MELBOURNE, AUSTRALIA – The macrophage has emerged as an important player in obesity-induced insulin resistance – a key factor in the development of the metabolic syndrome, explains Dr Graeme Lancaster, of the Cellular and Molecular Metabolism Laboratory, Baker IDI Heart and Diabetes Institute.
During his presentation at the APCMS Conference, Dr Lancaster spoke specifically on how obesity causes inflammation and discussed research that worked on the idea that inflammation – particularly activated pro-inflammatory macrophages – are intimately involved in obesity-related insulin resistance.
It is now evident that chronic low-grade inflammation is an important contributor to the aetiology of obesity-related insulin resistance, and that interaction between inflammatory macrophages and adipocytes play a key role in orchestrating the peripheral tissue inflammatory response, said Dr Lancaster.In defining the key roles of macrophages in this regard, Dr Lancaster pointed to mouse model studies in which researchers were able to show that, by disabling the macrophage inflammatory pathway, insulin resistance and the resultant metabolic syndrome could be prevented. This proved that macrophages, at least in part said Dr Lancaster, play a role in the development of insulin resistance.
“While macrophages exist is a wide range of states – from anti-inflammatory where they might be involved in tissue remodelling processes, to very pro-inflammatory where they might be involved in the defence of the host – it turns out that those found in the adipose tissue of [the obese] seem to be of a quite pro-inflammatory nature. This underlies their influence on systemic metabolism releasing soluble factors like TNF-alpha, Il-beta and Il-6, which are linked to insulin resistance and can influence the biology of the surrounding adipocytes,” said Dr Lancaster.
Monocytes, the precursers of macrophages, and found in white blood cells in the bone marrow, are key players in the immune response, he said. When these immune cells get into tissues, such as adipose or liver tissue, they release cytokines causing the neighbouring liver, muscle or fat cells to become insulin resistant.
Researchers have been able to demonstrate that by knocking out a key component of the inflammatory pathway in the macrophage, JNK1, they are able to decrease obesity-induced inflammation and, to a degree, prevent the development of insulin resistance. This was done through a procedure called adoptive bone marrow transfer, which resulted in the knockout of JNK1 in cells derived from the bone marrow, including macrophages.
Scientists are hopeful that further research into blocking the macrophage pathway can pave the way to novel drug development to fight insulin resistance and metabolic disease.
Dr Lancaseter and his team’s research focus is on the association between ceramide accumulation and lipid-induced macrophage activation.
