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HIF-2α Blows Out the Flames of Adipose Tissue Macrophages to Keep Obesity in a Safe Zone

In 1993, Hotamisligil et al. (1) broke new ground by linking immune response and metabolism. A striking observation in this early study was the upregulation of the inflammatory cytokine tumor necrosis factor-α in adipose tissue (AT) of obese and insulin-resistant animals. Although adipocytes were thought to be the major source of inflammatory cytokines in fat, Weisberg et al. (2) later showed that macrophages accumulate in the AT of obese animals, creating a state of low-grade inflammation that could trigger insulin resistance. Since then, the concept of “immunometabolism” has gradually evolved, and many types of immune cells have been shown to contribute to AT inflammation and insulin resistance (3). For instance, macrophages secrete proinflammatory cytokines and other factors, which could impair insulin sensitivity. In light of this evidence, it has been suggested that decreasing inflammation in AT could attenuate the diabetic state. In support of this idea is the fact that anti-inflammatory drugs appear to have provided proof-of-concept that inflammation is linked to the deleterious effects of insulin resistance in animals (4,5). Paradoxically, recent studies suggest that inflammation is also required for maintaining AT homeostasis (6–8). These complex findings emphasize the need for a more nuanced understanding of the role immune cells play in the development of insulin resistance.

Adipose tissue macrophages (ATMs) have been categorized into two distinct populations: proinflammatory (M1) and anti-inflammatory (M2). While ATM subpopulations have overlapping inflammatory …