Location: Obesity and Metabolism Research
Project Number: 2032-10700-003-000-D
Project Type: In-House Appropriated
Start Date: Mar 16, 2024
End Date: Mar 15, 2029
Objective:
The following research project addresses a key unmet need of the USDA Human Nutrition Program, namely to test the metabolic impact of the Dietary Guidelines for Americans (DGA) which has immediate nutrition policy implications. Furthermore, this project aims to identify dietary response phenotypes that may be used to improve dietary-based interventions intended to prevent liver fat accumulation and associated cardiometabolic diseases.To achieve these goals, project scientists have designed an interdisciplinary effort leveraging tools from analytical chemistry, biochemistry, clinical nutrition, endocrinology, exercise biology, genetics, molecular biology, physiology, and psychological/CNS-based assessments - applying cutting edge phenotyping tools alongside complementary basic research experiments.
Objective 1 is: Determine if achieving and maintaining a healthy body weight is the key health promoting recommendation of the Dietary Guidelines for Americans (DGA).
Sub-objective 1.A: Determine if achieving and maintaining a healthy body weight improves cardiometabolic risk in persons at-risk for metabolic disease.
Objective 2 is: Determine if individuals segregated by liver fat levels differ in their responses to meals with different macronutrient composition.
Sub-objective 2.A: Determine, using an acute challenge meal (CM) protocol in Mexican American men and women, the fasting and postprandial responses to a high-fat CM and a low-fat CM.
Sub-objective 2B: Determine if perceived chronic stress and stress system responsiveness partly explain variability among individuals with differing liver fat levels and who differentially respond to meals with different macronutrient composition.
Sub-objective 1C: Determine whether resveratrol-mediated protein kinase A (PKA) activation increases the ABHD5 availability pool in hepatocytes and determine the impact of high sucrose or high fat on the efficacy of resveratrol in preventing hepatocytes from fat accumulation.
Objective 3 is: Determine the metabolomic signatures associated with liver fat levels and their interactions with diet.
Sub-objective 3A: Determine if a Mediterranean style diet as described in the Dietary Guidelines for Americans improves Liver Fat, plasma Trimethylamine-N Oxide, and the plasma metabolomic profile in response to weight loss and liver fat reduction.
Sub-objective 3B: Determine and test the compositional changes of the gut microbiome in response to Mediterranean diet as described in the Dietary Guidelines for Americans and if altering the microbiome improves Liver Fat and plasma Trimethylamine-N Oxide.
Approach:
Objective 1 Hypotheses are: 1A1: Cardiometabolic improvements resulting from the Dietary Guidelines for Americans (DGA)-based diet will be greater in women who are overweight/obese when energy intake is restricted to result in weight loss; 1.A.2: Cardiometabolic benefits of energy restriction will be greater in women consuming a higher quality diet based on the DGA compared to a typical American diet. Objective 2 Hypotheses are: 2A: Individuals’ ability to metabolize consumed calories will be inversely related to liver fat levels, and the preferential metabolism of fat will be associated with higher levels of liver fat.; 2.B.1: Consumption of highly palatable foods from a voluntary snack food buffet will positively associate with higher liver fat, and those participants will also display higher subjective stress and stress-induced cortisol hypo-responsiveness; 2.B.2: Among participants with higher liver fat, participants having greater rates of postprandial carbohydrate-to-fat oxidation (utilization) will be more susceptible to eating highly palatable foods after an acute mental stress challenge.; 2.C.1: Resveratrol increases the availability of Abhydrolase Domain Containing 5 (ABHD5) for Adipose Triglyceride Lipase (ATGL) lipolytic activity, which negates the adverse effect of Patatin-like Phospholipase Domain-containing Protein 3 (PNPLA3) 148M variant on ATGL for triglyceride lipolysis during a high glucose or high fat challenge; 2.C.2: Resveratrol improves triglyceride hydrolysis in hepatocytes of mice overexpressing PNPLA3 148M during a high glucose or high fat diet challenge via increase in the ABHD5 availability pool in hepatocytes; 3.A: A Dietary Guidelines Diet will improve liver fat levels and reduce plasma Trimethylamine N-oxide (TMAO), and shift the plasma metabolome profile in a fashion consistent with greater metabolic health (e.g. reduce branched chain fatty acids). A Randomized Control Trial will be conducted to address hypotheses under Objectives 1 and 3. The study under Objectives 1 and 3 will be an intervention trial with women volunteers randomized to one of three diet groups in a parallel design: 1. participants will consume a DGA-based test diet and maintain energy balance; 2. participants will consume a DGA-based diet, restricted in calories in order to stimulate body weight loss; and 3. participants will consume a diet based on the typical American diet, restricted in calories in order to stimulate body weight loss. For sub-objectives 2A and 2B under Objective 2, an acute challenge meal (CM) protocol in Mexican American men and women with varying degrees of liver fat, will be used to determine fasting and postprandial metabolic responses to a high-fat CM and a low-fat CM. For sub-objective 2C, a series of animal and cellular experiments will be conducted to assess the impact and cellular mechanisms of a polyphenolic compound, resveratrol, on liver metabolism
