Pre-metabolic syndrome transcriptional response of adipose tissue and liver to obesity in the Ossabaw pig model

Background The global rise in obesity prevalence highlights an urgent need to understand its underlying pathophysiology, which ranges from preclinical obesity (excess body fat without overt disease) to clinical obesity with impairment of organ function. To study obesity, we fed obesity-prone Ossabaw pigs a medium cholesterol (0.5 weight %), high-fat (50% of energy) and high-fructose (21% of energy) diet (MC-HFD) for relatively short-term (11 weeks). Morphometric parameters, adipocyte area, and blood biomarkers of metabolic syndrome and inflammation were evaluated. Furthermore, RNA sequencing was adopted to characterize the transcriptome-wide response to this obesogenic challenge and identify key genes and molecular processes affected by the attained obesity state in visceral adipose tissue (VAT) and liver. Results Pigs fed the MC-HFD diet exhibited significant increases in body weight, body size, and adipocyte area compared to the control group. These pigs remained metabolically healthy, with normal C-reactive protein, triglyceride, glucose, and insulin levels, as well as only a minor and insignificant increase in low-density lipoprotein (LDL). In VAT, 666 differentially expressed transcripts (DETs) were identified, while only 40 were found in liver tissue. Notably, FASN was the only transcript that was regulated similarly (significantly downregulated) in both tissues of MC-HFD pigs, suggesting tissue-specific transcriptional signatures. In VAT, transcripts related to oxidative phosphorylation and protein synthesis were upregulated, while inflammation and signaling receptor complex related transcripts were generally downregulated. Compared to VAT, the liver of MC-HFD fed pigs exhibited a greater enrichment in transcripts commonly linked to obesity. Transcripts related to acyl-CoA metabolic processes and protein synthesis were suppressed, while extracellular matrix, signaling receptor activity and regulation of inflammation associated transcripts were upregulated. Conclusions Taken together the data presented here suggest that MC-HFD fed Ossabaw pigs attained a pre-metabolic syndrome state of obesity, i.e. obesity without any other risk factors of the metabolic syndrome, characterized by an ‘obesity tolerant’ transcriptional response in VAT in contrast to the liver response resembling an early canonical obesity response.