The effects of early life adversity on growth, maturation, and steroid hormones in male and female rats.

Early life adversity is a risk factor for psychiatric disorders, yet the mechanisms by which adversity increases this risk are still being delineated. Here, we used a limited bedding and nesting (LBN) manipulation in rats that models a low resource environment to examine effects on growth, developmental milestones, and endocrine endpoints. In LBN, dams and pups, from pups' postnatal days 2-9, are exposed to an environment where dams lack proper materials to build a nest. This manipulation is compared to control housing conditions, where rat dams have access to ample nesting materials and enrichment throughout pups' development. We found that the LBN condition altered maternal care, increasing pup-directed behaviors while reducing self-care. This, perhaps compensatory, increase in nursing and attention to pups did not mitigate against changes in metabolism, as LBN reduced weight gain in both sexes and this effect persisted into adulthood. Although adult stress hormone levels in both sexes and vaginal opening and estrous cycle length in females were not disrupted, there was other evidence of endocrine dysregulation. Compared to controls, LBN rats of both sexes had shortened anogenital distances, indicating reduced androgen exposure. LBN males also had higher plasma estradiol levels in adulthood. This combination of results suggests that LBN causes a demasculinizing effect in males that could contribute to lasting changes in the brain and behavior. Importantly, alterations in metabolic and endocrine systems due to early life adversity could be one mechanism by which stress early in life increases risk for later disease.

A Strategy for Discovery of Endocrine Interactions with Application to Whole-Body Metabolism.

Inter-tissue communication via secreted proteins has been established as a vital mechanism for proper physiologic homeostasis. Here, we report a bioinformatics framework using a mouse reference population, the Hybrid Mouse Diversity Panel (HMDP), which integrates global multi-tissue expression data and publicly available resources to identify and functionally annotate novel circuits of tissue-tissue communication. We validate this method by showing that we can identify known as well as novel endocrine factors responsible for communication between tissues. We further show the utility of this approach by identification and mechanistic characterization of two new endocrine factors. Adipose-derived Lipocalin-5 is shown to enhance skeletal muscle mitochondrial function, and liver-secreted Notum promotes browning of white adipose tissue, also known as "beiging." We demonstrate the general applicability of the method by providing in vivo evidence for three additional novel molecules mediating tissue-tissue interactions.

A systems genetics approach identifies Trp53inp2 as a link between cardiomyocyte glucose utilization and hypertrophic response.

Cardiac failure has been widely associated with an increase in glucose utilization. The aim of our study was to identify factors that mechanistically bridge this link between hyperglycemia and heart failure. Here, we screened the Hybrid Mouse Diversity Panel (HMDP) for substrate-specific cardiomyocyte candidates based on heart transcriptional profile and circulating nutrients. Next, we utilized an in vitro model of rat cardiomyocytes to demonstrate that the gene expression changes were in direct response to substrate abundance. After overlaying candidates of interest with a separate HMDP study evaluating isoproterenol-induced heart failure, we chose to focus on the gene Trp53inp2 as a cardiomyocyte glucose utilization-specific factor. Trp53inp2 gene knockdown in rat cardiomyocytes reduced expression and protein abundance of key glycolytic enzymes. This resulted in reduction of both glucose uptake and glycogen content in cardiomyocytes stimulated with isoproterenol. Furthermore, this reduction effectively blunted the capacity of glucose and isoprotereonol to synergistically induce hypertrophic gene expression and cell size expansion. We conclude that Trp53inp2 serves as regulator of cardiomyocyte glycolytic activity and can consequently regulate hypertrophic response in the context of elevated glucose content.NEW & NOTEWORTHY Here, we apply a novel method for screening transcripts based on a substrate-specific expression pattern to identify Trp53inp2 as an induced cardiomyocyte glucose utilization factor. We further show that reducing expression of the gene could effectively blunt hypertrophic response in the context of elevated glucose content.