Tirzepatide: Reversal of Lipotoxicity and Adipose Tissue Dysfunction in Humans With Overweight/Obesity

All participants will come to the Stanford University campus for their baseline, week 6, and week 22 (end of study) tests. Prior to starting the assigned intervention, all participants will undergo a supervised (by study dietitian) week of weight maintenance, followed by baseline tests including insulin resistance test (SSPG), Standardized Meal Tolerance Test (for hormone and metabolite profiles), oral glucose tolerance test (OGTT), DXA and MRI scans (to quantify total, regional, and intrahepatic fat), and a subcutaneous periumbilical adipose tissue needle biopsy. Following baseline testing, participants begin tirzepatide vs diet. weight loss will be aggressive for the first six weeks with diet to match the tirzepatide weight loss that is expected. After week 6 weight loss will occur naturally on both without matching. Patients will see the dietitian and coordinator every two weeks to review diet and physical activity, and evaluate tolerability/side effects, and obtain morning weight at Stanford. The metabolic tests, regional fat scans, and biopsy will be repeated at week 6 and week 22.

Inclusion criteria

• nondiabetic as defined by fasting plasma glucose < 126 mg/dL while off all glucose lowering medications
• BMI 27-39.9 kg/m2. Individuals with obesity (BMI 30-39.9 kg/m2) are not required to have an additional risk factor but those who are overweight (27-29.9 kg/m2) must have at least one weight-related factor as follows: hypertension defined as physician-diagnosed and taking antihypertensive medication or SBP> 130 or DBP > 80 mm Hg; dyslipidemia defined as physician diagnosed and taking medication or LDL > 160 mg/dL, TG > 150 mg/dL, HDL < 50 or < 40 mg/dL for women and men, respectively; prediabetes defined as fasting glucose 100-125 mg/dL off all antidiabetic or diabetogenic medications, physician diagnosed obstructive sleep apnea, non-alcoholic fatty liver disease, history of gallstones, and osteoarthritis.
• Age 18-70
• Pre and postmenopausal women will be eligible and details of last menstrual period and/or hormone replacement collected for statistical adjustment and formal testing for effect modification.

Exclusion criteria

• prior bariatric surgery or liposuction
• unstable body weight defined as self-reported weight change >2 kg over the past 6 weeks
• unstable hypertension (defined as BP >160/100 mm Hg)
• major organ disease
• chronic inflammatory conditions
• pregnancy/lactation
• active malignancy undergoing treatment
• use (current or within the past three months) of diabetogenic or weight loss medications, including GLP1 analogs
• active eating or psychiatric disorder
• heavy alcohol use (>2 drinks/day for women and > 3 drinks/day for men) will be excluded