Obesity Causes Inflammatory Responses in Fat Tissue

A new study, published in JCI Insight, has uncovered a complex inflammatory response that occurs in fat tissue during obesity progression.

In both adults and children, rates of obesity are increasing in an issue of “epidemic proportions” according to the World Health Organization. The increase in obesity rates is coupled with a corresponding increase in type 2 diabetes and cardiovascular disease cases.

In obesity, adipocytes – cells that store energy in the form of lipids – expand to store excess energy from the diet. When the adipocytes reach capacity, cell death and inflammation can occur.

To understand the link between fat accumulation and poor health outcomes for obese individuals, researchers are exploring how adipose tissue is structured and the mechanisms behind the inflammatory response.

Immune cells in adipose tissue

The researchers behind the new study used single-cell and spatial analyses to understand the different immune cell types in adipose tissue and where they are in relation to each other as obesity progresses.

The team fed mice a high-fat diet for 14 weeks, then collected fat tissue for analysis. Using a clustering computer model, they grouped the cells that had a similar genetic makeup.

From this analysis, they identified five subtypes of macrophages, a type of immune cell involved in clearing dead cells and cellular debris. “We knew going in that macrophages would likely have multiple subtypes… what surprised us were the number that came out that were highly different from each other and coming up at different times and becoming more dominant over time,” Dr. Lindsey Muir, research assistant and professor of Computational Medicine and Bioinformatics at the University of Michigan Medical School and lead author of the study, said.

Changes over time

The five subtypes of macrophage identified in the study have been named Mac1, 2, 3, 4 and 5.

Mac1 was found in adipose tissue in both obese and normal mice, whereas levels of Mac2 and Mac3 cells – which both expressed pro-inflammatory genes – were at their highest after the mice had been fed a high-fat diet for eight weeks.

Once the mice had been on the high-fat diet for 14 weeks, the numbers of Mac4 and Mac5 cells – which were characterized by lower pro-inflammatory gene expression – began to increase and the numbers of Mac2 and Mac3 cells declined.

“The thinking in the field has been that the type of macrophages that accumulate in obesity are promoting an inflammatory state. Based on these data there’s a lot more to the story,” said Muir.

She hypothesized that Mac4 and Mac5 cells are lipid-associated macrophages (LAMs), which are a subset of macrophages primarily found in adipose tissues of obese individuals. Here, they appear to play a protective role to counteract adipocyte growth, inflammation and metabolic dysfunction.

Spatial analysis brings new insights

The team conducted spatial transcriptomics analyses to capture gene expression across a thin section of fat tissue taken from the mice, mapping the locations of mRNA and imaging the tissue just before capturing the mRNA. This enabled the visualization of crown-like structures; macrophages surrounding dying fat cells in a crown-like pattern that indicate adipose tissue dysfunction.

The team identified the macrophages within the crown-like structures as being from the Mac4 and Mac5 subtypes.

The research provides new insights into the cellular makeup and spatial organization of adipose tissue in obesity, but more work is needed to understand the cell signaling processes needed to trigger the development of LAMs, and how they contribute to metabolic disorders.

Reference: Stansbury CM, Dotson GA, Pugh H, Rehemtulla A, Rajapakse I, Muir LA. A lipid-associated macrophage lineage rewires the spatial landscape of adipose tissue in early obesity. JCI Insight. 2023;8(19). doi: 10.1172/jci.insight.171701

This article is a rework of a press release issued by the University of Michigan. Material has been edited for length and content.