Scientists find the cause of inflammation in obesity

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While frequently demonized in popular narratives, fat tissue is an intricate and vital organ, playing pivotal roles in energy storage and hormone production.

Nonetheless, the escalating global prevalence of obesity — a fallout from modern lifestyles — propels a surge in allied conditions like type 2 diabetes and cardiovascular diseases.

Piercing Through the Complexity of Fat Tissue

Diligent researchers, including Lindsey Muir, Ph.D., and Ph.D. candidate Cooper Stansbury from the University of Michigan, are diving deep into the complexity of fat tissue, endeavoring to elucidate its structure and particularly, the inflammation linked with obesity.

Their objective is to decipher the relationship between fat accumulation and adverse health outcomes.

Their research, “A lipid-associated macrophage lineage rewires the spatial landscape of adipose tissue in early obesity,” innovatively employs single-cell gene expression analysis and spatial transcriptomics to reveal previously obscured immune cell types and their interactions within adipose tissue.

Spatial transcriptomics is a revolutionary technology that can map all gene expressions across a thin section of tissue, revealing intricate cellular dialogues and organizations.

In tissues organized into distinct layers, like the brain or spinal cord, identifying cell types and their gene expressions (X, Y, Z) is somewhat straightforward.

However, Muir highlights that studying adipose tissue presents unique challenges due to its cells being uniformly distributed without defined layers.

Linking Obesity, Cell Death, and Inflammation

In obesity, adipocytes (fat cells) expand, eventually hitting a threshold that instigates cell death and subsequent inflammation.

To unravel the conundrum of immune cells within adipose tissue and their spatial relationships amid obesity, the researchers fed mice a high-fat diet for 14 weeks, harvested the fat tissue, and employed single-cell and spatial analyses to gauge the mRNAs in the sample.

A computational technique known as clustering enabled them to categorize cells with similar genetic makeup, revealing surprising insights into the macrophage population within the samples.

Macrophages, immune cells tasked with clearing dead cells and debris, were expected to exhibit subtypes.

However, Muir expressed surprise at “the number that came out that were highly different from each other and coming up at different times and becoming more dominant over time.”

They identified five types, labeled Mac1 to Mac5. While Mac1 was resident in both lean and obese mice, Mac2 and Mac3, marked by their pro-inflammatory genes, peaked after 8 weeks on a high-fat diet.

Strikingly, Mac4 and Mac5, characterized by low pro-inflammatory gene expression, prevailed as the diet stretched to 14 weeks, coinciding with a decrease in pro-inflammatory Mac2 and Mac3 cells.

Challenging Existing Narratives and Looking Forward

Contrary to the prevailing notion that macrophages accumulating in obesity perpetuate an inflammatory state, Muir notes, “Based on these data, there’s a lot more to the story.”

Muir hypothesizes that Mac4 and Mac5 might be lipid-associated macrophages (LAMs) – possibly the body’s mechanism to mitigate inflammation from pro-inflammatory macrophages and perishing adipocytes, as previously suggested in other research.

Utilizing spatial transcriptomics, they identified locations of mRNA in the tissue, and subsequent analyses sought markers, specifically crown-like structures, that are linked with insulin resistance.

These structures, once formed, linger, indicating tissue dysfunction and showcasing gene expression indicative of the presence of Mac4 and Mac5 LAMs.

Muir signifies that forthcoming explorations will delve into the signaling processes and proteins involved in LAM development and associated metabolic disorders, promising deeper insights into the labyrinthine world of adipose tissue, obesity, and inflammation.

In conclusion, this innovative research not only provides new perspectives into our understanding of obesity, macrophage diversity, and adipose tissue inflammation but also paves the way for future studies that might one day unravel the precise molecular mechanisms driving these processes.

This, in turn, could provide new targets for therapeutic interventions in obesity and related metabolic disorders, shining a new light on fat and its multifaceted roles in health and disease.

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The research findings can be found in JCI Insight.

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