MIST (Metabolic Intervention With Semaglutide and THR-β Therapy) Trial

Inclusion Criteria: 1. Capable of providing written informed consent and complying with all trial procedures. 2. Willing to comply with contraception requirements (as applicable to males and females of childbearing potential). 3. Obese with BMI ≥30 kg/m\^2 and stable body weight within 6 months prior to screening. 4. HbA1c ≤6.5%. 5. Estimated glomerular filtration rate (eGFR) ≥60 mL/min/1.73 m\^2 (per CKD-EPI 2021 formula). 6. If participant consents to enter the imaging substudy, has liver fat content by MRI-PDFF \>8% at baseline (Week 9). Exclusion Criteria: 1. History or current diagnosis of type 1 or type 2 diabetes mellitus. 2. Weight change \>5% of total body weight within 6 months prior to screening or planned initiation of a weight loss program or use of weight-altering medication. 3. Obesity induced by endocrine disorders such as Cushing's syndrome or monogenic or syndromic obesity such as Prader-Willi syndrome. 4. Use of GLP-1 agonist treatment within the last 6 months prior to screening. 5. History or current evidence of a pituitary disorder. 6. Have current treatment with or history (within 3 months prior to screening) of treatment with medications that may cause significant weight gain. 7. ALT or AST \>1.5×ULN, or ALP \>1.5×ULN at screening. 8. Documented evidence or clinical signs/symptoms of advanced liver disease including liver cirrhosis, portal hypertension, or hepatic decompensation. 9. History of significant alcohol consumption for \>3 consecutive months within a year prior to screening. 10. Current or past therapy with THR-β agonists (eg, resmetirom). 11. Active untreated hyperthyroidism or hyperthyroidism currently treated with antithyroid medications including methimazole or propylthiouracil. 12. Clinically significant thyroid dysfunction including uncontrolled hypothyroidism or hyperthyroidism. 13. History of bariatric surgery, fitting of a weight loss device, or intestinal bypass surgery within 5 years prior to screening. 14. History of major surgery within 8 weeks prior to screening. 15. Clinically relevant acute or chronic medical condition or unstable disease of the cardiovascular, gastrointestinal, hepatic, renal, endocrine, pulmonary, neurologic, psychiatric, immune or dermatologic system.