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SRC-2 orchestrates polygenic inputs for fine-tuning glucose homeostasis

Significance Maintenance of glucose concentrations within a homeostatic range is essential for preserving the function of glucose-sensitive tissues. Perturbations in the mechanisms that control this homeostasis give rise to a continuum of glucopathologies associated with aberrant carbohydrate metabolism. Here we show Steroid Receptor Coactivator 2 (SRC-2) to be an integral coregulator that couples gene output with energetic demand by stabilizing and amplifying transcriptional complexes. This study highlights the collective importance of transcriptional coregulators for coordination of gene expression events and may provide insight for understanding components of polygenic diseases such as type 2 diabetes mellitus. Despite extensive efforts to understand the monogenic contributions to perturbed glucose homeostasis, the complexity of genetic events that fractionally contribute to the spectrum of this pathology remain poorly understood. Proper maintenance of glucose homeostasis is the central feature of a constellation of comorbidities that define the metabolic syndrome. The ability of the liver to balance carbohydrate uptake and release during the feeding-to-fasting transition is essential to the regulation of peripheral glucose availability. The liver coordinates the expression of gene programs that control glucose absorption, storage, and secretion. Herein, we demonstrate that Steroid Receptor Coactivator 2 (SRC-2) orchestrates a hierarchy of nutritionally responsive transcriptional complexes to precisely modulate plasma glucose availability. Using DNA pull-down technology coupled with mass spectrometry, we have identified SRC-2 as an indispensable integrator of transcriptional complexes that control the rate-limiting steps of hepatic glucose release and accretion. Collectively, these findings position SRC-2 as a major regulator of polygenic inputs to metabolic gene regulation and perhaps identify a previously unappreciated model that helps to explain the clinical spectrum of glucose dysregulation.