New Mechanisms of Obesity (NMoO)

January 26, 2026 updated by: Yale University

Pathogenic Mechanisms of Obesity and Its Cardiometabolic Complications

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.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

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 Type

Interventional

Enrollment (Estimated)

55

Phase

  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Locations

  • United States
    • Connecticut
      • New Haven, Connecticut, United States, 06520
        • Recruiting
        • Yale University

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Child
  • Adult

Accepts Healthy Volunteers

No

Description

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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Basic Science
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Remote physical exercise
Other: Lactulose Oral Product
Each arm will undergo a study to induce colonic fermentation through lactulose at the beginning and at the end of the 12 weeks.
Active Comparator: Control physical exercise
Other: Lactulose Oral Product
Each arm will undergo a study to induce colonic fermentation through lactulose at the beginning and at the end of the 12 weeks.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
CHANGES IN ADIPOSE TISSUE LIPOLYSIS (ATL)
Time Frame: 6 hours
Changes in adipose tissue lipolysis occurring after colonic fermentation (stimulated by lactulose) will be compared between youth with obesity and insulin resistance (OIR) and with obesity and without insulin resistance (OIS). Lipolysis will be measured by using change in D5-glycerol concentration.
6 hours
CHANGES IN GLUCONEOGENESIS
Time Frame: 6 hours
Gluconeogenesis (GLC) will be measured using change in deuterium oxide concentration after colonic fermentation due to lactulose ingestion and compared between OIS and OIR.
6 hours
CHANGES IN ADIPOSE TISSUE LIPOLYSIS (ATL)
Time Frame: 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. Lipolysis will be measured by using change in D5-glycerol concentration.
Baseline and 12 weeks

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
CHANGES IN PEPTIDE YY (PYY) concentration
Time Frame: Baseline and 12 weeks
Changes in PYY concentration after lactulose intervention will be compared between OIS and OIR.
Baseline and 12 weeks
CHANGES IN GHRELIN concentration
Time Frame: Baseline and 12 weeks
Changes in GHRELIN concentration after lactulose intervention will be compared between OIS and OIR.
Baseline and 12 weeks

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Yale University

Collaborators

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
National Institutes of Health (NIH)

Investigators

  • Principal Investigator: NICOLA SANTORO, MD, PhD, Yale University

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

November 13, 2025

Primary Completion (Estimated)

March 31, 2030

Study Completion (Estimated)

March 31, 2030

Study Registration Dates

First Submitted

January 6, 2025

First Submitted That Met QC Criteria

January 6, 2025

First Posted (Actual)

January 10, 2025

Study Record Updates

Last Update Posted (Actual)

January 28, 2026

Last Update Submitted That Met QC Criteria

January 26, 2026

Last Verified

January 1, 2026

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 2000038988
  • R01DK140672 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

YES

IPD Plan Description

Published IPD will be shared at the end of the study

IPD Sharing Time Frame

a year after the completion of the study

IPD Sharing Access Criteria

Published IPD will be made available as an appendix to the paper published using the data generated through FigShare or other websites.

IPD Sharing Supporting Information Type

  • ANALYTIC_CODE

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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