Mitochondrial regulation and white adipose tissue homeostasis

Abstract

The important role of mitochondria in the regulation of white adipose tissue (WAT) remodeling and energy balance is increasingly appreciated. The remarkable heterogeneity of the adipose tissue stroma provides a cellular basis to enable adipose tissue plasticity in response to various metabolic stimuli. Regulating mitochondrial function at the cellular level in adipocytes, in adipose progenitor cells (APCs), and in adipose tissue macrophages (ATMs) has a profound impact on adipose homeostasis. Moreover, mitochondria facilitate the cell-to-cell communication within WAT, as well as the crosstalk with other organs, such as the liver, the heart, and the pancreas. A better understanding of mitochondrial regulation in the diverse adipose tissue cell types allows us to develop more specific and efficient approaches to improve adipose function and achieve improvements in overall metabolic health.

Figure 1.. Intracellular homeostasis in white adipose tissue

Cellular homeostasis in WAT.

Figure 2.. Mitochondrial regulation of intercellular communication in white adipose tissue

Mitochondrial regulation of intercellular communications in WAT. Adipocyte progenitor cells (APCs) differentiate into adipocytes and gain increased mitochondrial content and OXPHOS activity. Mitochondrial dysfunction reduces adipogenic potential of APCs, whereas it promotes the inflammatory effects of adipose regulatory progenitor cells (ARCs), which in turn, inhibits adipogenesis and enhances inflammation in a cytokine-mediated paracrine manner. On the other hand, white adipocytes secrete extracellular vesicles (EVs) that link different adipose cell types such as progenitor cells and adipose tissue macrophages (ATMs) for adapting metabolic alterations. In addition, adipocytes directly transfer mitochondria to ATMs via a heparan sulfate (HS)-dependent mechanism. In obesogenic conditions, ATMs are activated towards proinflammatory polarization and further promotes inflammation in WAT.

Figure 3.. Mitochondrial regulation of white adipose tissue-derived inter-organ communication

Mitochondrial regulation of WAT-centered inter-organ communications. The mitochondrial dicarboxylate carrier (mDIC) controls lipolysis in adipocytes. Deletion of mDIC in adipocytes leads to unconstrained fatty acid release and subsequent hepatic lipotoxicity. Moreover, mitochondrial dysfunction in adipocytes, as seen in the adipocyte-specific mitochondrial ferritin (FtMT)-transgenic mice, promotes remarkable pancreatic β-cell hyperplasia by an unclear mechanisms. In addition, adipocytes produce EVs carrying mitochondrial-derived components. In the FtMT-transgenic mice, compromised mitochondrial vesicles packaged into EVs that derived from adipocytes exert potent mitohormetic effects on cardiomyocytes by inducing mild ROS-mediated damage that preconditions the heart to more severe oxidative stress, such as in an ischemia/reperfusion model.