Drug that treats diabetes to exert powerful control over macrophages in the control of inflammation

July 28, 2018

When a tissue is damaged, one of the first responders of the body's inflammatory immune system are macrophages, cells usually referred to as "construction workers" who clean tissue debris damaged and initiate the repair. However, prolonged inflammation promotes the progression of many diseases, including obesity. Now a common clbad of drugs used to treat diabetes has been found to exert powerful control over macrophages by controlling the metabolic fuel that they use to generate energy. Preventing macrophages from overexploiting work can inhibit the onset of obesity and diabetes as a result of tissue inflammation. These findings are detailed in a study published online this month in Genes and Development led by Mitchell Lazar, MD, PhD, director of the Institute for Diabetes, Obesity and metabolism at the Perelman School of Medicine in Pennsylvania.

Overeating, an excessive intake of calories that can lead to obesity, causes an accumulation of fat that can cause considerable tissue damage. When this happens, macrophages infiltrate affected tissues, sequester free fatty acids and help repair damaged tissue – essentially acting as a protector of the body during periods of metabolic stress. However, prolonged stress on these tissues activates the inflammatory characteristics of macrophages that contribute to several systemic effects of obesity, including diabetes, atherosclerosis, and cardiovascular disease.

Thiazolidinediones (TZD) -based drugs control the expression of genes. "It was known that PPAR gamma is important for macrophages to enter an active state to reduce inflammation and promote healing," said co-lead author Victoria Nelson, PhD, a postdoctoral fellow at Lazar's lab. "We wanted to know if this was controlled by macrophage metabolism."

The Lazar team discovered that TZDs, which act on PPAR gamma, promote the metabolism of an amino acid called glutamine, a protein required for macrophage activation. The team found that macrophages lacking PPAR gamma are unable to use glutamine as a source of energy and are therefore more sensitive to inflammatory stimulation

"These results are very relevant to the Treatment strategies using TZD for diabetes to treat systemic inflammation that accompanies many types of diseases, including obesity and diabetes, said Lazar