Obesity, Childhood
Conditions
Brief summary
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.
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.
Interventions
DIETARY_SUPPLEMENTobese 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).
DIETARY_SUPPLEMENTlean 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).
Sponsors
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Yale University
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
15 Years to 21 Years
Healthy volunteers
Yes
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Rate of Appearance of Acetate | Pre lactulose (average values at 2, 2.5, 3 hours) and Post lactulose (average of values at 7, 8, 9 and 10 hours) | 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. |
| Percent of Hepatic de Novo Lipogenesis. | Pre lactulose (average values at 2, 2.5, 3 hours) and Post lactulose (average of values at 7, 8, 9 and 10 hours) | 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. |
| Change in the Rate of Appearance of Acetate | Pre lactulose (average values at 2, 2.5, 3 hours) and Post lactulose (average of values at 7, 8, 9 and 10 hours) | 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). |
Countries
United States
Participant flow
Recruitment details
Children and adolescents between 15 and 25 years of age.
Participants by arm
| Arm | Count |
|---|---|
| Youth With Obesity Obese adolescents with a body mass index (BMI) \>95th percentile. | 19 |
| Lean Youth Lean adolescents with a body mass index (BMI) \<85th percentile. | 19 |
| Total | 38 |
Baseline characteristics
| Characteristic | Youth With Obesity | Lean Youth | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 12 Participants | 16 Participants | 28 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 7 Participants | 3 Participants | 10 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 5 Participants | 1 Participants | 6 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 14 Participants | 18 Participants | 32 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 8 Participants | 0 Participants | 8 Participants |
| Race (NIH/OMB) More than one race | 5 Participants | 2 Participants | 7 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 6 Participants | 17 Participants | 23 Participants |
| Rate of appearance of acetate | 7.40 μmol · kg-1 · min-1 STANDARD_DEVIATION 4.44 | 7.69 μmol · kg-1 · min-1 STANDARD_DEVIATION 7.541 | 7.55 μmol · kg-1 · min-1 STANDARD_DEVIATION 6.097 |
| Sex: Female, Male Female | 11 Participants | 9 Participants | 20 Participants |
| Sex: Female, Male Male | 8 Participants | 10 Participants | 18 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 19 | 0 / 19 |
| other Total, other adverse events | 0 / 19 | 0 / 19 |
| serious Total, serious adverse events | 0 / 19 | 0 / 19 |
Outcome results
Primary
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).
Time frame: Pre lactulose (average values at 2, 2.5, 3 hours) and Post lactulose (average of values at 7, 8, 9 and 10 hours)
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Youth With Obesity | Change in the Rate of Appearance of Acetate | Pre Diet | -2.34 micromol/Kg/minute | Standard Deviation 6.57 |
| Youth With Obesity | Change in the Rate of Appearance of Acetate | Post Diet | -1.59 micromol/Kg/minute | Standard Deviation 7.55 |
| Lean Youth | Change in the Rate of Appearance of Acetate | Pre Diet | 1.63 micromol/Kg/minute | Standard Deviation 1.75 |
| Lean Youth | Change in the Rate of Appearance of Acetate | Post Diet | -0.96 micromol/Kg/minute | Standard Deviation 6.76 |
p-value: 0.399t-test, 2 sided
Primary
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.
Time frame: Pre lactulose (average values at 2, 2.5, 3 hours) and Post lactulose (average of values at 7, 8, 9 and 10 hours)
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Youth With Obesity | Percent of Hepatic de Novo Lipogenesis. | Pre Lactulose | 1.96 Percentage | Standard Error 0.159 |
| Youth With Obesity | Percent of Hepatic de Novo Lipogenesis. | Post Lactulose | 1.97 Percentage | Standard Error 0.192 |
| Lean Youth | Percent of Hepatic de Novo Lipogenesis. | Pre Lactulose | 2.53 Percentage | Standard Error 0.364 |
| Lean Youth | Percent of Hepatic de Novo Lipogenesis. | Post Lactulose | 3.38 Percentage | Standard Error 0.62 |
Primary
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.
Time frame: Pre lactulose (average values at 2, 2.5, 3 hours) and Post lactulose (average of values at 7, 8, 9 and 10 hours)
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Youth With Obesity | Rate of Appearance of Acetate | Pre-lactulose | 7.40 umol/kg/min | Standard Error 1.73 |
| Youth With Obesity | Rate of Appearance of Acetate | Post-lactulose | 9.29 umol/kg/min | Standard Error 1.44 |
| Lean Youth | Rate of Appearance of Acetate | Pre-lactulose | 7.69 umol/kg/min | Standard Error 1.02 |
| Lean Youth | Rate of Appearance of Acetate | Post-lactulose | 14.7 umol/kg/min | Standard Error 2.33 |