Meta-inflammation and endotoxemia in a highly translational porcine model of diet-induced obesity

Abstract

Meta-inflammation (chronic, low-grade systemic inflammation) is increasingly recognized as an essential link between obesity and the development of various noncommunicable diseases. However, large animal models for studying obesity-related meta-inflammation are lacking. Minipigs have great potential as models for human diseases, warranting investigation of the performance of the Göttingen minipig as a model for obesity-associated meta-inflammation. Here, we fed 26 pigs a high-fat, fructose and cholesterol diet (HFFC) or a standard diet (SD) for 103 days, resulting in the HFFC group having a 45% higher body weight and 16% larger abdominal circumference by the end of the experiment. Meta-inflammation was shown in the HFFC group by elevated serum concentrations of the acute phase protein C-reactive protein for more than 60 days during development of obesity, accompanied by increased numbers of circulating neutrophils and monocytes. Additional obesity-related abnormalities included dyslipidemia, hepatosteatosis and transcriptional changes to genes related to inflammation and metabolism in circulating leukocytes, liver and visceral adipose tissue. Notably, the transcription of genes related to lipid metabolism, namely ATP-binding cassette subfamily A member 1 (ABCA1) and ATP-binding cassette subfamily G member 1 (ABCG1), was elevated in liver, visceral adipose tissue and circulating leukocytes (ABCA1 only) in the HFFC group compared with the SD group. The development of obesity was accompanied by endotoxemia, indicated by a 2.5-fold increase in serum lipopolysaccharide concentration in the HFFC group compared with the SD group, suggesting increased intestinal permeability. In conclusion, the described Göttingen minipig model convincingly links diet-induced obesity, meta-inflammation and endotoxemia, achieved by short-duration HFFC dieting.