and could also represent a risk factor for excessive weight gain. The proposed 2-site research study uses a longitudinal cohort design in 102 children aged 9–11 yr including baseline MRI and functional MRI (fMRI), in-depth eating behavior testing, and measurement of hormone profiles. Serial measurement of weight and self-reported eating habits will occur over 2 yr, with a repeated MRI at 2 yr. The study aims to: 1) test if MBH gliosis is associated with impaired intake regulation and poor weight outcomes over 2 yr in children, 2) determine if CNS appetitive processing is negatively affected when evidence of MBH gliosis is present, and 3) test for other brain regions in which gliosis is present in association with excess adiposity in children. An exploratory aim will assess changes in gliosis in children over 2 yr and their relation to changes in body weight and adiposity. In sum, basic science advances have identified hypothalamic cellular responses that facilitate weight gain during times of nutritional abundance. However, this neurobiological process is capable of forming glial scars that are detrimental to neuronal functioning. The proposed study represents the first investigation of whether gliosis within body- weight regulating areas of the hypothalamus has implications for appetite regulation and weight trajectories in children. As such, the potential insights could trigger entirely new lines of investigation at both the basic science and translational level. Clinically, findings could foster an expansion of our conception of children's eating behavior from a modifiable risk factor (i.e., indicative of poor choices) to a neurobiologically-mediated symptom requiring targeted pharmacologic, behavioral, and preventive approaches.