Tirzepatide: Reversal of Lipotoxicity and Adipose Tissue Dysfunction in Humans With Overweight/Obesity
brief summary
Obesity, affecting 40% of US adults and costing 173b annually, represents a significant health care burden (1). It is associated with increased risk for multiple chronic diseases including hypertension, type 2 diabetes (T2D), cardiovascular disease, and NAFLD, as well as cancer, osteoarthritis, and obstructive sleep apnea. The investigators plan to test the hypothesis that tirzepatide, a dual GLP/GIP agonist, improves metabolic health (insulin resistance and regional fat distribution and cardiovascular risk profile) not only by inducing weight loss via GLP1-agonism, but also via beneficial cellular and molecular changes in adipose tissue, given that GIP binds receptors in human fat cells. Based on studies in mice showing that GIP alone or tirzepitide treatment decreases inflammation, increases lipid buffering (fat storage in the fat cells instead of releasing it into the bloodstream), and improves glucose homeostasis. The investigators believe that the GIP component of tirzepatide will make fat cells healthier and reverse lipotoxicity, which is one of the mechanisms by which obesity leads to insulin resistance, disordered regional fat distribution, and type 2 diabetes. To date, the effect of dual GLP1 and GIP agonist treatment on adipose tissue has not been evaluated in humans. Given the existing but limited data, dual GIP/GLP-1 agonist treatment in obese humans with metabolic risk factors is an attractive pharmacologic candidate that would lead to both weight loss and healthier fat, potentially offering uniquely powerful synergistic clinical benefits. It is thus of tremendous importance to define the biological effects of dual-agonist treatment on human adipose tissue structure and function, as well as related improvements in regional fat distribution and systemic adipose and muscle insulin sensitivity. In this study, the investigators will randomize overweight (with risk factors) or obese nondiabetic individuals to hypocaloric diet or tirzepatide for 22 weeks with matched weight loss for the first 6 weeks. The investigators will quantify insulin resistance, fat and lean mass, including regional fat distribution, and changes in adipose tissue (needle biopsy from abdominal fat tissue) to see if tirzepatide effects differ from dietary weight loss.
detailed description
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.