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.”
