The expression signatures in liver and adipose tissue from obese Göttingen Minipigs reveal a predisposition for healthy fat accumulation

Background: Model animals are valuable resources for dissecting basic aspects of obesity and metabolism, but translational relevance requires understanding comparative molecular pathophysiology. Despite overt obesity and dyslipidemia, pigs often lack key human hepatic pathologies such as hepatocellular ballooning and abundant steatosis. Objectives: To elucidate why these histopathological characteristics did not occur in a high fat, fructose and cholesterol (FFC) diet-induced obese Göttingen Minipig model. Methods: High-throughput expression profiling (>90 metabolically relevant genes) was performed in liver, subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) from male minipigs fed standard chow (SD, n=7), FFC diet (n=14), or FFC diet with streptozotocin-induced diabetes (FFCDIA, n=8). Histopathology of SAT and VAT was assessed. Results: In FFC vs SD, 12, 4 and 1 genes were highly significantly differentially expressed in liver, SAT and VAT, respectively; corresponding numbers were 15, 2 and 1 for FFCDIA vs SD. Despite severe obesity and dyslipidemia, insulin-signaling pathways were largely unaffected. Four hepatic genes involved in lipid acquisition/removal (PPARG, LPL, CD36, FABP4) were markedly upregulated. Minimal macrophage-associated pro-inflammatory response was detected in adipose tissues, suggesting expansion without adverse impact on adipose metabolism. Conclusion: Morbidly obese Göttingen Minipigs are protected against many metabolic and hepatic abnormalities associated with obesity due to a remarkable capacity to expand adipose compartments and accommodate excess calories.

Susanna Cirera, Emirhan Taşöz, Mette Juul Jacobsen, Camilla Schumacher-Petersen, Berit Østergaard Christoffersen, Rikke Kaae Kirk, Trine Pagh Ludvigsen, Henning Hvid, Henrik Duelund Pedersen, Lisbeth Høier Olsen, Merete Fredholm