New Mechanisms of Obesity

Not Applicable

Not yet recruiting

• Conditions: Obesity and Overweight; Insulin Resistance

• Registration Number: NCT06768827
• Lead Sponsor: Yale University

Brief Summary

Given the pervasiveness of Pediatric Obesity, it is imperative to understand its pathophysiology and develop alternative strategies to reverse this condition. Herein, investigators propose to elucidate the interaction between colonic fermentation and insulin resistance in modulating metabolism in youth with obesity.

Detailed Description

Pediatric obesity is a major health burden affecting millions of children and adolescents as it predisposes to the development of cardio-metabolic diseases early in life, such as insulin resistance, fatty liver disease and type 2 diabetes. Investigators have recently completed a series of studies to understand the relationship between the intestinal microbial activity and human metabolism in youth. It was observed that intestinal fermentation, a process through which fermentable carbohydrates are processed by intestinal bacteria, results in a variety of biological responses aimed at protecting the human body from developing obesity and some of its metabolic complications, such as insulin resistance and ectopic fat accumulation. In particular, investigators observed that intestinal fermentation causes 1- a reduction of plasma free fatty acids (FFA), due to the inhibition of adipose tissue lipolysis (ATL); 2- a marked entero-endocrine response to reduce appetite, characterized by an increase in the production of peptide YY (PYY) and glucagon-like peptide1 (GLP-1) and a reduced production of ghrelin. In addition, investigators observed that some intestinal fermentation responses are impaired in youth with obesity and insulin resistance (OIR). In light of this evidence, the current proposal will address: 1- how adipose tissue lipolysis response to intestinal fermentation is affected by insulin resistance; 2- whether changes in ATL, observed when fermentation occurs, are also associated with a reduction of glycerol derived neo-gluconeogenesis; 3- if physical activity may restore the entero-endocrine and adipose tissue response to intestinal fermentation in youth with insulin resistance. This is the first study to test the effect of insulin resistance on the relationship between intestinal microbial metabolic activity and human metabolism (namely adipose tissue lipolysis, gluconeogenesis and entero-endocrine response). The results obtained will provide fundamental insight into how insulin resistance occurring in youth with obesity affects the metabolic response to fermentable carbohydrates. In fact, despite the large body of literature showing an association between intestinal microbial fermentation and human metabolism, how and whether insulin resistance may modulate this association remains unknown.

Study Timeline

• Status Verified: 2025-01
• Study First Submitted: 2025-01-06
• Study First Submitted QC: 2025-01-06
• Last Update Submitted: 2025-01-06
• Study First Posted: 2025-01-10
• Last Update Posted: 2025-01-10
• Study Start: 2025-09-01
• Primary Completion: 2030-03-31
• Study Completion: 2030-03-31

Recruitment & Eligibility

• Status: NOT_YET_RECRUITING
• Sex: All
• Target Recruitment: 55

Inclusion Criteria

• Age 15 to 22 years, in puberty (girls and boys: Tanner stage III-V); BMI >85th; girls who begin menstruating must have a negative pregnancy test during the study.

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Exclusion Criteria

• Pregnancy; the presence of endocrinopathies (e.g., Cushing syndrome); adolescents with substance abuse; use of medications affecting insulin resistance such as metformin, GLP-1 analogues; high fibers intake (> 30g/day) as assessed by a 3-day food record.

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Primary Outcome Measures

Name	Time	Method
CHANGES IN GLUCONEOGENESIS	6 hours	Gluconeogenesis (GLC) will be measured using deuterium oxide after colonic fermentation due to lactulose ingestion and compared between OIS and OIR.
CHANGES IN ADIPOSE TISSUE LIPOLYSIS (ATL)	Baseline and 12 weeks	Changes in ATL due to colonic fermentation will be measured in two groups of OIR youth. One group will undergo physical activity for 12 weeks and another group will undergo a control intervention.

Secondary Outcome Measures

Name	Time	Method
CHANGES IN PEPTIDE YY (PYY) concentration	Baseline and 12 weeks	Changes in PYY after lactulose intervention will be compared between OIS and OIR.
CHANGES IN GHRELIN concentration	Baseline and 12 weeks	Changes in GHRELIN after lactulose intervention will be compared between OIS and OIR.

Trial Locations

Locations (1)

Yale University; 🇺🇸 New Haven, Connecticut, United States