The Interplay Between Tissue Niche and Macrophage Cellular Metabolism in Obesity

Abstract

Obesity is associated with the development of metabolic diseases such as type 2 diabetes and non-alcoholic fatty liver disease. The presence of chronic, low-grade inflammation appears to be an important mechanistic link between excess nutrients and clinical disease. The onset of these metabolic disorders coincides with changes in the number and phenotype of macrophages in peripheral organs, particularly in the liver and adipose tissue. Macrophage accumulation in these tissues has been implicated in tissue inflammation and fibrosis, contributing to metabolic disease progression. Recently, the concept has emerged that changes in macrophage metabolism affects their functional phenotype, possibly triggered by distinct environmental metabolic cues. This may be of particular importance in the setting of obesity, where both liver and adipose tissue are faced with a high metabolic burden. In the first part of this review we will discuss current knowledge regarding macrophage dynamics in both adipose tissue and liver in obesity. Then in the second part, we will highlight data linking macrophage metabolism to functional phenotype with an emphasis on macrophage activation in metabolic disease. The importance of understanding how tissue niche influences macrophage function in obesity will be highlighted. In addition, we will identify important knowledge gaps and outstanding questions that are relevant for future research in this area and will facilitate the identification of novel targets for therapeutic intervention in associated metabolic diseases.

Keywords: adipose tissue; insulin resistance; liver; macrophages; metabolism; non-alcoholic fatty liver disease; obesity.

Figure 1

Overview of macrophages subsets in lean and obese adipose tissue and liver. Single-cell RNA sequencing has identified macrophage subpopulations that accumulate in liver and adipose tissue in the setting of obesity. These obese adipose tissue macrophages (ATMs) and NASH-associated macrophages (NAMs) are derived from infiltrating monocytes and display distinct surface markers (Trem2, CD9) and functions compared to resident tissue macrophages. In the liver, loss of resident KCs in NASH induces the appearance of monocyte-derived KCs (mo-KCs), which likely fill the empty KC niche and may exert similar functions to resident KCs.

Figure 2

Modulation of obesity and metabolic disorders by tissue macrophages. Tissue macrophages can affect obesity and the development of associated metabolic disorders by affecting energy intake and energy expenditure via brain, brown adipose tissue, and skeletal muscle. Alternatively, tissue macrophages modulate development of metabolic disorders in obesity by regulating adipose tissue and liver metabolism and tissue remodeling as well as by contributing the systemic inflammation. Metabolic reprogramming via targeted therapeutics may alter macrophage activation and subsequently improve metabolic disease.

Figure 3

Metabolic reprogramming of tissue macrophages in obesity. In obesity, tissue macrophages are exposed to an excessive and altered nutrient environment and receive a variety of danger signals from damaged parenchymal cells. This can rewire the metabolic programming of tissue macrophages, altering the activation state of these cells. Although these macrophages may exert protective functions as shielding and clearance of apoptotic cells, they can also release local and systemic mediators that can further exacerbate metabolic disease.