Fasting induces significant shifts in substrate utilization with signs of acute insulin resistance (IR), while obesity is associated with chronic IR. Nonetheless, both states substantially influence adipose tissue (AT) function. Therefore, in this interventional study (NCT04260542), we investigated if excessive adiposity in premenopausal women alters insulin sensitivity and AT metabolic and endocrine activity in response to a 60-h fast and a subsequent 48-h refeeding period. Using physiological methods, lipidomics, and AT explants, we showed that obesity partially modified AT endocrine activity and blunted the dynamics of AT insulin resistance in response to the fasting/refeeding challenge compared to that observed in lean women. AT adapted to its own excess by reducing lipolytic activity/free fatty acids (FFA) flux per mass. This adaptation persisted even after a 60-h fast, resulting in lower ketosis in women with obesity. This could be a protective mechanism that limits the lipotoxic effects of FFA; however, it may ultimately impede desirable weight loss induced by caloric restriction in women with obesity.

Centre Hospitalier Universitaire de Toulouse Toulouse France

Department of Hygiene 3rd Faculty of Medicine Charles University Prague Czech Republic

Department of Internal Medicine 3rd Faculty of Medicine Charles University and Královské Vinohrady University Hospital Prague Czech Republic

Department of Movement Sciences Exercise Physiology Research Group KU Leuven Leuven Belgium

Department of Pathophysiology Centre for Research on Nutrition Metabolism and Diabetes 3rd Faculty of Medicine Charles University Prague Czech Republic

Franco Czech Laboratory for Clinical Research on Obesity 3rd Faculty of Medicine Charles University Prague and Université Toulouse 3 Paul Sabatier Toulouse France

Institute for Clinical and Experimental Medicine Prague Czech Republic

Institute of Metabolic and Cardiovascular Diseases I2MC University of Toulouse Inserm Toulouse 3 University Paul Sabatier Toulouse France

Institute Universitaire de France Paris France

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