Mechanisms of Obesity and Its Metabolic Complications in Youth

The overarching goal of this project is to determine whether the effect of gut microbiota on human metabolism might be mediated by short chain fatty acids (SCFA) and whether the SCFA might modulate lipid metabolism.

Study Overview

• Status: Completed
• Conditions: Obesity, Childhood
• Intervention / Treatment: Dietary supplement: obese carbohydrate diet; Dietary supplement: lean carbohydrate diet

Detailed Description

This would be the first study determining the effect of SCFA synthesis on hepatic de novo lipogenesis and to assess whether and how isocaloric dietary changes (namely low carbohydrates) might modify the composition of the gut microbiota and reduce the synthesis of SCFA during adolescence, a sensitive period for the development of obesity.

• Study Type: Interventional
• Enrollment (Actual): 38
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • Connecticut
    • New Haven, Connecticut, United States, 06520
      • Hospital Research Unit

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 15 years to 21 years (Child, Adult)
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

• Good general health,
• Taking no medication on a chronic basis
• Age 15 to 21 years,
• In puberty (girls and boys: Tanner stage III - V)
• BMI >25th and <85th for lean cohort; BMI >95th for obese cohort
• Girls who begin menstruating must have a negative pregnancy test during the study.

Exclusion criteria:

• Baseline creatinine >1.0 mg
• Food allergies
• Pregnancy
• Presence of endocrinopathies (e.g. Cushing syndrome)
• Significant chronic illness.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: obese carbohydrate diet; Obese adolescents with a body mass index (BMI) >95th percentile.	Dietary supplement: obese carbohydrate diet; The experimental diet will consist of 30% carbohydrates (CHO), 35% protein, and 35% fat. Since the experimental diet is lower in CHO, the fiber and sugar content will be calculated based on total CHO in the same percentage as the control (0.25 g fiber per each kcal of CHO and 18.2% sugar for total CHO).
Active Comparator: lean carbohydrate diet; Lean adolescents with a body mass index (BMI) <85th percentile.	Dietary supplement: lean carbohydrate diet; The control diet composition will follow the American Dietary Guidelines of 55% carbohydrates (CHO), 15% protein, and 30% fat. CHO content will be primarily complex CHO of high quality (14 g fiber/1,000 kcals and <10% of total kcals in the form of sugar).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Rate of Appearance of Acetate	Starting at 08:00, we began a 10-h, primed, continuous, peripheral venous infusion of 99% sodium [d3]-acetate with a priming dose of 200 μg · kg-1 · min-1 for 4 min and a continuous infusion rate of 59.5 μg · kg-1 · min-1 for 10 h. After 180 min from the start of the infusion, subjects received 20 g of lactulose per os, dissolved in 30 mL of water.	Pre lactulose (average values at 2, 2.5, 3 hours) and Post lactulose (average of values at 7, 8, 9 and 10 hours)
Percent of Hepatic de Novo Lipogenesis.	The percent of hepatic de novo lipogenesis (DNL) refers to the proportion of fatty acids in the liver that are derived from a de novo synthesis pathway, rather than from dietary sources.	Pre lactulose (average values at 2, 2.5, 3 hours) and Post lactulose (average of values at 7, 8, 9 and 10 hours)
Change in the Rate of Appearance of Acetate	The changes in rate of appearance of acetate (RaAcetate) are measured averaging the basal RaAcetate 9 timepoints (2 and 3 hours) and the post-lactulose RaAcetate (timepoints 7, 8, 9 and 10 hours).	Pre lactulose (average values at 2, 2.5, 3 hours) and Post lactulose (average of values at 7, 8, 9 and 10 hours)

Collaborators and Investigators

• Sponsor: Yale University
• Collaborators: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
• Investigators: Principal Investigator: Nicola Santoro, Phd,MD, Yale University

Publications and helpful links

General Publications

• Galuppo B, Cline G, Van Name M, Shabanova V, Wagner D, Kien CL, Santoro N. Colonic Fermentation and Acetate Production in Youth with and without Obesity. J Nutr. 2021 Nov 2;151(11):3292-3298. doi: 10.1093/jn/nxab277.
• Monga Kravetz A, Testerman T, Galuppo B, Graf J, Pierpont B, Siebel S, Feinn R, Santoro N. Effect of Gut Microbiota and PNPLA3 rs738409 Variant on Nonalcoholic Fatty Liver Disease (NAFLD) in Obese Youth. J Clin Endocrinol Metab. 2020 Oct 1;105(10):e3575-85. doi: 10.1210/clinem/dgaa382.
• Galuppo B, Umano GR, Li Z, Van Name M, Samuels SL, Kien CL, Cline GW, Wagner DA, Barbieri E, Trico D, Santoro N. Comparison of Metabolic Response to Colonic Fermentation in Lean Youth vs Youth With Obesity. JAMA Netw Open. 2023 May 1;6(5):e2312530. doi: 10.1001/jamanetworkopen.2023.12530.

Study record dates

Study Major Dates

• Study Start (Actual): August 18, 2018
• Primary Completion (Actual): June 30, 2024
• Study Completion (Actual): June 30, 2024

Study Registration Dates

• First Submitted: February 19, 2018
• First Submitted That Met QC Criteria: February 26, 2018
• First Posted (Actual): March 6, 2018

Study Record Updates

• Last Update Posted (Estimated): October 9, 2025
• Last Update Submitted That Met QC Criteria: September 23, 2025
• Last Verified: September 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Nutrition Disorders; Overnutrition; Body Weight; Overweight; Obesity; Pathological Conditions, Signs and Symptoms; Nutritional and Metabolic Diseases; Signs and Symptoms; Pediatric Obesity
• Other Study ID Numbers: 2000022239; 1R01DK114504-01A1 (U.S. NIH Grant/Contract)

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.: Yes