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Michael Rudolph

Developmental Origins of Obesity and its Prevention. The hallmark of obesity is too much fat tissue, and the ways in which fat tissues respond and grow during excessive food intake are established very early in life. In humans and in rodent models, we have shown that infants accrue more body fat at an early age if mother’s milk has an elevated omega-6 to omega-3 fatty acid ratio (n6/n3). We investigate how exposure to high and low n6/n3 ratios in the pre- and postnatal window change the ways adipocytes develop into metabolic tissues throughout the lifespan. Adipocyte Precursor Cell (APC) transcriptomic signatures are directly changed by high or low n6/n3 exposure that can adversely affect the way adipose tissues work. We will discover if changes in APCs are long-lasting by transplanting APCs programmed by high or low n6/n3 ratio exposures into adult mice. Ultimately, improving whole-body metabolism using re-programmed APCs will be a major advance and may unlock new therapeutic strategies toward treating obesity.

Maternal Health and Breastmilk Bioactive Composition. We recently used state-of-the-art molecular analyses to better understand human milk composition and have identified, for the first time, a new substance in human milk called 12,13-diHOME. It is a lipid that has been shown to activate brown fat in humans and mice, and brown fat is known to burn nutrients in contrast to white fat that stores them. We are investigating whether induction of brown fat activating molecules in mother’s milk follows acute maternal exercise, and whether the abundance of 12,13-diHOME in infant blood associates with activated measures of infant metabolism (Indirect Calorimetry, Infrared Thermogenesis, Brown Fat Volume by MRI.

Cell-intrinsic Metabolism of Adipocyte Precursor Cells. A large and growing body of evidence supports the concept of perinatal programming, through which maternal nutrition during pregnancy and lactation affects the development of neonatal tissues, setting the stage for future obesity. Yet, the mechanisms, timing, and specific drivers of early life adipogenesis remain poorly understood. We identify how exposure to low omega-6 to omega-3 fatty acid ratios (n6/n3 ratio) during the first 12-days of life regulates the fate of adipocyte precursor cell (APC)s at the molecular and cellular level through customized flow cytometry, bulk and single cell RNA-sequencing, epigenetics (DNA methylation) and lipid mass spectrometry. Prior to their functional adipocyte differentiation, we identify a metabolic mRNA signature programmed by low n6/n3 ratios in APCs leading to enhanced APC-intrinsic lipid burning.