SMRT regulates metabolic homeostasis and adipose tissue macrophage phenotypes in tandem

The Silencing Mediator of Retinoid and Thyroid Hormone Receptors (SMRT) is a nuclear corepressor that regulates the transcriptional activity of many transcription factors critical for metabolic processes. While the importance of SMRT’s role in the adipocyte has been well-established, prior mouse models have yielded contradictory phenotypes, limiting our understanding of its in vivo function in the context of homeostatic maintenance. Multiple models suggest that SMRT deficiency leads to increased adiposity, though the effects of SMRT loss on glucose tolerance and insulin sensitivity have been variable. We therefore generated an adipocyte-specific SMRT knockout (adSMRT-/-) mouse to more clearly define SMRT’s metabolic contributions. In doing so, we found that SMRT deletion in the adipocyte does not, in fact, lead to obesity, despite increased food consumption in knockouts – even when mice are challenged with a high-fat diet. This suggests that prior adiposity phenotypes described in generalized models were due to effects beyond the adipocyte. However, an adipocyte-specific SMRT deficiency still led to dramatic effects on systemic glucose tolerance and adipocyte insulin sensitivity, impairing both. This metabolically deleterious effect was coupled with a surprising immune phenotype, wherein most genes differentially expressed in the adipose tissue of adSMRT-/- mice were upregulated in pro-inflammatory pathways. Flow cytometry and conditioned media experiments demonstrated that secreted factors from knockout adipose tissue strongly informed resident macrophages to develop a pro-inflammatory, MMe (metabolically activated) phenotype. Taken together, these studies suggest a novel role for SMRT as an integrator of metabolic and inflammatory signals to effectively maintain physiological homeostasis. RNA sequencing on 20-week old high-fat diet-fed mice was conducted on a total of 8 mouse perigonadal whole adipose tissue samples, which were collected from either wildtype or knockout age- and weight-matched mice (4 mice/genotype). Following sample homogenization, RNA was collected using a commercially available kit (E.Z.N.A Total RNA Kit, Omega Bio-Tek, GA) per manufacturer’s instructions. Samples were then prepared for RNAseq on the Illumina HiSeq4000 platform, and provided to the University of Chicago’s Center for Research Informatics core for sequencing.