Abstract Throughout the US, Brazil and LMICs, obesity and metabolic syndrome are ongoing epidemic crises, presenting major public health challenges and significant economic burdens. The developmental programming effects of the in utero environment is demonstrated by the increased risk of childhood and adult obesity in offspring of overweight/obese (OW/OB) mothers. A murine model of maternal OB has been established in the US and Brazil, with studies from collaborating laboratories demonstrating that maternal OB and high fat diet results in offspring hyperphagia and obesity, similar to human programming effects. Based on published and preliminary studies in the US and Brazil, maternal OB “programs” the offspring putative appetite center, the arcuate nucleus (ARC). We propose that maternal OB induces neuroprogenitor cell (NPC) mitochondrial dysfunction, alters putative bHLH neurogenic signals and preferentially differentiates ARC to increased orexigenic (NPY/AgRP) vs anorexigenic (POMC) neurons, leading to hyperphagia and obesity. We propose to dissect the underlying molecular and epigenetic mechanisms by which fetal/neonatal nutrition alters hypothalamic neurogenesis, using complementary in vivo and in vitro studies, including Cre- recombinase mice, in order to identify targets for prevention/intervention. We will initiate studies of infant breast milk and formula intake, breast milk composition, and a novel preventative strategy of titrated infant weight gain to break the cycle of maternal-offspring OW/OB. The goals of this project are (i) combine Brazilian expertise on functional characterization of OB offspring with US expertise and experimental strategies on NPC culture, mitochondrial function and NPC stereotaxic transplantation, (ii) dissect the role of each candidate pathway in the neurogenic programming paradigm in vivo and in vitro, (iii) test an innovative, highly applicable intervention to prevent early life obesity, and (iv) expand the scientific, training and technical capabilities of Brazilian basic science and clinical research. Together, we will utilize in vivo and in vitro models to explore the pathway by which oxidative stress alters hypothalamic neurogenesis, and examine a novel strategy for prevention of programmed hyperphagia. This project will foster local and US training of Brazilian students and investigators in advanced techniques for brain studies, enhance and approaches to optimize infant feeding, stimulate nationwide public health awareness for the prevention of pre-conception and infant obesity, and build collegial networks between US and Brazil research communities to comprehensively tackle the problem of obesity.

Narrative During developmental periods, exposure to maternal obesity (OB) and high-fat diet increases the risk of childhood and adult obesity, in part a result of increased food intake. In OB offspring, the neurons that regulate food intake are altered such that there is an increase in appetite and decrease in satiety neurons. We propose to study (i) the mechanism contributing to this altered ratio of neuron and offspring hyperphagia in mice, and (ii) the contribution of increased infant caloric intake to rapid weight gain during early life in humans, and a novel preventative strategy to normalize infant weight gain to prevent the development of infant obesity, the generational obesity cycle, and the neuropathologic consequences.