The focus of this proposal is on overweight (25>BMI<30 kg/m2) subjects, as these individuals exhibit a high risk of becoming obese and/or developing metabolic diseases. We hypothesize that in some overweight individuals there is a "metabolic program" in skeletal muscle which predisposes them to the development of obesity. Findings may lead to clinical screening tools for determining risk for obesity in non-obese individuals and targeting this group for prevention.

Our overall hypothesis is that increased reliance on anaerobic glycolysis in muscle shifts fasting metabolism from fat towards carbohydrate utilization, which results in metabolic inflexibility and subsequent metabolic disease (i.e. obesity). To test our hypothesis, overweight subjects (BMI 25 to 30 kg/m2) will be recruited and screened for reliance on anaerobic glycolysis (resting/fasting plasma lactate concentrations). Subjects with high (top quartile) and low (bottom quartile) resting/fasting plasma lactate will be chosen. The premise of this screening is that subjects with low lactate will have high muscle aerobic substrate oxidation, while those with elevated lactate will have low muscle oxidative metabolism. Severely obese subjects will be studied as a comparator group. In aim 1 in vivo muscle lactate release and respiratory exchange ratio (RER) will be determined to investigate if subjects with high reliance on anaerobic glycolysis exhibit a shift towards carbohydrate utilization at the whole-body level. Aim 2 will test whether subjects with elevated reliance on anaerobic glycolysis in muscle are metabolically inflexible. To establish causality, aim 3 is designed to follow subjects after an intervention that shifts skeletal muscle metabolism from carbohydrate to fat utilization. Our preliminary findings indicate that bariatric surgery normalizes muscle lactate production; therefore, severely obese subjects will be studied before and after gastric bypass surgery (aim 3).

The study (MetFlex) will enroll 74 adults; (Group 1) 60 overweight (BMI 25 to 30 kg/m2) males and females ages 18-50 years old and (Group 2) 14 severely obese (BMI 40 to 50 kg/m2) adult females who are scheduled for bariatric surgery.

Endpoints to be investigated in the 3 specific aims.

Carbohydrate/fat oxidation (RER) in the fasting condition. High lactate vs low lactate groups (aim 1). Pre-surgery vs post-surgery (aim 3)

Muscle oxygen consumption (substrate oxidation) in the fasting condition. High lactate vs low lactate groups (aim 1). Pre-surgery vs post-surgery (aim 3)

Muscle lactate release in the fasting condition. High lactate vs low lactate groups (aim 1). Pre-surgery vs post-surgery (aim 3)

Endogenous glucose production in the fasting condition. High lactate vs low lactate groups (aim 1). Pre-surgery vs post-surgery (aim 3)

Insulin sensitivity (clamp M value). High lactate vs low lactate groups (aim 1)

Change in Carbohydrate/fat oxidation (RER) in response to glucose + insulin (metabolic flexibility). High lactate vs low lactate groups (aim 2)

Change in muscle fat oxidation in response to high fat feeding (metabolic flexibility). High lactate vs low lactate groups (aim 2)

Change in muscle oxygen consumption (substrate oxidation) in response to high fat feeding (metabolic flexibility). High lactate vs low lactate groups (aim 2)

Our basic premise is that elevated fasting plasma lactate causes glucose production to be increased and that a "Vicious Cori cycle" is the underlying cause of the metabolic syndrome.

Inclusion Criteria:

• 18-50 years old
• BMI of 25 - 30 kg/m2
• BMI > 40kg/m2
• Lactate levels in top and lower 25%

Exclusion Criteria:

• Pregnant women
• Mentally disabled
• Prisoners
• Smokers
• Subjects with heart disease
• Type 1 and 2 diabetes
• Endocrine disease
• Hypertension
• Musculoskeletal disease
• Peripheral occlusion
• Hepatic disease
• Have had weight fluctuations exceeding + 3% in the previous 12 months
• On medications which alter carbohydrate metabolism will not be studied

High oxidizers Low oxidizers Obese