Role of GPS2 in the regulation and maintenance of adipose tissue physiology and function under metabolic stress and obesity
Embargo Date
2024-11-02
OA Version
Citation
Abstract
Obesity, Type 2 Diabetes, and metabolic stress are systemic health issues that result from dysfunctions of white adipose tissue (WAT). As an endocrine organ, WAT is often possessed of a high degree of plasticity, capable of matching the metabolic conditions of which it is presented and responsible for maintaining an overall homeostatic energy balance. However, a clearer understanding of this expansile capacity, the cellular interactions within the tissue, and the mechanisms that drive deleterious pathophysiology remains to be elucidated. Many players are involved in these processes, but the focus of this dissertation centered around G-protein pathway suppressor 2 (GPS2), a protein with well-characterized connections to adipocytes, adipose stromal cells, and the maintenance of metabolism in response to dietary stress. Previous in vivo work showed that selective loss of GPS2 under high-fat diet (HFD) conditions leads to a Type 2 Diabetic-like phenotype. Here, through the implementation of this same adipocyte-specific GPS2 knockout mouse model, we have demonstrated that insulin resistance, inflammation, and unhealthy adipose tissue expansion arises within the first few weeks of exposure to a high-fat diet. In addition, characterization of the heterogeneous cellular milieu that exists within WAT via single-cell RNA sequencing and flow cytometric analyses identified changes in the non-immune adipocyte progenitor populations, along with immune macrophage subsets, the likes of which collectively contribute to adipose tissue remodeling in response to dietary challenge, and are impacted by the loss of GPS2 in the adipocytes. Insights into the mechanisms of cellular communication that are driving the observed cell-specific changes and whole-body mouse phenotype were provided via bulk RNA sequencing of the GPS2-null adipocytes following an acute HFD challenge, whereby we observed transcriptional signatures related to secretion of factors related to inflammation, tissue remodeling, and communication via exosomes. By additionally profiling adipocyte-secreted exosomes via semi-quantitative mass spectrometry, we were able outline specific connections between adipocytes and cell types found within the adipose stroma, along with GPS2-dependent, functionally consequential changes in exosomal cargo related to pro-fibrotic and anti-adipogenic proteins (processes that are critical in healthy adipose tissue expansion). Collectively, our data reveal that the selective loss of GPS2 in adipocytes impairs the reprogramming of adipose-derived signaling to other cells within the stroma in response to HFD, with this impairment mediated by exosomal cargo that has a local functional impact on both immune and non-immune cell types, and global impact on whole-body adipose tissue dysfunction.