Oxidized Lipids Generated by Fat Tissue Lead to Inflammatory Macrophages
Excess visceral fat tissue is demonstrably harmful to long term health; overweight people have a higher risk of age-related disease, higher lifetime medical costs, and a shorter life expectancy. The more overweight, the worse the prognosis. One of the noteworthy mechanisms by which fat tissue leads to harm is the generation of chronic inflammation via the activities of fat cells. Inflammation spreads widely in the body, disrupting cellular metabolism and accelerating the progression of all of the common age-related diseases.
What causes this inflammation? One mechanism is that fat cells produce signals, inflammatory cytokines for example, that rouse the immune system to what is ultimately useless activity. Some of the signal molecules secreted by fat cells overlap with those produced by cells suffering infection. When fat cells die, they produce forms of debris that spur inflammatory reactions. Macrophages are the cells responsible for cleaning up this sort of waste material, and it has been shown that fat tissue is rich in macrophages with an inflammatory polarization.
Macrophages can be classified into polarizations by their behavior and surface features. M1 macrophages are inflammatory and aggressive, while M2 are more helpful, aiding in regeneration. There are other types, and in reality cells have shifting tendencies rather than clear and lasting demarcations between subtypes, but the classification does have value. In old tissues there are usually more M1 macrophages than would be optimal, and this is tied to the inflammation of aging.
Further exploring the theme of macrophages in fat tissue, the research results noted here identify the generation of oxidized lipids as a mechanism by which macrophages are induced to take on an inflammatory polarization in fat tissue. We can also consider the broader harms that might be done by oxidized lipids throughout the body. Some persistent forms of oxidized lipid are an important contributing factor in atherosclerosis, for example. On balance it seems a good idea to maintain less fat tissue rather than more, regardless of how difficult this modern age of low cost calories might make that ideal.
Discovery reveals how obesity causes disease - and two ways to stop it
Researchers were able to explain why resident immune cells in fat tissue - immune cells that are thought to be beneficial - turn harmful during obesity, causing unwanted and unhealthy inflammation. The research team found that damaging "free radicals" produced within our bodies react with substances known as lipids inside fat tissue. That results in a process called "lipid oxidation." At first the scientists expected the oxidized lipids would prove harmful, but it wasn't that simple. Some of the oxidized lipids were causing damaging inflammation - reprogramming immune cells to become hyperactive - but other oxidized lipids were present in healthy tissue. Specifically, shorter "truncated" ones are protective, while longer "full-length" ones were inflammatory.
Now that scientists know which oxidized lipids are causing problems, and how, they can seek to block them to prevent inflammation. They may be able to develop a drug, for example, that would reduce the number of harmful, full-length oxidized lipids. Alternately, doctors might want to promote the number of beneficial, shorter phospholipids. "Inflammation is important for your body's defenses, so you don't want to eliminate it completely. It's a question of finding the right balance."
Macrophages sense pathogen-associated molecular patterns as well as endogenously formed danger-associated molecular patterns (DAMPs) derived from cell and tissue damage to adapt their functional phenotype and cellular metabolism. Because oxidative stress is a hallmark of highly metabolic healthy tissue, as well as inflamed tissue, the formation of oxidation-derived DAMPs is an important signal for macrophage adaptation to oxidative tissue damage.
In adipose tissue, accumulating evidence supports a role for adipose tissue macrophages (ATMs) in regulating tissue-specific glucose homeostasis and inflammation. Both insulin sensitivity and obesity-associated insulin resistance are affected by tissue redox homeostasis and oxidative stress. However, whether ATMs play a role in regulating tissue redox homeostasis remains unknown. Furthermore, how ATMs adapt to tissue oxidation status is unknown.
We have previously shown that oxidized phospholipids (OxPL) induce the formation of the Mox phenotype in macrophages by inducing Nrf2-dependent gene expression. Recently, we found that OxPL redirect macrophage metabolism and bioenergetics to support production of antioxidant metabolites, but also promote a low level of inflammation via Toll-like receptor 2 (TLR2). However, individual OxPL species promote different cellular responses. This implies that the relative abundance of individual OxPL species within tissues determines cellular responses and metabolic adaptation.
Here we characterize the bioenergetic profile of ATMs from lean and obese mice. We used flow cytometry to link the ATM bioenergetics profile to established in vitro macrophage polarization states (i.e., proinflammatory M1, antiinflammatory M2, or antioxidant Mox). Furthermore, quantification of individual OxPL species in whole blood and the ATM-containing stromal vascular fraction (SVF) of adipose tissue allowed us to define the unique OxPL compositions present in physiological and pathological states of obesity. Finally, we tested the different OxPL compositions that we found in vivo on their ability to differentially reprogram macrophage bioenergetics and phenotypic polarization states in vitro.