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.
