Adipose tissue is a key metabolic organ responsible for maintaining energy homeostasis throughout the body. Healthy adipocytes respond to physiological changes and perform a variety of important functions to regulate glucose and lipid metabolism. Dysregulation of adipose tissue function, on the other hand, is strongly associated with the development of metabolic diseases. Peroxisome Proliferator Activated Receptor gamma (PPARγ) is a key transcription factor that regulates various activities in adipocytes as well as other cell types. A growing body of evidence indicates a more complex role for PPARγ beyond its classical ligand-dependent activity, including the exploration of posttranslational modifications and associated target proteins in non-canonical adipogenic reservoirs and adipocyte-associated cells.
The first part of the thesis describes our study identifying Adipsin as a downstream target of PPARγ deacetylation and further uncovers its function within the bone marrow niche. Unlike peripheral adipose tissues, marrow adipose tissue has been shown to be uniquely responsive to nutrient fluctuations, hormonal changes, and metabolic disturbances such as obesity and diabetes mellitus. Expansion of marrow adipose tissue has also been strongly associated with bone loss in mice and humans. However, the regulation of bone marrow plasticity remains poorly understood, as does the mechanism that links changes in marrow adiposity with bone remodeling. We show that Adipsin was robustly induced in the bone marrow during bone loss in mouse and humans, in a manner dependent on PPARγ acetylation. Ablation of Adipsin inhibited marrow adipose expansion and improved skeletal health in bone loss conditions of calorie restriction, thiazolidinedione treatment for insulin resistance, and aging. These effects were mediated by Adipsin’s downstream effector, Complement Component 3, to prime common progenitor cells toward adipogenesis rather than osteoblastogenesis through the inhibition of Wnt/β-catenin signaling. Together, our findings reveal an unknown function of Adipsin, mediated by PPARγ acetylation, to promote adiposity and affect skeletal remodeling in the bone marrow niche.
The second part of the thesis addresses another novel role for PPARγ, through acetylation in macrophages, to promote adipose tissue inflammation. Chronic, low-grade inflammation characteristic of obesity and metabolic dysfunction is partially driven by macrophage infiltration of adipose tissue and associated inflammatory signaling. PPARγ plays a critical role in regulating anti-inflammatory, M2 polarization of macrophages. However, the involvement of post-translational modifications, such as acetylation, in macrophages is unknown. Here we generated a macrophage specific, PPARγ constitutive acetylation-mimetic mouse line (K293Qflox/flox;LysMcre, mK293Q) to dissect its role. Upon stimulating macrophage infiltration into adipose tissue by high-fat diet feeding, we assessed the overall metabolic profile and tissue-specific phenotype of the mutant mice. We found that the mK293Q mutant promotes pro-inflammatory macrophage infiltration and subsequent fibrosis specifically in epididymal but not subcutaneous white adipose tissue, driving an impaired metabolic response including decreased energy expenditure, insulin sensitivity, glucose tolerance, and adipose tissue function. These detriments are driven by suppressed anti-inflammatory activation of macrophages. Furthermore, mK293Q mice are resistant to improvements in adipose remodeling by Rosiglitazone treatment. Our study reveals acetylation as a new layer of PPARγ regulation in macrophage activation. These findings highlight the importance of post-translational modifications in determining the function of PPARγ when regulating metabolism and promote the discovery of anti-inflammatory associated therapeutics.
| Identifer | oai:union.ndltd.org:columbia.edu/oai:academiccommons.columbia.edu:10.7916/xpb1-2019 |
| Date | January 2022 |
| Creators | Aaron, Nicole |
| Source Sets | Columbia University |
| Language | English |
| Detected Language | English |
| Type | Theses |
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