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

Abstract

Background: Model animals are valuable resources for dissecting basic aspects of the regulation of obesity and metabolism. The translatability of results relies on understanding comparative aspects of molecular pathophysiology. Several studies have shown that despite the presence of overt obesity and dyslipidemia in the pig key human pathological hepatic findings such as hepatocellular ballooning and abundant steatosis are lacking in the model. Objectives: The aim of this study was 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 of more than 90 metabolically relevant genes was performed in liver, subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) of male minipigs diet fed: standard chow (SD, n = 7); FFC diet (n = 14); FFC diet in streptozotocin-induced diabetic pigs (FFC DIA , n = 8). Moreover, histopathological assessment of SAT and VAT was performed. Results: 12, 4 and 1 genes were highly significantly differentially expressed in liver, SAT and VAT when comparing the FFC and SD groups whereas the corresponding numbers were 15, 2, and 1 when comparing the FFC DIA and SD groups. Although the minipigs in both FFC groups developed sever obesity and dyslipidemia, the insulin-signaling pathways were not affected. Notably, four genes involved in lipid acquisition and removal, were highly deregulated in the liver: PPARG, LPL, CD36 and FABP4. These genes have been reported to play a major role in promoting hepatic steatosis in rodents and humans. Since very little macrophage-associated pro-inflammatory response was detected in the adipose tissues the expansion appears to have no adverse impact on adipose tissue metabolism. Conclusion: The study shows that morbidly obese Göttingen Minipigs are protected against many of the metabolic and hepatic abnormalities associated with obesity due to a remarkable ability to expand the adipose compartments to accommodate excess calories.

Unraveling molecular mechanisms involved in the development of leptin resistance using the pig as a model

“…However, it has also been shown that, in particular, the GM breed is protected against many of the metabolic abnormalities associated with obesity in humans owing to a remarkable ability to expand the adipose compartments to accommodate excess calories, exhibiting a phenotype comparable with the metabolic healthy obese phenotype described in humans (Cirera et al . 2020). Nonetheless, the more relaxed ethical concerns in sampling leptin‐relevant tissues (i.e.…”

Diet-Dependent Changes of the DNA Methylome Using a Göttingen Minipig Model for Obesity

“…Obesity triggers low-grade chronic inflammation which can act as risk factor for obesity-related complications, such as NAFLD (Greenberg and Obin, 2006). However, as described in Schumacher-Petersen et al (2019) and Cirera et al (2020), in spite of the metabolic challenges imposed by the FFC diet, hepatic steatosis and other key human pathological findings characterizing NAFLD are lacking in this GM model. The increased inflammation and impaired lipid and cholesterol metabolism resulting from methylation changes observed in this study may have impact on generation of fibrosis in the liver (Chiang et al, 2011;Ahmed et al, 2012).…”

“…Parameters with Benjamini-Hochberg corrected P-value <0.05 were considered significant. These baseline, metabolic, and morphometric parameters have been described previously (Andreasen et al, 2018;Schumacher-Petersen et al, 2019;Cirera et al, 2020). with minor modifications.…”

“…Specifically, we have worked with the GM breed as an obesity model, providing evidence of a genetic predisposition for an MHO-like phenotype in this breed (Frederiksen et al, 2017 ). We have further shown that GM fed a high fat diet become obese but do not develop hepatic steatosis (Schumacher-Petersen et al, 2019 ), and that severely obese GM have a large capacity for adipose tissue expansion and are protected against many of the metabolic and hepatic abnormalities associated with obesity (Cirera et al, 2020 ). In the present study, we have compared the promoter methylome in liver tissue of GM fed a high fat/fructose/cholesterol (FFC) diet with the promotor methylome of GM fed the FFC diet and reverted to standard chow (FFC/SD), and GM fed standard chow (SD), respectively in order to see a possible influence of diet in gene regulation mechanisms.…”

Atorvastatin impairs liver mitochondrial function in obese Göttingen Minipigs but heart and skeletal muscle are not affected

“…We took advantage of a cohort of Göttingen Minipigs being available in conjunction with a larger study. Selected data, including basic characteristics of the Göttingen Minipigs used in this study, have therefore been published previously elsewhere for other scientific purposes [24][25][26][27][28] . One group of minipigs was induced with obesity through a diet-intervention and a subset of the obese minipigs was superimposed with chronic atorvastatin treatment.…”