People who are obese often have insulin resistance (inability of insulin to properly control blood sugar) and high blood sugar. However, not all people with obesity have this problem. About one-third of people with obesity have normal sugar metabolism (the way your body uses sugar). Similarly, not all people who are lean are also metabolically healthy and a subset of people who are lean are referred to as metabolically abnormal lean (MAL) or metabolically obese lean because they have the abnormalities in glucose metabolism typically associated with obesity. The reasons why some people with obesity have a problem with blood sugar control and others do not are not entirely clear. It is thought that impaired muscle sugar uptake is the main problem related to high blood sugar in people with obesity. However, adipose tissue (fat tissue) also consumes a substantial amount of blood sugar. Therefore, it is unclear whether muscle or adipose tissue (fat tissue) are primarily responsible for altered blood sugar concentrations in persons with metabolically abnormal obesity (MAO) (those with insulin resistance), compared to those with metabolically normal (healthy) obesity (MNO), or whether "healthy" adipose tissue (fat tissue) expansion in MNO people compared with lean people provides a vessel for blood sugar removal that helps maintain normal blood sugar concentration.

Accordingly, the investigators will determine the amount of sugar that is taken up by the body and in the cells of adipose tissue (fat tissue) and muscle by infusing labeled sugar into the blood and looking at its disappearance from blood and appearance in adipose tissue (fat tissue) and muscle. The investigators will also determine how well insulin, a hormone that controls blood sugar, turns on signals that stimulate sugar uptake in fat and muscle cells. These studies will be done after an overnight fast and during an infusion of sugar and insulin (hyperinsulinemic-euglycemic clamp), in sex- and age-matched people who are insulin resistant and insulin sensitive. People with obesity will also be invited to complete a ~10% diet-induced weight loss program and will be studied again after they have achieved the weight loss goal. A group of sex- and age-matched metabolically normal lean participants will serve as control group. An attempt will be made to also study a group of sex- and age-matched metabolically abnormal lean participants.

Inclusion Criteria:

All subjects

• Age: greater than or equal to 18 years but <65 years
• Weight stable (i.e., ±2 kg for at least 3 months)
• Sedentary (less than 1 hour of structured exercise per week)
• No evidence of significant organ system dysfunction or disease (e.g., diabetes, impaired kidney function, cancer, etc.)

In addition, subjects must fulfill all of the following inclusion criteria.

Metabolically Normal Lean

• BMI greater than or equal to 18.5 but <25.0 kg/m2
• Fasting blood glucose: <100 mg/dl
• Blood glucose 2 h after an OGTT: <140 mg/dl
• HbA1c <5.7 %.

Metabolically Normal Obese, likely insulin sensitive

• BMI greater than or equal to 30.0 but <45.0 kg/m2
• Fasting blood glucose: <100 mg/dl
• Fasting insulin: <20 mU/l
• Blood glucose 2 h after an OGTT: <140 mg/dl
• HbA1c <5.7 %.

Metabolically Abnormal Obese, likely insulin resistant

• BMI greater than or equal to 30.0 but <45.0 kg/m2
• Fasting blood glucose ≥100 mg/dl or blood glucose 2 h after an OGTT ≥140 mg/dl or fasting insulin >20 µU/mL or HbA1c >5.7 %.

Metabolically Abnormal Lean

• BMI greater than or equal to 18.5 but <25.0 kg/m2
• Fasting blood glucose ≥100 mg/dl or blood glucose 2 h after an OGTT ≥140 mg/dl or fasting insulin >20 µU/mL or HbA1c >5.7 %.

The investigators plan to study a total of 45 men and women of all races and ethnic groups: 15 MAO (metabolically abnormal obese, likely insulin resistant), 15 MNO (metabolically normal obese, likely insulin sensitive), and 15 lean. All three groups will be balanced with regards to sex and race/ethnicity distribution, and the two obese groups will also be matched on percent total body fat. They will also attempt to recruit 15 metabolically abnormal lean participants.

The investigators do not currently anticipate to share IPD, but will do so upon request.