Study Uncovers Why Some Obese Individuals Stay Metabolically Healthy While Others Develop Diabetes and Inflammation

Medical News: A new study by researchers from H+ Yangji Hospital, Soonchunhyang University, and Kyung Hee University Hospital in South Korea has revealed key immune system differences in people with obesity that may explain why some develop serious health problems like type 2 diabetes while others remain relatively healthy.


Study Uncovers Why Some Obese Individuals Stay Metabolically Healthy While Others Develop Diabetes
and Inflammation

Obesity, which now affects nearly one in four people globally, is known to increase the risk of various metabolic diseases. But not all obese individuals suffer the same consequences. A subset of people categorized as having “metabolically healthy obesity” or MHO appear to avoid these issues, while others with “metabolically unhealthy obesity” or MUO develop severe conditions including insulin resistance, hypertension, and cardiovascular problems. The reason for this disparity has long puzzled scientists. Now, this Medical News report sheds new light on how the immune system - and specifically T cells - might be involved.
 
Immune Fingerprints Inside Blood and Fat
In the study, scientists collected blood and omental fat tissue samples from 28 severely obese patients undergoing bariatric surgery. These individuals were grouped into MHO and MUO based on their blood sugar levels, lipid profiles, and other metabolic indicators. Using advanced flow cytometry and high-throughput sequencing techniques, the researchers analyzed both the types of T cells present and the diversity of their T-cell receptors (TCRs), which help the immune system recognize foreign substances.
 
They found that people in the MUO group had a significantly higher proportion of memory-type CD4+ T cells - particularly a subtype called central memory T cells - in both their blood and fat tissue. This shift away from naïve T cells, which are usually inactive and waiting to respond to infections, suggests ongoing immune activity and chronic inflammation in MUO patients.
 
In contrast, the CD8+ T cell levels were higher in the blood of MUO patients but their subtypes remained similar across groups. In fat tissue, however, MUO patients had more CD4+ T cells, while the number of CD8+ T cells stayed consistent.
 
A More Restricted and Skewed Immune Profile in Unhealthy Obesity
One of the most striking findings involved the TCR repertoire - the unique set of T-cell receptor gene sequences that help T cells recognize different threats. In MUO individuals, the diversity of these receptors was significantly reduced in fat tissue, indicating a more narrow and potentially overactive immune response. Specific TCR genes such as TRBV7-9, TRBV18, and TRBV12-4 were amplified in MUO patients, showing signs of clonal expansion - where certain immune cells rapidly multiply in response to perceived threats.
 
Additionally, unique patterns in TCR gene combinations (called V-J pairings) were observed. Some combinations, like TRB V9-J2-2 and V10-3- J1-1, were much more frequent in MUO patients, especially in adipose tissue. These specific TCR patterns may act as biomarkers of metabolic dysfunction.
 
The study also noted differences in the lengths of the CDR3 regions - the most variable part of the TCR that determines what the T cell can recognize. MUO patients tended to have shorter CDR3 regions, which might reflect abnormal immune training or chronic stimulation.
 
The Bigger Picture Behind Inflammation and Metabolic Disease
This research provides powerful evidence that metabolically unhealthy obesity is closely linked to a unique immune profile that includes increased inflammatory memory T cells and a less diverse TCR repertoire. These immune changes likely contribute to the chronic low-grade inflammation seen in diabetes and other obesity-related conditions.
 
In contrast, metabolically healthy obese individuals appear to retain a more balanced and less inflammatory T-cell landscape. Understanding these differences could lead to early detection tools or even immune-based therapies that target the specific T cells driving inflammation in MUO patients.
 
Conclusions
This study offers a detailed and unprecedented view of how the immune system operates differently in people with metabolically healthy versus unhealthy obesity. The identification of specific T-cell types and T-cell receptor patterns unique to MUO individuals not only provides potential biomarkers for disease but also opens up the possibility for precision treatments that target the immune pathways involved in metabolic dysfunction. These findings highlight the need to treat obesity not as a uniform condition but as a spectrum of immune and metabolic states that require tailored interventions.
 
The study findings were published in the peer reviewed: International Journal of Molecular Sciences.
https://www.mdpi.com/1422-0067/26/7/3372
 
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