Paracrine Regulation of Adipose Tissue Macrophages by Their Neighbors in the Microenvironment of Obese Adipose Tissue

Obesity has recently been defined as a chronic low-grade inflammatory disease. Obesity-induced inflammation of adipose tissue (AT) is an essential trigger for insulin resistance (IR) and related metabolic diseases. Although the underlying molecular basis of this inflammation has not been fully identified, there is consensus that the recruited and activated macrophages in AT are the most important culprits of AT chronic inflammation. Adipose tissue macrophages (ATMs) are highly plastic and could be polarized from an anti-inflammatory M2 to proinflammatory M1 phenotypes on stimulation by microenvironmental signals from obese AT. Many efforts have been made to elucidate the molecular signaling pathways of macrophage polarization; however, the upstream drivers governing and activating macrophage polarization have rarely been summarized, particularly regulatory messages from the AT microenvironment. In addition to adipocytes, the AT bed also contains a variety of immune cells, stem cells, as well as vascular, neural, and lymphatic tissues throughout, which together orchestrate the AT microenvironment. Here, we summarize how the aforesaid neighbors of ATMs in the AT microenvironment send messages to ATMs and thus regulate its phenotype during obesity. Deciphering the biology and polarization of ATMs in the obese environment is expected to provide a precise immunotherapy for adipose inflammation and obesity-related metabolic diseases.