Obesity
Conditions
Keywords
Obesity, Microbiome, High protein diet
Brief summary
The objective of this study is to test and determine whether a high protein diet induces weight loss by modulating the composition and function of the intestinal microbiome in obesity. This will be investigated in a randomized clinical study comparing the effect of isocaloric high and normal protein diets on the intestinal microbiome composition, gene content, and metabolome of obese subjects.
Detailed description
A high protein diet has been shown in preclinical rodent models and clinical trials to be an effective obesity treatment that is associated with greater loss of body weight and fat mass and increased satiety compared to isocaloric standard protein diets. However, the mechanisms of this response have not been fully elucidated. The investigators recently demonstrated in a rodent model that a high protein diet induces shifts in the intestinal microbiome including a bloom of Akkermansia muciniphila, a microbe reported to have an anti-obesity effect. Based on these preliminary studies, the investigators hypothesize that a high protein diet induces alterations in the intestinal microbiome that mediate its clinical efficacy for obesity. More than three quarters of Veterans are overweight or obese, making obesity a public health problem of tremendous importance to the VA medical system. The results of the proposed study will provide insight into the specific microbes that drive the clinical response to a high protein diet and may identify candidate anti-obesity microbes that could be further developed into novel microbial therapeutics. More broadly, establishing a microbiome-dependent mechanism for the efficacy of a dietary intervention would be a breakthrough in the investigators' understanding of obesity treatment. It would pave the way for larger scale clinical and translational studies investigating the role of the microbiota in other diets and for the development of microbial therapeutics used alone or in combination with dietary intervention to treat obese Veterans. To investigate the role of the intestinal microbiome in mediating the effect of a high protein diet, the investigators will study 216 overweight and obese Veterans (BMI 27) who will be randomized 1:1 to isocaloric high protein (30%) or normal protein (15%) 1500 calorie diets for 16 weeks utilizing existing clinical infrastructure at the West Los Angeles VA Medical Center established for a recently completed clinical trial of a high protein diet. In Aim 1, the effect of a high protein diet on the composition and function of the intestinal microbiome will be assessed by 16S rRNA sequencing, shotgun metagenomics, and metabolomics. In Aim 2, bioinformatics analysis will be performed to identify fecal microbes, bacterial genes, and metabolites that are associated with weight loss, reduced body fat, decreased hepatic steatosis, altered lipid profiles, reduced hemoglobin A1c, decreased high sensitivity C-reactive protein, increased satiety, and circulating levels of hormones affecting satiety (leptin, ghrelin glucagon, glucagon-like peptide-1, peptide YY).
Interventions
DIETARY_SUPPLEMENTProtein powder supplement, standard dosage based on 0.5 gram protein per pound of subject's lean body mass
Standard protein diet as control, based on 0.5 gram protein per pound of lean body mass, isocaloric (same number of calories) and consisting of 15% protein and 55% carbohydrate.
DIETARY_SUPPLEMENTProtein powder supplement, High Level Protein, based on 1 gram of protein per pound of lean body mass: 25% protein and 45% carbohydrate
High level of protein diet, based on 1 gram of protein per pound of subject's lean body mass, isocaloric (same number of calories) and consisting of 30% protein and 40% carbohydrate.
Sponsors
VA Office of Research and Development
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
OTHER
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
20 Years to 60 Years
Healthy volunteers
Yes
Inclusion criteria
* Men and women between 20 and 60 years of age, * BMI 27 to 40 kg/m\^2, * non-smoker or stable smoking habits for at least 6 months prior to screening and agreement not to change such habits during the study; * subjects on non-obesity prescription medication may be included.
Exclusion criteria
* Weight change of \>3.0 kg in the month prior to screening, weight loss of \>10 kg in the 6 months prior to screening, * calorie restriction diet (\<1500 kcal/day) for a period of 4 months or more in the 12 months prior to screening, * use of any other investigational drug(s) within 8 weeks prior to screening, * abnormal baseline laboratory parameters (serum creatinine \> 1.6 mg/dl; ALT, AST, total bilirubin \> 2.0 times the upper limit of normal; * triglycerides \> 500 mg/dl, total cholesterol \> 350 mg/dl, TSH outside of normal range), * consumption of more than 1 alcoholic beverage per day, pregnancy or intention to become pregnant.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Weight Loss (% Change) in Response to Dietary Intervention Change | Primary outcome of weight loss is measured by subtracting the baseline weight on Day 1 from the weight at the end of the 16 week study period for each subject, and converting to % of baseline weight. | The primary objective is to compare weight loss between each of the two diets, a high-protein diet versus a standard protein diet. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Steatosis From Baseline as Measured by Fibroscan in Response to Dietary Intervention | Changes in liver steatosis will be measured at baseline and at the end of the 16 week study period for each subject. | Association of change in fat mass on a high protein diet versus standard protein diet will be measured by Fibroscan (CAP score). |
| Change in Liver Fibrosis From Baseline as Measured by Fibroscan in Response to Dietary Intervention | Changes in liver steatosis will be measured at baseline and at the end of the 16 week study period for each subject. | Association of change in hepatic fibrosis on a high protein diet versus standard protein diet will be measured by Fibroscan elastography. |
Countries
United States
Participant flow
Pre-assignment details
106 individuals were consented but only 87 completed the first study visit and were considered to have started the study.
Participants by arm
| Arm | Count |
|---|---|
| Standard Diet Standard protein diet group as control based on 0.5 gram protein per pound of lean body mass with same calories: 15% protein and 55% carbohydrate.
Protein powder supplement, standard dosage based on 0.5 gram protein per pound of subject's lean body mass: Standard protein diet as control, based on 0.5 gram protein per pound of lean body mass, isocaloric (same number of calories) and consisting of 15% protein and 55% carbohydrate. | 40 |
| High Protein Diet High protein diet group based on 1 gram of protein per pound of lean body mass: 30% protein and 40% carbohydrate.
Protein powder supplement, High Level Protein, based on 1 gram of protein per pound of lean body mass: 25% protein and 45% carbohydrate: High level of protein diet, based on 1 gram of protein per pound of subject's lean body mass, isocaloric (same number of calories) and consisting of 30% protein and 40% carbohydrate. | 47 |
| Total | 87 |
Baseline characteristics
| Characteristic | Standard Diet | High Protein Diet | Total |
|---|---|---|---|
| Age, Continuous | 53.9 years STANDARD_DEVIATION 12.4 | 56.2 years STANDARD_DEVIATION 10.4 | 55.1 years STANDARD_DEVIATION 11.4 |
| Race/Ethnicity, Customized African American | 12 Participants | 17 Participants | 29 Participants |
| Race/Ethnicity, Customized Asian | 3 Participants | 1 Participants | 4 Participants |
| Race/Ethnicity, Customized Hispanic | 5 Participants | 13 Participants | 18 Participants |
| Race/Ethnicity, Customized Non-Hispanic White | 20 Participants | 14 Participants | 34 Participants |
| Race/Ethnicity, Customized Other | 0 Participants | 2 Participants | 2 Participants |
| Region of Enrollment United States | 40 Participants | 47 Participants | 87 Participants |
| Sex: Female, Male Female | 11 Participants | 11 Participants | 22 Participants |
| Sex: Female, Male Male | 29 Participants | 36 Participants | 65 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 40 | 0 / 47 |
| other Total, other adverse events | 0 / 40 | 0 / 47 |
| serious Total, serious adverse events | 0 / 40 | 0 / 47 |
Outcome results
Primary
Weight Loss (% Change) in Response to Dietary Intervention Change
The primary objective is to compare weight loss between each of the two diets, a high-protein diet versus a standard protein diet.
Time frame: Primary outcome of weight loss is measured by subtracting the baseline weight on Day 1 from the weight at the end of the 16 week study period for each subject, and converting to % of baseline weight.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Standard Diet | Weight Loss (% Change) in Response to Dietary Intervention Change | -3.83 percentage weight change from baseline | Standard Error 0.75 |
| High Protein Diet | Weight Loss (% Change) in Response to Dietary Intervention Change | -3.89 percentage weight change from baseline | Standard Error 0.74 |
Secondary
Change in Liver Fibrosis From Baseline as Measured by Fibroscan in Response to Dietary Intervention
Association of change in hepatic fibrosis on a high protein diet versus standard protein diet will be measured by Fibroscan elastography.
Time frame: Changes in liver steatosis will be measured at baseline and at the end of the 16 week study period for each subject.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Standard Diet | Change in Liver Fibrosis From Baseline as Measured by Fibroscan in Response to Dietary Intervention | -1.77 kPa | Standard Error 0.71 |
| High Protein Diet | Change in Liver Fibrosis From Baseline as Measured by Fibroscan in Response to Dietary Intervention | -0.07 kPa | Standard Error 0.57 |
Secondary
Change in Steatosis From Baseline as Measured by Fibroscan in Response to Dietary Intervention
Association of change in fat mass on a high protein diet versus standard protein diet will be measured by Fibroscan (CAP score).
Time frame: Changes in liver steatosis will be measured at baseline and at the end of the 16 week study period for each subject.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Standard Diet | Change in Steatosis From Baseline as Measured by Fibroscan in Response to Dietary Intervention | -18.3 dB/m | Standard Error 13.3 |
| High Protein Diet | Change in Steatosis From Baseline as Measured by Fibroscan in Response to Dietary Intervention | 3.5 dB/m | Standard Error 22.1 |