Maternal obesity, AMPK and Developmental Programming

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Maternal obesity, AMPK and Developmental Programming Over 30% of pregnant American women are obese and an additional 30% are over-weight, conditions which negatively affect fetal development with long-term consequences for offspring health, including pre-disposition to obesity and type 2 diabetes (T2D). The underlying mechanisms remain poorly defined. Skeletal muscle (SM) accounts for >30% body weight and is a key tissue for the oxidation of fatty acids and glucose, as is brown adipose tissue (BAT). Under the support of our previous award, we demonstrated that maternal obesity (MO) elicits early onset of fibrotic and fatty infiltration (FFI) in offspring SM and BAT, which impairs their functions and programs metabolic disorders in offspring. We found that AMP-activated protein kinase (AMPK), a known target for metformin, is robustly inhibited due to MO, correlates with FFI and worsened offspring SM/BAT functions. In the early embryo, both myogenic and fibrogenic cells are derived from progenitor cells (PCs) in the dermomyotome. While the embryonic myogenic cells are the sources of both myogenic and brown adipogenic cells, embryonic fibrogenic cells are sources of fibrogenic and white adipogenic cells in offspring SM/BAT. Because of this, our previous studies point to embryonic origins for developmental abnormalities of offspring SM/BAT due to MO, but this is yet to be examined. Using single cell RNA sequencing (scRNA-seq), we found that embryonic myogenesis is attenuated in E9.5 MO embryos. We hypothesize that MO suppresses AMPK, which inhibits myogenic commitment and drives uncommitted PCs to fibrogenesis during embryonic development, programming FFI in offspring SM/BAT. Accordingly, we have three specific aims: 1) Study AMPK inhibition due to MO in impairing embryonic myogenic commitment; 2) Evaluate AMPK in linking MO to enhanced embryonic fibrogenesis; and 3) Analyze AMPK as a target for improving embryonic SM/BAT development of MO and the resulting offspring SM/BAT functions. We will use single cell “omics” for analyzing embryonic tissues, and embryoid body culture for mechanistic exploration. Knowledge obtained will identify molecular targets for therapeutics to improve embryonic SM/BAT development and subsequent metabolic health of MO offspring, helping the increasing populations of obese mothers to deliver healthy children.