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.

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).

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.