Investigating the Metabolic Syndrome

Abstract

The metabolic syndrome (MetS), a cluster of dyslipidemia, hypertension, and diabetes, and an important contributor to cardiovascular morbidity and mortality, occurs in nearly 35% of adults and 50% of the aging population in the United States. However, the underlying mechanisms by which MetS orchestrates and amplifies cardiovascular events remain elusive. Furthermore, traditional therapeutic strategies addressing lifestyle modifications and individual components of MetS are often unsuccessful in decreasing morbidity due to MetS. The availability of an adequate experimental platform that mimics the complexity of MetS may allow development of novel management techniques. Swine models, including domestic pigs and minipigs, have made important contributions to our understanding of many aspects of MetS. Given their similarity to human anatomy and physiology, those models may have significant predictive power for elucidating the pathophysiology of MetS in a manner applicable to humans. Moreover, experimental maneuvers and drugs can be tested in these pre-clinical models before application in patients with MetS. This review highlights the utility of the pig as an animal model for metabolic disorders, which may play a crucial role in novel drug development to optimize management of MetS.

Experimental Metabolic Syndrome Model Associated with Mechanical and Structural Degenerative Changes of the Aortic Valve

“…Pigs have become widely used in cardiovascular research for similarities to human anatomy and physiology 23 . Studies have utilized pigs with MetS to study the effects of HF diet on aortic calcification 10 . The aortic cusp is composed of a fibrosa, spongiosa, and ventricularis layer that are primarily composed of proteoglycans and the fibrous proteins collagen and elastin.…”

“…Pigs (n = 12) were nursed for 28 days and weened into a normal diet for 4 weeks before being transported to the Mayo Clinic facilities. After the initial 7 weeks, 6 pigs were randomly selected and given a HF diet while the remaining 6 pigs continued a normal feeding regimen for 16 weeks 10,12,16,17 . Animals in the control group (n = 6; female) were fed a normal diet consisting of a standard swine feed containing 14.5% protein and 3% fat with 3.3 Kcal/g of feed (Purina Animal Nutrition LLC, Shoreview MN).…”

“…Rodents are commonly used in cardiovascular research, but these models do not capture the vascular anatomy, physiology, or pathology found in humans. A MetS model that is widely utilized for its ability to elucidate the pathophysiology of MetS in humans is domestic pigs 10–12 . Zhang et al .…”

“…Zhang et al . has described this model in greater depth and observed that MetS-induced pigs develop increased abdominal circumference and concentrations of serum insulin and total cholesterol compared to male pigs making it an appropriate model in studying the effects of MetS 10–12 . Studies have postulated that the metabolic stress associated with a high fat (HF) diet leads to the pathogenesis of calcific aortic stenosis and atherosclerosis 13 .…”

Inclusion of endophenotypes in a standard GWAS facilitate a detailed mechanistic understanding of genetic elements that control blood lipid levels

“…In the present study, we investigate the power of including endophenotypes in the analyses instead of increasing sample size. Furthermore, we use the pig, which is an established model for the highly prevalent human diseases involving lipid metabolism (metabolic syndrome, diabetes, obesity, and cardiovascular diseases) 21 – 23 . The pig offers an attractive alternative model to rodents because of their anatomical and physiological similarities to humans and the availability of genomic, transcriptomic, metagenomic, proteomic, and metabolomic tools for analysis of this species 24 .…”