- People with obesity are at higher risk of developing insulin resistance and type 2 diabetes than those of a healthy weight.
- However, the conditions to develop insulin resistance do not affect everyone with obesity.
- Now, scientists investigating why some remain healthy and others do not have discovered that adipose (fat) tissue may influence cell function.
- Their research, which they conducted in mouse models, suggests that, in some individuals, obesity disrupts the function of macrophages — which clean up cell fragments — leading to inflammation and metabolic disorders.
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People with obesity have a
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Obesity
- high blood pressure
- high LDL (“bad”) cholesterol, low HDL (“good”) cholesterol, and high triglycerides
- sleep apnea and breathing problems
- coronary heart disease
- stroke
- some cancers
- type 2 diabetes.
However, many people with obesity will not develop these conditions, and scientists at the University of Gothenburg, Sweden, may have found a reason why some are more likely to progress to metabolic disorders than others.
Why do only some people with obesity develop diabetes?
In a mouse study, the researchers found that, in some people, adipose tissue disrupts the function of white blood cells called macrophages, preventing them from cleaning up fragments of collagen.
This may lead to inflammation, increasing the likelihood of type 2 diabetes.
The study is published in PNAS.
Sebnem Unluisler, genetic engineer at the London Regenerative Institute, not involved in this research, commented to Medical News Today:
“This study adds to a growing body of evidence highlighting the complex interplay between obesity, adipose tissue dysfunction, and metabolic disease. Understanding the mechanisms underlying these relationships is crucial for developing more effective strategies for preventing and treating conditions like type 2 diabetes.”
High-fat diet leads to collagen breakdown
For this study, the researchers placed 7-week-old mice on a high-fat diet for 1 week, which resulted in a significant gain in adipose tissue compared with control mice fed a regular diet.
In the mice on the high-fat diet, more collagen type 1 was broken down into fragments, and macrophage numbers in the adipose tissue increased. These macrophages cleared the collagen fragments.
However, in high-fat diet-induced obese insulin-resistant male mice, the macrophages were unable to clear the fragments, and instead caused an inflammatory reaction.
The researchers conclude that collagen fragments are not inert metabolites and solely markers of tissue remodeling, but change the microenvironment within the adipose tissue.
Dysfunctional adipose tissue leads to insulin resistance
Prof. Ingrid Wernstedt Asterholm, corresponding author and research leader in the Department of Physiology/Metabolic Physiology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at University of Gothenburg, Sweden, told MNT:
“We are not 100% sure why the macrophages fail to take up fragmented collagen, but our data suggest that too high levels of nutrients drive this. And when these macrophages fail there will be accumulation of fragments in adipose tissue, and we show that such fragments trigger inflammation which may aggravate adipose tissue dysfunction.”
“Dysfunctional adipose tissue cannot effectively store excess nutrients which then leads to deleterious fat deposition in, for example, the liver […] this will then lead to systemic insulin resistance that eventually can cause metabolic disorders such as type-2 diabetes,” she continued.
The researchers saw similar effects in vitro when they treated human macrophages with palmitate, high glucose and high insulin to mimic conditions that lead to obesity.
Prof. Wernstedt Asterholm told us: “We show that human macrophages have similar function and regulation. Our current research focuses on translating our mouse findings to the human setting and it looks promising so far. I would also like to see whether and how this macrophage-collagen-axis plays a role in other tissues such as in the heart.”
Potential for diabetes diagnosis and treatment
“Dysregulation of adipose tissue function, characterized by altered collagen turnover and macrophage activity, has been implicated in the pathogenesis of metabolic diseases. Understanding the specific cellular and molecular mechanisms involved could lead to novel therapeutic strategies for managing these conditions,” Unluisler told us.
Although the researchers behind this study found that isolated human cells reacted in a similar way to mouse cells, Unluisler said that she would like to see further research to confirm that similar adipose dysfunction occurs in people.
“While findings from animal studies can give us valuable insights, we need to be cautious when applying them to humans. Mice and humans have similarities, but also differences that might affect how findings translate. Further research with human subjects is necessary to confirm these results,” she told MNT.
And the researchers are planning more research into both treatment and diagnosis of type 2 diabetes, as Prof. Asterholm noted:
“Hopefully we will identify a macrophage target that can be used for developing better therapeutics..but in a more near future one could imagine that certain collagen fragments from adipose tissue end up in the circulation and thereby can be used as biomarkers to identify individuals that are at higher risk for developing type 2 diabetes.”
So, it is early days, but this study adds to the evidence that obesity may lead to adipose tissue dysfunction and metabolic diseases, and offers an explanation for why this might happen. It could help identify those at greater risk of type 2 diabetes and even help the development of more effective therapies.
