The cellular mechanisms of obesity-induced inflammation and metabolic dysfunction

Researchers from Pohang University of Science and Technology (POSTECH) has uncovered the mechanisms governing inflammation and metabolic dysfunction in tissues associated with obesity. The significance of this research lies in its identification of TM4SF19, present on inflammatory macrophages, as pivotal in mitigating inflammation and enhancing metabolic function in cases of obesity.

TM4SF19 mechanism regulating inflammatory response within adipose tissue (Credit: POSTECH)

Overconsumption of nutrients prompts the infiltration of diverse types of macrophages into adipose tissue. Among them, certain macrophages play a role in clearing deceased cells and upholding tissue balance while others elicit inflammatory reactions. In patients with obesity, the population of these inflammatory macrophages escalates swiftly, exacerbating issues related to inflammation and metabolic function.

Employing animal trials, single-nucleus RNA sequencing, and intravital imaging techniques, the research team led by Professor Jong Kyoung Kim, from the Department of Life Sciences at POSTECH, and others, scrutinised TM4SF19, a protein specifically present in inflammatory macrophages.

The findings revealed a notable increase in TM4SF19 levels within the adipose tissue of animal subjects subjected to a high-fat diet. Remarkably, the researchers unveiled that this protein inhibits a pump (V-ATPase) present in lysosomes, which harbour various hydrolytic enzymes and play a crucial role in lysosomal pH regulation. Consequently, this impedes the phagocytic process through which macrophages eliminate spent adipocytes.

Conversely, macrophages deficient in TM4SF19 demonstrated significantly enhanced efficacy in clearing deceased adipocytes. This not only deterred weight gain induced by a high-fat diet but also improved metabolic dysfunction by curbing tissue inflammation and insulin resistance.

"We have finally unravelled the mechanism governing TM4SF19 protein's mechanism to regulate lysosomal activity,” said Kim. “Our discoveries may open new avenues for treating obesity and related metabolic disorders."

The findings were reported in the paper, ‘TM4SF19-mediated control of lysosomal activity in macrophages contributes to obesity-induced inflammation and metabolic dysfunction’, published in Nature Communications. To access this paper, please click here