BOSTON—In the midst of a growing obesity epidemic in the developed world, scientists are learning more about the active role that adipose tissue and metabolism in general plays in inflammation.
Global Health Impact
Many factors play a role in disease pathogenesis, including dietary, microbial, genetic, environmental and metabolic, said Dr. Hotamisligil. “All of this is a constant negotiation between environmental inputs and our adaptive systems, including our immune system. If the stress is successfully negotiated, health is restored. If the adaptive systems fall short, disease ensues.”
Evolutionary, selective forces like infection or starvation—no longer a major factor in a developed world where overeating is more common—all play a role in immunometabolic integration and subsequent immune responses. Chronic, immunometabolic conditions, such as cardiovascular disease (CVD), fatty liver disease and Type 2 diabetes, are a few potential results.
“The immune response is extremely, energetically expensive,” he added. As a result, the immune system constantly communicates with metabolic cells, sometimes to the body’s detriment. These diseases are a huge global public health crisis. By 2025, as many as 1 billion people may have diabetes and related chronic metabolic diseases worldwide, Dr. Hotamisligil said. “There are already millions of people not being treated for diabetes. The problem is immense.”
Insulin resistance has long been linked to the immune response and inflammation. More recently, scientists linked it to metabolic disease by studying inflammatory cytokine expression in white, adipose tissue as well as other metabolically critical organs.
“Adipose tissue is a rich bed of immune response. We can see interactions between the immune response and the metabolic response,” said Dr. Hotamisligil. During metabolic stress brought on by obesity, metainflammation is the body’s powerful reaction. Adipose tissue becomes inflamed during obesity, but so do liver, pancreatic and brain tissue. In this active adipose tissue, inflammatory macrophages, mast cells, T cells, B cells and eosinophils all may be present.
Inflammatory Targets
More than 50 cytokines, chemokines and inflammatory mediators produced by obesity are linked to the immune response and chronic diseases, such as diabetes, said Dr. Hotamisligil. At this time, there is no single, dominant inflammatory mediator to target to produce therapeutic efficacy. Targeted disruptions of individual cytokines in mice, including TNF-α, IL1b and MCP1, as well as ablation of immune cells, have metabolic consequences, he noted.
Researchers now look for specific molecules to block for more effective treatments for chronic metabolic diseases. A study on the TNF inhibitor, etanercept, showed decreased glucose levels in control group participants with metabolic syndrome symptoms, as well as increased adiponectin, a protein that helps regulate glucose levels. Diabetes incidence in rheumatoid arthritis and psoriatic arthritis patients is decreased with use of TNF inhibitors, he said. Scientists still can’t say for sure that TNF-α is the right pathway to target or if there are others, he added. Promising results also exist for IL-1 inhibitors, and clinical trials are ongoing.
“There is no question that chronic inflammation is a major contributor to metabolic disease. But there doesn’t appear yet to be a single agent we can target to get to good metabolic control,” said Dr. Hotamisligil. Signaling networks that control for multiple immunometabolic pathways and overcome the redundancies between individual cytokines may be better targets, he said.
More than 50 cytokines, chemokines & inflammatory mediators produced by obesity are linked to the immune response and chronic diseases, such as diabetes.
One promising pathway is the c-Jun N-terminal kinases, or JNK, which plays a critical role in transmitting inflammatory signals that lead to diabetes. “The challenging aspect of JNK is that it’s very difficult to make specific inhibitors of it under the current pharmacological model,” he said. Plenty of existing data show that JNK is highly activated in human adipose tissue, and that levels can be lowered with weight loss and, as a result, reduce diabetes levels. Dr. Hotamisligil’s laboratory is studying JNK in order to understand the molecular mechanisms underlying metabolic inflammation. “We need to find new ways to exploit this mechanism and develop therapies,” he said.
Another promising mechanism involves endoplasmic reticulum (ER) stress and the activation of the unfolded protein response, which is linked to insulin resistance, Type 2 diabetes and obesity, he said. Chronic excess of energy and nutrients in the body leads to ER disruption. In comparisons of lean and obese liver tissue, Dr. Hotamisligil noted that ER stricture is altered and it starts wrapping around mitochondria in the obese liver samples. “ER and mitochondria in metabolic stress have a dysfunctional relationship, and this is also critical for immunometabolic homeostasis,” he said. “ER is really an immunometabolic signaling hub where many metabolic and inflammatory signals intersect.”
Chronic inflammation may impair the normal engagement of the unfolded protein response (UPR), which is activated in the presence of ER stress. However, these processes do not function normally in an inflammatory environment, such as in obesity. For example, inflammatory signals can modify the function of critical UPR molecules responsible for restoring ER function, such as the splicing of XBP1 by the protein IRE1. In one study, this process did not occur properly in mice, resulting in dysfunctional ER and activation of the JNK pathway, which plays a role in inflammation, Dr. Hotamisligil said. This vicious cycle of inflammation and ER stress also may be seen in beta cells in Type 1 diabetes. Restoring the unfolded protein response in pancreatic beta cells protects mice against diabetes.
Over a lifetime, exposure to obesity and other metabolic stresses can create a bottleneck of macrophages and other immune cells that lead to inflammation. This condition disrupts metabolism and causes further immune activity, launching an endless, vicious cycle, Dr. Hotamisligil said.
“Adipose tissue is a nasty, hostile environment and has lots of noxious cargo. Neither adipocytes nor other critical metabolic cells can operate in full capacity when there is constant immune activity. You can no longer support metabolic homeostasis in a chronic inflammatory environment.” the rheumatologist
Susan Bernstein is a freelance medical journalist based in Atlanta.
