The growth hormone receptor (GHR) is part of a highly conserved set of receptors known as the type I cytokine family. GHR is homologous to many receptors involved in inflammation and host defense including the interleukin-2, interleukin-6 and colony stimulating family of receptors. They share many downstream signaling mechanisms including the Janus kinase (JAK)/ signal transducer and activator of transcription (STAT) mechanism of inducing transcriptional regulation of target genes. Growth hormone (GH), a pituitary-derived hormone best known for its role in growth and development, also serves important metabolic functions including mediating lipolysis in adipose tissue during periods of starvation. The precise mechanism by which the JAK/ STAT pathway activation promotes lipolysis in response to GH has yet to be elucidated. Our preliminary data has shown that growth hormone stimulation of adipose tissue leads to the transcriptional upregulation of the basic leucine zipper transcription factor ATF-like 3 (Batf3) gene. This gene is a known response element in the promotion of dendritic cell development and cytotoxic T-cell function in response to pathogens. It is also known to associate with interferon regulatory factors, such as interferon regulatory factor 4 (Irf4) as heterodimers to promote proliferative gene expression in context of inflammatory signals. Recent work has also shown that Irf4 is a key transcription factor in adipose tissue that drives thermogenesis and lipolysis. We have identified that Irf4 transcripts are also induced during GH stimulation. We hypothesize that the Batf3/Irf4 signaling mechanism is conserved in the growth hormone pathway and is important in driving lipolysis, altering mitochondrial respiration and affecting IGF-1/insulin signaling. We will address our hypothesis by performing functional genomics on adipose tissue both in vivo and in vitro. The metabolic consequences of Batf3 and Irf4 induction will be examined by disrupting these genes in adipocytes using CRISPR-based approaches and adipocyte-specific knockout mice. We will examine adipose tissue for lipolytic capacity, body composition and respiratory dynamics to determine the metabolic importance of the Batf3/Irf4 system in adipose tissue under both growth hormone and lipopolysaccharide (LPS) signaling. The goal of these studies is to prove the importance of evolutionarily conserved inflammatory signaling cascades in altering metabolism.
The metabolic complications of obesity remain an epidemic that would benefit from preventative and ameliorative therapies. Investigating the effect of hormones and inflammation on fat cell biology are necessary to identify novel therapies. Here we will study a mechanism regulating the fat-mobilizing activity of growth hormone, a pituitary hormone, in order to identify new therapeutic targets to promote healthy changes in fat metabolism and body composition.
