Abstract
Anti-inflammatory therapies have the potential to become an effective treatment for obesity-related diseases. However, the huge gap of immune system between human and rodent leads to limitations of drug discovery. This work aims at constructing a transgenic pig model with higher risk of metabolic diseases and outlining the immune responses at the early stage of metaflammation by transcriptomic strategy. We used CRISPR/Cas9 techniques to targeted knock-in three humanized disease risk genes, GIPRdn, hIAPP and PNPLA3I148M. Transgenic effect increased the risk of metabolic disorders. Triple-transgenic pigs with short-term diet intervention showed early symptoms of type 2 diabetes, including glucose intolerance, pancreatic lipid infiltration, islet hypertrophy, hepatic lobular inflammation and adipose tissue inflammation. Molecular pathways related to CD8+ T cell function were significantly activated in the liver and visceral adipose samples from triple-transgenic pigs, including antigen processing and presentation, T-cell receptor signaling, co-stimulation, cytotoxicity, and cytokine and chemokine secretion. The similar pro-inflammatory signaling in liver and visceral adipose tissue indicated that there might be a potential immune crosstalk between the two tissues. Moreover, genes that functionally related to liver antioxidant activity, mitochondrial function and extracellular matrix showed distinct expression between the two groups, indicating metabolic stress in transgenic pigs’ liver samples. We confirmed that triple-transgenic pigs had high coincidence with human metabolic diseases, especially in the scope of inflammatory signaling at early stage metaflammation. Taken together, this study provides a valuable large animal model for the clinical study of metaflammation and metabolic diseases.
Highlights
Obesity-related diseases such as type 2 diabetes mellitus (T2DM), non-alcoholic fatty liver disease (NAFLD), and atherosclerosis are a cluster of chronic metabolic disorders with multifactorial etiology, involving genetic variation, western diet, and unhealthy lifestyle [1]
Real-time quantitative PCR (RT-qPCR) analysis showed that PNPLA3I148M was highly expressed in the liver; GIPRdn and human islet amyloid polypeptide (hIAPP) were highly expressed in the pancreas of TG pigs, while these target genes were almost absent in wild-type controls (WT) pigs (Figure 1D)
This study reports the basic physiology, histology, and transcriptomic characteristics of PNPLA3I148M-GIPRdn-hIAPP triple-transgenic Bama pigs
Summary
Obesity-related diseases such as type 2 diabetes mellitus (T2DM), non-alcoholic fatty liver disease (NAFLD), and atherosclerosis are a cluster of chronic metabolic disorders with multifactorial etiology, involving genetic variation, western diet, and unhealthy lifestyle [1]. It is well established that the chronic, low-grade inflammation originated from overnutrition, called metaflammation, contributes to the common pathogenesis of obesity-related metabolic diseases [2]. Immune cells in metabolic organs, including adipose, liver, and pancreas may sense the changes of micro-environment and interact with local cells, leading to insulin resistance, fibrosis, islet dysfunction, and disrupted metabolic homeostasis [3]. It has been revealed that inflammation in VAT is the predominant source of global metaflammation and leads to insulin resistance and T2DM [4]. Studies on obesity patients and rodent models suggested that excessive nutrients bring lipotoxicity, mitochondrial dysfunction, endoplasmic reticulum stress and hypoxia in adipose tissue, lead to pro-inflammatory cytokine and chemokine secretion, and trigger inflammation infiltration [5]
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