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Jed Friedman

METABOLIC REGULATION: Maternal Metabolism and Developmental programming: In parallel with the childhood obesity epidemic, chronic metabolic diseases like type 2 diabetes (T2D) and non-alcoholic fatty liver disease (NAFLD) are on the rise among youth worldwide. NAFLD is the most common liver disease worldwide and affects nearly 40% of obese youth and up to 10% of the general pediatric population. While the behavioral and biological underpinnings are complex and multifaceted, a “Western diet” (WD) high in refined carbohydrates and unhealthy fats during pregnancy is recognized as a key risk factor. Our lab has focused on the causal mechanisms of maternal diet driving macrophage remodeling and NAFLD at the molecular, endocrine, and epigenetic levels (Nat Reviews-GI & Hepatology, 2017). We find that maternal WD causes tissue-specific changes in offspring mitochondria, widespread inflammation, hepatic steatosis, and NAFLD in mouse, monkey, and man. (Diabetes 2014; JCI Insights, 2016; Molecular Metabolism 2018; Hep Comm, 2018; JCI Insights 2022). One biological mechanism linking a WD to obesity and obesity-related conditions is early microbiome dysbiosis that alters gut-derived bioactive factors affecting distal tissues resulting in local and systemic inflammation that subsequently leads to hepatic and systemic insulin resistance, activation of the innate immune system, and dyslipidemia. We discovered that transplanting the human microbiome from infants born to obese mothers into germ-free mice induces changes in innate immunity, and susceptibility to obesity and NAFLD (Nat Comm 2018). Our findings, in conjunction with the literature, suggest that the infant microbiome, derived from obese mothers may be a marker and/or instigator of shared pathophysiological processes.