Clinical trial NCT06768827: New Mechanisms of Obesity
Official title: Pathogenic Mechanisms of Obesity and Its Cardiometabolic Complications
Study type: INTERVENTIONAL
Overall status: NOT_YET_RECRUITING
Phase: NA
Conditions: Obesity and Overweight
Insulin Resistance
Obesity and Obesity-related Medical Conditions
Keywords: Obesity
Youth
Insulin Resistance
Intestinal Fermentation
Lead sponsor: Yale University
Sponsor class: OTHER
Collaborators: name: National Institutes of Health (NIH)
First posted: 2025-01-10
Enrollment: 55
Sex: ALL
Minimum age (years): 15
Maximum age (years): 22
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: BASIC_SCIENCE

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.

Eligibility criteria: Inclusion Criteria:

* Age 15 to 22 years
* In puberty (girls and boys: Tanner stage III-V);
* BMI \>85th

Exclusion Criteria:

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

Primary outcomes:
measure: CHANGES IN ADIPOSE TISSUE LIPOLYSIS (ATL)
timeFrame: 6 hours
measure: CHANGES IN GLUCONEOGENESIS
timeFrame: 6 hours
measure: CHANGES IN ADIPOSE TISSUE LIPOLYSIS (ATL)
timeFrame: Baseline and 12 weeks
Secondary outcomes:
measure: CHANGES IN PEPTIDE YY (PYY) concentration
timeFrame: Baseline and 12 weeks
measure: CHANGES IN GHRELIN concentration
timeFrame: Baseline and 12 weeks
Other outcomes:
Locations:
city: New Haven
country: United States
facility: Yale University
state: Connecticut
Study officials:
affiliation: Yale University
name: NICOLA SANTORO, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References: