Effects of extensive Weight loss on Insulin resistance and Lipid-kinetics in people with obesity and fatty liver Disease

INTERVENTION: Product Name: Wegovy 2.4 mg FlexTouch solution for injection in pre‐filled pen,Product Code: PRD9862226,Pharmaceutical Form: SOLUTION FOR INJECTION,Other descriptive name: ,Strength: Semaglutide 3.2mg CONDITION: MedDRA version: 20.0Level: PTClassification code: 10029883Term: ObesitySystem Organ Class: 100000004861 MedDRA version: 22.0Level: LLTClassification code: 10029530Term: Non‐alcoholic fatty liverSystem Organ Class: 10019805 MedDRA version: 22.0Level: PTClassification code: 10053219Term: Non‐alcoholic steatohepatitisSystem Organ Class: 100000004871 Obesity, Non‐alcoholic Fatty Liver Disease ; MedDRA version: 20.0Level: PTClassification code: 10029883Term: ObesitySystem Organ Class: 100000004861 ; MedDRA version: 22.0Level: PTClassification code: 10053219Term: Non‐alcoholic steatohepatitisSystem Organ Class: 100000004871 ; MedDRA version: 22.0Level: LLTClassification code: 10029530Term: Non‐alcoholic fatty liverSystem Organ Class: 10019805 Therapeutic area: Diseases [C] ‐ Nutritional and Metabolic Diseases [C18] PRIMARY OUTCOME: Main Objective:We aim to investigate the changes in very low‐density lipoproteins‐ and triglycerides (VLDL‐TG) kinetics before, during, and after extensive weight loss in women diagnosed with both obesity and non‐alcoholic fatty liver disease. Primary end point(s):Changes in VLDL‐TG kinetics 8 months after treatment initiation, when their weight loss has stabilized: I) Changes in relation to the degree of weight loss. II) Changes in relation to the amount of fat in the liver, assessed by MRS/MRI‐PDFF. Secondary Objective:To study the changes in VLDL‐TG kinetics between the two intervention arms during weight loss and 8 months after treatment initiation. SECONDARY OUTCOME: Secondary end point(s):Changes during and 8 months after treatment initiation compared to baseline and between the groups, in respect to: I) Hepatic secretion of VLDL‐TG particles, II) Circulating lipids, III) Insulin resistance, IV) Biochemical markers of inflammation, V) The ratio of neutrophilic granulocytes and lymphocytes, VI) intestinal‐ and saliva microbiota, VII) The Fibrosis‐4 index, VIII) NAFLD fibrosis score and, in the surgical group only, IX) Changes in liver histology and gene expression. INCLUSION CRITERIA: 1. Women who meet the Danish health authorities' criteria for being offered surgical treatment of severe obesity, which are: (i) Body mass inde X(BMI) over 35 and at least one of the following comorbidities: osteoarthritis in the lower extremities, documented sleep apnea, or severe uncontrolled hypertension, or (ii) extreme obesity with BMI over 50., 2. Age above 18., 3. Understands and speaks Danish., 4. Either MRS/MRI‐PDFF with more than 5% steatosis in the liver or a CAP greater than 280 dB/m.