Investigating Obesity-Driven Inflammation in Adolescents

Many of the earliest biological changes that drive disease progression in childhood obesity remain poorly understood. At Cincinnati Children’s, researchers in the Division of Diabetes and Endocrinology are studying how obesity alters communication between organs and immune cells—work that may ultimately help identify which adolescents are at greatest risk for severe metabolic and inflammatory complications.

The Nakamura Lab at Cincinnati Children’s, led by Takahisa Nakamura, PhD, is investigating:

• How obesity changes the RNA cargo inside small extracellular vesicles
• How these signals contribute to chronic low-grade inflammation
• Whether these molecular messengers could eventually serve as biomarkers or therapeutic targets for obesity-related disease

The Inflammatory Impact of Pediatric Obesity

More than 30% of children in the United States are living with overweight or obesity, Nakamura says. While obesity itself doesn’t typically cause immediate illness in childhood, its long-term effects are substantial.

“For children with a BMI at or above the 95th percentile, for example, the risk of cardiovascular mortality later in life is five times higher,” Nakamura says.

Nakamura’s research lab at Cincinnati Children’s focuses on chronic low-grade inflammation, a hallmark of obesity that contributes to insulin resistance, type 2 diabetes, cardiovascular disease, metabolic dysfunction-associated steatotic liver disease (MASLD) and other obesity-related conditions.

“We’re interested in understanding what actually initiates the inflammatory response in obesity,” Nakamura says. “Even after very short exposure to unhealthy diets, we can already observe inflammatory changes.”

Rather than viewing obesity simply as excess adiposity, Nakamura and his team study it as a systemic inflammatory condition that involves complex communication between organs, metabolic tissues and immune cells. Their goal is to understand how cells exchange inflammatory signals.

Cell Communication in Obesity

Historically, researchers studied RNA activity primarily within individual cells. Nakamura and his fellow researchers are instead investigating whether obesity-related molecular changes can spread between tissues through extracellular vesicles.

“These vesicles function almost like biological delivery systems,” Nakamura says. “They carry RNA cargo from one tissue to another, and we believe these signals may influence immune responses and metabolic dysfunction.”

The team is particularly interested in liver-derived extracellular vesicles. In obesity, nutrient excess activates inflammatory pathways within hepatocytes, altering the RNA profile packaged into these vesicles. Once released into circulation, the vesicles may interact with immune cells such as macrophages, potentially triggering inflammatory reprogramming throughout the body.

The work builds on growing evidence that extracellular vesicles play an important role in interorgan communication and metabolic regulation.

Studying Metabolic Changes After Bariatric Surgery

To better understand how extracellular vesicle signaling changes during metabolic improvement, Nakamura’s team collaborated with clinicians to study adolescents undergoing vertical sleeve gastrectomy. From blood sample analysis, researchers identified significant reductions in liver-enriched RNA cargo following surgery, alongside improvements in metabolic markers.

One particularly important finding involved branched-chain amino acids (BCAAs), which are frequently elevated in obesity and type 2 diabetes. The team found that reductions in liver-derived RNA cargo correlated closely with decreases in circulating BCAA levels after surgery.

“That correlation suggested to us that liver-derived extracellular vesicles may actually influence metabolic regulation,” Nakamura says.

The findings also reinforced existing evidence that some benefits of bariatric surgery occur before substantial weight loss alone could explain them.

From Human Correlations to Mechanistic Research

Although human studies revealed strong associations between extracellular vesicle cargo and metabolic improvement, Nakamura says they also highlighted an important limitation: correlation does not establish causation.

To understand how liver-derived vesicles travel and influence recipient tissues, Nakamura and his team developed a preclinical model to track them. Through the model, they can observe which organs and immune cell populations receive vesicle cargo under different metabolic conditions.

“We wanted to move beyond simply observing associations in patient samples,” he says. “With this model, we can investigate mechanisms directly.”

The researchers are now using this system to study how obesity-related nutrient excess alters liver signaling, how extracellular vesicles affect macrophage activation, and how these processes contribute to chronic inflammation and susceptibility to severe infection.

Exploring Biomarkers for Severe Infectious Disease Risk

One of the most clinically promising aspects of the work may involve risk stratification for infectious disease complications in adolescents with obesity, Nakamura says.

While obesity is associated with increased severity of infectious illness, clinicians currently don’t have the tools to predict which patients are most vulnerable.

“That’s where we think these extracellular vesicle signatures may eventually have clinical application,” Nakamura says.

The long-term goal is to identify noninvasive biomarkers—and, potentially, future therapeutic targets—that could help clinicians intervene earlier in high-risk pediatric patients.

Bridging Translational Science and Clinical Collaboration

Nakamura emphasizes that his team’s work depends heavily on collaboration across Cincinnati Children’s, including partnerships with endocrinologists, bariatric surgeons, clinical and basic research teams, and bioinformaticians.

As the field continues to evolve, Nakamura believes extracellular vesicle biology may help reshape how clinicians think about obesity-related disease progression—not simply as a consequence of excess weight, but as a dynamic network of inflammatory communication occurring across multiple organs and immune systems.

“Obesity changes how tissues communicate with each other,” he says. “Understanding those signals may help us identify entirely new ways to predict and treat disease.”

(Published May 2026)

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