The Yucatan minipig model: A new preclinical model of malnutrition in obese patients with acute or chronic diseases.

Background & Aims: Malnutrition can develop in patients with obesity suffering from acute or chronic illness or after obesity surgery, promoting sarcopenic obesity. A better understanding of this pathophysiology and the development of new therapeutics for chronic diseases, that are often complicated with malnutrition and obesity, justify the development of new animal experimental models close to the human physiology. This study aims to characterize the effects of obesity and underfeeding on Yucatan obese minipigs, assessing its validity as a preclinical model for obesity-related malnutrition.

Methods: Sixteen 30-month-old Yucatan minipigs were divided into two groups for 8 weeks: a standard diet group (ST, n = 5) and an obesogenic diet group (OB, n = 11). After 8 weeks, the OB group was further divided into two sub-groups: a standard diet group (OB-ST, n = 5) and a low-calorie/low-protein diet group (OB-LC/LP, n = 6) for 8 weeks. Body composition by CT-Scan and blood parameters were monitored, and trapezius muscle biopsies were collected to analyse signaling pathways involved in protein turnover and energy metabolism.

Results: At W8, OB-ST animals exhibited significantly higher body weight (+37.7%, p = 0.03), muscle mass (+24.9%, p = 0.02), and visceral fat (+192.0%, p = 0.03) compared to ST. Trapezius cross sectional area (CSA) normalized to body weight was lower in OB-ST animals (-15.02%, p = 0.017). At W16, no significant changes were observed in protein turnover markers, although REDD1 increased in OB-ST (96.4%, p = 0.02). After 8 weeks of low-caloric/low protein diet, OB-LC/LP showed decreased body weight (-9.8%, p = 0.03), muscle mass (-6.5%, p = 0.03), and visceral fat (-41.5%, p = 0.03) compared to OB-ST animals. Trapezius fiber CSA significantly decreased in OB-LC/LP (-36.1%, p < 0.0001) and normalized to body weight (-25.4%, p < 0.0001), combined to higher ubiquitinated protein content (+38.3%, p = 0.02).

Conclusion: Our data support that the Yucatan minipig model mimics nutritional and skeletal muscle phenotypes observed in obese patients, with or without protein-energy malnutrition. It also reproduces muscle atrophy observed in chronic diseases or post-obesity surgery, making it a promising preclinical model for obesity-related malnutrition.