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ReviewTranslational Physiology

High-fidelity porcine models of metabolic syndrome: a contemporary synthesis

Published Online:08 Apr 2022https://doi.org/10.1152/ajpendo.00413.2021

Abstract

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This review aims to describe and compare porcine models of metabolic syndrome. This syndrome and its associated secondary comorbidities are set to become the greatest challenge to healthcare providers and policy makers in the coming century. However, an incomplete understanding of the pathogenesis has left significant knowledge gaps in terms of efficacious therapeutics. To further our comprehension and, in turn, management of metabolic syndrome, appropriate high-fidelity models of the disease complex are of great importance. In this context, our review aims to assess the most promising porcine models of metabolic syndrome currently available for their similarity to the human phenotype. In addition, we aim to highlight the strengths and shortcomings of each model in an attempt to identify the most appropriate application of each. Although no porcine model perfectly recapitulates the human metabolic syndrome, several pose satisfactory approximations. The Ossabaw miniature swine in particular represents a highly translatable model that develops each of the core parameters of the syndrome with many of the associated secondary comorbidities. Future high-fidelity porcine models of metabolic syndrome need to focus on secondary sequelae replication, which may require extended induction period to reveal.

INTRODUCTION

Metabolic syndrome (MetS) is an interrelated cluster of metabolic dysfunctions and risk factors which arises as a direct result of genetics, environmental exposures, and lifestyle choices. Defining criteria have varied between health organizations, but diagnosis commonly necessitates some degree of truncal obesity, in combination with type 2 diabetes, insulin resistance, dyslipidemia, or hypertension (Fig. 1) (1). We are only now beginning to identify and understand the downstream links with anatomic structural remodeling processes and important secondary comorbidities during MetS, such as hepatic steatosis, periorgan adiposity, heart dysfunction, and end-organ failure. Of the secondary functional changes, perhaps one of the most compelling for the coming decades is the inflammation and subsequent remodeling of cardiac tissue with impaired pump function, which in turn can lead to heart failure and arrhythmia (2).

Figure. 1.

Figure. 1.Metabolic syndrome core components and secondary end-organ sequelae in porcine models. HF-pEF, heart failure with preserved ejection fraction; MetS, metabolic syndrome; NAFLD, nonalcoholic fatty liver disease; NASH, nonalcoholic steatohepatitis; TAG, triacylglycerol. Created using Biorender.com.
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Despite the propensity for expansion of MetS superpathology across global populations, a satisfactory understanding of this relatively complex cardiometabolic disease state is still lacking. Therefore, physicians and consequently, their patients have a dearth of effective therapies available to them which go beyond symptom management. However, given the current global metabolic syndrome trajectory, with exponentially rising obesity rates (3), an ever-expanding elderly population (4) and inadequate preventive therapies for heart failure with preserved ejection fraction (HF-pEF) and atrial fibrillation, these secondary pathologies are likely to quickly become the central scourge of Western healthcare systems for decades to come. To further our understanding and thus provide ensuing therapeutic options for the management of MetS and its associated comorbidities, it is essential that we develop high-fidelity animal models which not only display similar pathophenotype, but respond similarly to known disease state modifiers. Sus scrofa as a species offers an excellent degree of similarity to human physiology. In addition, pigs as omnivores are amenable to different dietary programs, including the “Western”-type diet—rich in carbohydrates, saturated fats, cholesterol and salt—which is central to the instigation of MetS (5). These two characteristics make the species an extremely useful model for metabolic disease research and therapeutic development.

This review aims to present a contemporary update of the studies which have used porcine models of MetS. In addition, we aim to critically appraise and contrast the relative strengths of each in an attempt to create a comprehensive reference material for metabolic researchers seeking to select the model most appropriate to their study design and objectives. Finally, we aim to highlight the advantages of porcine models of MetS and identify their current shortcomings and limitations to guide future development.

METHODS

Search Strategy and Criteria

MEDLINE, SCOPUS, and PUBMED databases were searched using the following keywords: “Swine,” “Pig,” “Porcine,” “Model,” “Metabolic Syndrome,” “Metabolic dysfunction.” To ensure the focus was maintained on the most current data, only studies published following 01 January 2005 were included in this review and the final update search was conducted in June 2021. Review articles were entirely excluded from the initial searches and only English language publications were considered. We intended to include every study in which a group of pigs (population) was treated with a diet, drug, or procedure (intervention) that recapitulated the features of MetS (outcome), when compared with untreated animals or baseline (control). The search strategy limited the results to articles which explicitly indicated that a pig model of MetS was applied or created. However, several models that met the definition of MetS were also included, although they were not explicitly deemed so within their respective reports and, as such, would otherwise not be uncovered by the search approach. Studies that lacked a comparative control or did not report on the core parameters of interest were excluded.

Data Extraction

All studies that were ultimately included in the final review were assessed for animal breed and inducing factors (diet, drugs or procedures), as well as study aims and outcomes. In addition, each study was assessed for presence or absence of primary and secondary features of MetS displayed by the model, including obesity, hypertension, insulin resistance, glucose intolerance, hypercholesterolemia, hypertriglyceridemia, microbiota alterations, intestinal permeability, fatty liver disease, systemic and adipose tissue inflammation, cardiac disease, and neurological disorder. Studies that exclusively focused on atherosclerosis and vascular disease were excluded since these aspects of MetS have been extensively reviewed elsewhere (6–8).

RESULTS

Search Returns

The initial search strategy uncovered 72 studies of relevance in MEDLINE, 243 studies of relevance in SCOPUS, 76 studies of relevance in PUBMED, with 25 additional studies added during unstructured reviewing of the literature and reference lists. After removal of duplicates, the titles and abstracts of 379 studies were screened for suitability, after which 144 articles remained. Finally, 17 more articles were excluded due to model unsuitability, leaving 127 articles describing the use of a porcine model of MetS. Seven of the included articles reported on Bama minipig (9–15), 1 on Chinese miniature pig (16), 21 on the domestic pig (17–37), 2 on Duroc pig (38, 39), 1 on Duroc × Landrace × Yorkshire pig (40), 12 on Göttingen minipig (41–52), 4 on Iberian pig (53–56), 4 on Landrace pig (55, 57–59), 5 on Lee-Sung and Lanyu minipigs (60–64), 3 on Microminipig (65–67), 46 on Ossabaw miniature swine (51, 68–112), 12 on Yorkshire pig (18, 92, 113–123), 4 on Yorkshire × Landrace cross pig (124–127), 6 on Yucatan minipig (90, 128–132), and 1 on Tibetan minipig (133). A summary of the metabolic disease profile of the identified models is presented in Fig. 2. It is of note that this figure does not include the vascular and atherosclerotic consequences of MetS to avoid repetition with other reviews (6). In addition, representative values of MetS core components for each porcine model are provided in Table 1.

Figure 2.

Figure 2.Summary of disease profile of known porcine models of metabolic syndrome. AB-HT, aortic-banding-induced hypertension; BF, body fat; BW, body weight; DOCA-HT, deoxycorticosteroneactetate-induced hypertension; GIT, glucose intolerance; HT, hypertension; IR, insulin resistance; MetS, metabolic syndrome; NASH, nonalcoholic steatohepatitis; RVH, renovascular hypertension; STZ, streptozotocin; TC, total cholesterol; TG, triglycerides; YL, Yorkshire × Landrace. Green, Presence or increase of parameter or disease state. Yellow, Modest or variable finding. Red, Unchanged parameter or absence of disease state. Blank, Not assessed or not reported. *Fig. 2 does not include the vascular and atherosclerotic consequences of MetS to avoid repetition with the content of other reviews (6).
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Table 1. Representative parameters showing the spectrum of known porcine models of metabolic syndrome
Porcine Model of MetS Starting Age Study Duration, wk BW, kg SBP/DBP or MAP, mmHg FBG, mg/dL HOMA-IR TG, mg/dL TC, mg/dL HDL-C, mg/dL References
Livestock breeds
 Domestic na 8 MetS 31 111/54 16 196 40 (28)
Ctl 27 117/57 18 48 30
 Domestic 3 mo 16 MetS 93 146/110 109 1.9 15 372 144 (23)
Ctl 78 126/89 106 0.60 8.4 81 46
 Domestic + RVH 7 wo 16 MetS 87 130/99 154 12 446 136 (18)
Ctl 65 115/82 144 7.0 77 45
 Domestic + RVH na 16 MetS 51 149/115 6.0 425 159 (21, 37)
Ctl 49 125/97 7.5 92 105
 Iberian 2 to 3 yo 14 MetS 252 172/118 117 0.28 28 112 27 (54)
Ctl 208 148/95 113 0.15 21 68 31
 Duroc 9 to 10 wo 10 MetS 60 109 1.56 29 156 61 (38)
Ctl 53 81 1.09 22 126 45
 DLY 8 wo 13 MetS 70 116 42 102 37 (40)
Ctl 72 122 34 89 31
 Landrace + DOCA-HT 3 mo 12 MetS 74 165/97 81 3.3 66 553 209 (57, 58)
Ctl 67 102/58 62 1.0 30 69 38
 Yorkshire 8 wo 12 MetS 75 165 2.6 116 259 52 (123, 122)
Ctl 64 92 1.1 59 43 18
 Yorkshire 8 wo 12 MetS 40* 96 86 495 209 (116)
Ctl 30* 75 92 69 38
 YL + STZ + RVH 2 to 3 mo 26 MetS 79 115 409 0.4 103 650 197 (126)
Ctl 102 90 110 0.3 31 85 43
Miniature breeds
 Ossabaw na 16 MetS 69 128/87 85 6.2 67 486 75 (107, 106)
Ctl 47 111/73 74 3.9 43 87 40
 Ossabaw 5 to 10 mo 24 MetS 86 158/104 88 3.9 130 629 83 (79)
Ctl 57 110/62 78 2.0 24 71 39
 Ossabaw 5 to 6 wo 39 MetS 100 130/99 308 6.3 78 190 56 (100)
Ctl 37 110/72 121 0.91 28 80 41
 Ossabaw 7 mo 54 MetS 111 160/108 83 2.5 39 215 56 (94)
Ctl 64 116/77 67 0.8 25 48 18
 Ossabaw + AB-HT 2 mo 43 MetS 76 124/74 0.92 54 475 (88)
Ctl 46 89/64 0.65 24 75
 Göttingen 11 wo 43 MetS 54 72 112 657 49 (46)
Ctl 24 70 30 73 31
 Göttingen 6 to 7 mo 56 MetS 78 67 1.1 56 462 (43)
Ctl 39 62 0.47 30 66
 Göttingen 11 to 13 mo 70 MetS 115 70 5.5 35 90 (42)
Ctl 45 68 2 35 85
 Göttingen + DOCA-HT 14 mo 20 MetS 46 167/106 55 1.5 350 250 (47)
Ctl 32 95/69 50 1.2 75 25
 Lee-Sung 5 mo 26 MetS 70 150/85 80 45 100 65 (61)
Ctl 30 120/65 70 25 60 35
 Lee-Sung 2 yo 52 MetS 153 72 1.6 81 70 41 (60)
Ctl 98 65 0.2 17 70 30
 Microminipig 3 to 4 mo 60 MetS 58 146/na 130 9 232 59 (65)
Ctl 25 114/na 65 12 63 42
 Bama na 26 MetS 45 293 12 855 189 (9)
Ctl 30 89 2.4 134 65
 Bama 8 mo 26 MetS 58 100 5.9 70 145 87 (14)
Ctl 35 74 1.8 22 77 32
 Bama 6 mo 100 MetS 140 90 5.6 152 132 38 (10)
Ctl 51 119 1.5 39 46 10
 Yucatan 5 mo 26 MetS 79 108/52 51 0.70 43 95 (129)
Ctl 36 99/55 42 0.20 24 69
 Tibetan 3 mo 24 MetS 49 180/127 98 5.7 25 407 121 (133)
Ctl 33 127/90 84 3.7 24 96 34

AB-HT, aortic-banding-induced hypertension; BW, body weight; ctl, control group; DBP, diastolic blood pressure; DLY, duroc × landrace × yorkshire; DOCA-HT, deoxycorticosteroneactetate-induced hypertension; FBG, fasting blood glucose; HDL-C, high-density lipoprotein cholesterol; HOMA-IR, homeostatic model assessment for insulin resistance; MAP, mean arterial pressur; MetS, metabolic syndrome group; mo, months old; na, not assessed or not reported; RVH, renovascular hypertension; SBP, systolic blood pressure; STZ, streptozotocin; TC, total cholesterol; TG, triglycerides; wo, weeks old; YL, yorkshire × landrace; yo, years old.

*Body mass index (kg/m3).

Domestic Pig

Domestic pigs are large breeds mostly used as livestock. Although readily available and affordable, they present the disadvantage of rapidly increasing in size, thus complicating husbandry and handling over long-term interventions. It is of note that the designation “domestic pig” encompasses a large variety of breeds and crossbreeds that can differ in their anatomy and growth rate (134). Consequently, the domestic pig may suffer from poor standardization due to its ambiguous denomination.

The domestic pig exhibited all core features of MetS within 16 wk of “Western” diet intervention (25, 28, 33). This model developed moderate obesity, with 3-mo-old individuals reaching ∼90 kg of body weight after 16 wk of high-fat-fructose diet, and 70 kg when fed a standard diet. The high-fat-fructose diet intervention also consistently induced hypertension, insulin resistance, hypertriglyceridemia and hypercholesterolemia, as well as high high-density lipoprotein-cholesterol (HDL-C) levels. Interestingly, certain high-fat-cholesterol diets failed to induce obesity and hypertriglyceridemia to any convincing degree (17, 37). Finally, it is noteworthy that domestic pigs did not develop MetS over excessively short studies. Indeed, Shimabukuro et al. reported that an 8-wk long intervention solely produced hypercholesterolemia without evidence of concomitant hypertriglyceridemia, hypertension, or obesity in this model (28).

Although suffering from hypertension, high-fat-fructose diet-fed domestic pigs did not develop cardiac hypertrophy or contractile dysfunction (25, 28, 35). Authors only reported slight alterations of cardiac markers of metabolic and immune function (25, 28). These markers may nonetheless constitute useful tools for guiding disease diagnosis before the appearance of marked MetS comorbidities. Remarkably, the induction of renovascular hypertension (RVH) along with “Western” diet consistently produced cardiac structural changes with myocardial hypertrophy, fibrosis, inflammation, and impaired left ventricle (LV) function similar to those observed in patients suffering from HF-pEF within 16 wk of intervention (17, 18, 22, 37). Interestingly, RVH models had blood pressure parameters similar to diet-induced models at study termination, suggesting that the combination of RVH and “Western diet” did not aggravate hypertension. Therefore, the cardiac sequelae observed in these models may be attributable to an earlier induction of hypertension rather than a more severe phenotype. Finally, domestic pig fed high-fat-cholesterol or high-fat-fructose diet with renal artery coiling or stenosis accurately recapitulated the clinical features of renovascular disease (17, 32, 33).

The domestic pig stands out as a robust model of MetS with substantial cardiac remodeling upon surgically induced RVH. It is of note that dietary interventions alone did not produce marked secondary cardiac comorbidities, with a notable absence of myocardial hypertrophy, potentially due to time limitations inherent in the use of large porcine breeds. Finally, it is also important to consider that, due to their fast growth rate, such breeds as the domestic pig are generally studied over juvenile stages of development, a phenotype that differs from adult animals (135).

Iberian Pig

The Iberian pig is a breed of leptin-resistant animals reared in central and southern Spain which is predisposed to the development of intramuscular adiposity, obesity, and insulin resistance when maintained on a “Western”-type diet (55). Investigators should be aware of the large adult size of such animals, with lean Iberian pigs growing up to 200 kg within 2 yr, and typically exceeding 250 kg when fed a diet enriched in saturated fats (54). The Iberian model also develops spontaneous hypertension as a consequence of leptin resistance (136), with standard diet-fed animals presenting systolic and diastolic blood pressure of ∼150 and 95 mmHg, respectively. Remarkably, in a study conducted by Torres-Rovira et al. (54), Iberian pigs fed a diet rich in saturated fat developed MetS in only 3 mo, which is relatively short when compared with other models. In this study, animals had ad libitum access to food, which may have accelerated development of MetS. However, unrestricted food intake may also result in poor model reproducibility with increased inter-individual variability. Recently, Rodriguez et al. (53) characterized further the model by demonstrating secondary glomerular changes that were associated with the development of a “diabetoid” phenotype after 100 days of “high-fat diet”. Using the same breed, Hernandez et al. sought to develop a model of MetS with nonalcoholic steatohepatitis (NASH) in juvenile Iberian pigs fed a high-fat-fructose diet. Although NASH was successfully reproduced, the model failed to replicate certain core features of MetS including obesity and insulin resistance (56). This may have been caused by an excessively short study duration (10 wk) and the use of a piglet model (13 days old). In spite of this, authors demonstrated that the intervention resulted in robust alterations in gut microbiota, intestinal mucosa structure, and bile acid metabolism that may have initiated NASH and preceded the clinical manifestation of MetS (56).

Although the Iberian pig appears to be well suited to MetS research, previous studies on this model have produced conflicting results. Moreover, studies using this model remain scarce, which may be in part explained by the inherent commercial value of the Iberian pig (i.e., Jamón ibérico).

Landrace and Yorkshire Swine

The Landrace pig was originally bred in Denmark in the first half of the 20th century. The breed results from a cross between the Large White and the Danish native pig. The original Danish Landrace pig has been subsequently exported and crossed again, giving rise to diverse Landrace breeds (137). The Landrace swine has been selectively bred for intensive meat production and now represents one of the largest porcine models used in preclinical research. Landrace piglets gain over 100 kg in their first 6 mo; females reach ∼250 kg at maturity, whereas their male counterparts can weigh up to 320 kg. Landrace swine quickly develops organs with dimensions comparable to humans; however, an excessive body size complicates husbandry, pharmacological dosing, and experimental procedures. Consequently, the Landrace swine is generally studied during juvenile stages of development and over short periods. Finally, Landrace breed affordability represents a considerable asset in developing large animal models for preclinical research (137, 138).

Landrace swine fed a diet enriched in fat, salt, cholesterol, cholate, and sugar with mineralocorticoid (deoxycorticosterone acetate, DOCA)-induced hypertension developed MetS with HF-pEF within 12 wk of intervention. In this model, Schwarzl et al. (57) reported hypertriglyceridemia and hypercholesterolemia with secondary organ comorbidities including glomerular alterations and kidney fibrosis as well as cardiac hypertrophy and contractile dysfunction that were similar to that observed in the human HF-pEF. Interestingly, authors provided insights into the cardiovascular pathology by reporting a shift in titin isoforms that were indicative of myocardial stiffening. Our group furthered the characterization of this model for MetS core and secondary parameters by reporting glucose intolerance, insulin resistance, gut microbiota alteration, systemic inflammation, altered bile acid metabolism, and hepatic steatosis upon an identical intervention (58). Finally, Zhang et al. (59) induced HF-pEF by combining a “Western” diet with DOCA and angiotensin II-induced hypertension that resulted in marked cardiac hypertrophy and fibrosis as early as 9 wk after intervention. Authors also demonstrated that dapagliflozin, a sodium-glucose co-transporter 2 inhibitor, exerted a protective effect against MetS and HF-pEF, which supports the strength of the Landrace swine as a preclinical model.

The Yorkshire swine is one of the most common large commercial breeds in the world and is generally recognized for its lean mass and backfat development. Although this breed has found utility in studies concerned with vascular pathophysiology (115, 116, 123, 139), it has not been frequently employed in MetS studies. In fact, streptozotocin challenge was found to be necessary to induce true dysfunction in glucose metabolism for these animals in several studies (124, 125). Nonetheless, the Yorkshire breed may represent an affordable model with high relevance for MetS research since it effectively reproduced features of MetS organ sequelae with cardiac steatosis, fibrosis, inflammation, apoptosis and LV dysfunction; as well as hepatic steatosis upon a high-cholesterol diet (113, 115, 116). It is of note that the Yorkshire × Landrace crossbreed also represents a robust model of MetS secondary outcome with successful reproduction of microbiota alteration (127) and hepatic steatosis (125). Sorop et al. set out to develop a Yorkshire × Landrace model of MetS with secondary sequelae induced by streptozotocin injection, RVH, and high-fat-sugar-cholesterol diet. This model developed cardiac fibrosis, cardiomyocyte atrophy, and impaired LV contractile function after 6 mo of intervention (126).

The Landrace and Yorkshire livestock breeds represent useful models for studying MetS in larger, naturally leaner animals. Indeed, they have the notable advantage of being readily available in large numbers and can achieve most biochemical aspects of the MetS in a matter of months. The Landrace breed stands out as a more robust model, with already characterized secondary outcomes including microbiota, hepatic, and cardiovascular sequelae. Particularly, the combination of “Western” diet and DOCA repetitively demonstrated its reliability in inducing MetS with HF-pEF in this breed.

Ossabaw Minipig

The Ossabaw minipig is a small-sized animal that reaches 40 kg at sexual maturity. The breed is described in the literature as displaying a “thrifty” phenotype, with the ability to extract high proportions of energy from its diet and accrue fat mass with great efficiency (92). This animal was transferred from Spain to Ossabaw Island in Georgia, USA, as a future food source for the 16th century explorers. In the year 2000, in an attempt to protect the native loggerhead turtle population, the US Government ordered the eradication of Ossabaw breed from the island. Recognizing the potential value of such a pig in advancing MetS research, Dr. Michael Sturek of Indiana University School of Medicine led an expedition to capture and export 26 disease-free feral animals, with a view to setting up a breeding colony on the mainland (140). In an attempt to unravel Ossabaw’s phenotype, genetic investigation revealed a single amino acid mutation, Val199 to Ile, in the regulatory γ3 subunit of the AMP-activated kinase gene. This mutation is associated with reduced muscle glycogen and an increased level of intramuscular adiposity; two traits that are consistent with the Ossabaw “thrifty” phenotype and potentially key to its metabolic dysfunction (141). Finally, this “thrifty” phenotype closely resembles human physiology, which strengthens the relevance of the Ossabaw model for translational studies (142).

When maintained on a high-fat-fructose diet for 6 to 9 mo, the Ossabaw miniature swine developed every core feature of MetS (79, 94, 100, 106, 107). This model exhibited severe obesity and researchers reported that animals exceeded 100 kg over long-term interventions (94). In addition, Panasevich et al. (97, 102) demonstrated that a high-fat-fructose diet intervention induced intestinal permeability and alterations in gut microbe populations that were associated with immune system regulation and metabolic function. The Ossabaw minipig also stands out as a powerful model for cardiovascular research. Indeed, Olver et al. accurately recapitulated MetS-induced cardiovascular disease in Ossabaw miniature swine by inducing clinical features of HF-pEF using aortic banding on top of a high-fat-fructose diet over 16 mo (88). In this model, authors also investigated the pathological processes involved in right ventricular remodeling using transcriptomic analysis (109). Interestingly, Lee et al. (79, 83) compared the effects of three “Western” diets on MetS and NASH development in the Ossabaw model. These “fructose,” “atherogenic,” and “modified-atherogenic” diets were isocaloric and mainly differed in their sources of fat and carbohydrates. The “fructose” diet contained 72% carbohydrates and 10.5% fat, whereas the two “atherogenic” diets contained ∼40% carbohydrates and 45% fat. However, the “modified-atherogenic” diet was supplemented with coconut oil and lard on top of hydrogenated soybean oil. “Fructose” diet-fed animals only developed obesity and insulin resistance, whereas their “atherogenic” diet-fed counterparts accurately replicated MetS. Interestingly, the “modified-atherogenic” diet resulted in accentuated hypertriglyceridemia, hypercholesterolemia and resulted in soaring serum leptin and tumor necrosis factor-α levels. Finally, this “modified-atherogenic” diet also induced the full spectrum of NASH diagnosis criteria, whereas animals fed the “fructose” or “atherogenic” diet alone did not develop any of these disease features (83). These data highlight the importance of the source of dietary components when modeling MetS and NASH in the Ossabaw model. Differences between Ossabaw MetS models were also noticed when investigating adipose tissue (AT) inflammation. Vieira-Potter et al. (100) reported that Ossabaw miniature swine subjected to a “Western” diet over 9 mo developed MetS in absence of systemic and AT inflammation compared with low-fat diet-fed animals. Authors postulated that visceral AT inflammation was not an essential component of MetS pathophysiology in their Ossabaw model, potentially due to the breed’s “thrifty” phenotype that enabled AT expansion without inflammation. Supporting this concept, Uceda et al. (96) reported increased pericardial AT deposition in the absence inflammation following 26 wk of ad libitum high-fat-fructose diet. However, several independent studies conducted on the Ossabaw model have induced systemic and AT inflammation upon varied “Western” diets (83, 95, 99). These conflicting results imply that study parameters are critical for accurately reproducing the inflammatory aspect of MetS in Ossabaw miniature swine. The precise elements that dictate the development of systemic inflammation in this breed remain to be identified for improved model fidelity.

The Ossabaw minipig stands out as the most explored and characterized porcine model of MetS, with high relevance to human pathology. The robustness of this model is also supported by numerous interventional studies that have explored varied secondary comorbidities of MetS. Moreover, a recent study has produced a high-quality assembly of the Ossabaw genome, which will greatly facilitate gene-targeted experimentation in porcine models (142). However, the prolonged period of dietary intervention and the genetic background required for this model may increase studies cost and thereby limit the number of trials that can be conducted.

Göttingen Minipig

The Göttingen minipig was first explored as a potential model of MetS in 2001, when Johansen et al. (45) induced obesity and dyslipidemia, without any appreciable effect on insulin sensitivity, through a 5-wk long high-fat, high-energy diet intervention. More recent efforts to build upon this model by Christoffersen et al. (41) explored the relationship between sex and the development of MetS. The study showed that female Göttingen minipigs were prone to a more complete phenotype than their male counterparts, displaying increased adiposity, hypercholesterolemia, hypertriglyceridemia and, crucially, insulin resistance. The authors postulated that this may be explained by the fact that male Göttingen minipigs maintain a disproportionately high level of circulating testosterone and estradiol when compared with the females of the same breed, which may protect them from MetS. Further studies demonstrated that male and female Göttingen minipigs eventually develop insulin resistance after a 13 to 16 mo-long high-fat-fructose-cholesterol or high-fat, high-energy diet (42, 43, 46), suggesting again that the progression of MetS is slow when induced by a dietary intervention alone.

Van den Dorpel et al. (49) overcame this limitation by combining high-fat-cholesterol diet intervention with streptozotocin-induced β-cell toxicity that resulted in deregulated glucose and lipid metabolism with cardiac diastolic dysfunction as early as 3 mo after intervention. It is also of note that Göttingen minipigs developed remarkably severe obesity upon high-fat fructose cholesterol diet, with animals weighing up to 80 kg after 56 wk of intervention, whereas their standard diet-fed counterparts did not exceed 40 kg (43). More recently, Sharp et al. induced MetS with HF-pEF in Göttingen minipigs fed a high-fat-fructose-cholesterol diet with DOCA-induced hypertension. Whereas the model suffered from an excessive mineralocorticoid dosage, it effectively developed MetS core components with peripheral organ co-morbidities including clinical features of HF-pEF within 20 wk of intervention (47). Although the Göttingen model of MetS stands out as a suitable model for cardiovascular research, it hardly reproduces the hepatic sequelae of MetS. Indeed, although resulting in marked obesity and dyslipidemia, a 1-yr long high-fat-fructose-cholesterol diet intervention did not produce any observable NASH feature in this model (43). Finally, Renner et al. (42) reported that the Göttingen model fed a high-fat, high-energy diet for 70 wk exhibited visceral fat inflammation with fibrotic and necrotic lesions. Authors postulated that adipose tissue inflammation may have promoted insulin resistance in these animals.

The Göttingen minipig, and especially the female of this breed, may represent a particularly useful model for cardiovascular research in obesity and MetS. The relatively small size of this animal facilitates husbandry and pharmacological studies while allowing the use of human-scale imaging and therapeutics for cardiovascular disease.

Lee-Sung and Lanyu Minipigs

The Taiwanese Lee-Sung miniature breed is a Lee × Landrace cross, which grows to roughly the weight of an adult human in just over one-and-a-half year (143). The Lanyu minipig breed is a genetically distinct pig population which was discovered on the Lanyu Islet, off the coast of Taiwan (144). When given an “atherogenic” diet, the Lanyu presented a metabolically healthy obese phenotype, with increased body weight and adiposity but normal lipidemia and glycaemia (61), suggesting that the model might be best applied to diabetes research. On the other hand, the “atherogenic” diet-fed Lee-Sung minipig model accurately reproduced MetS with remarkably severe obesity after 6 mo of feeding. In the study performed by Li et al. (61), Lee-Sung minipigs fed a “Western” diet developed insulin resistance only after 6 mo of intervention, whereas hyperglycemia was detectable as early as 3 mo. In addition, this model developed hepatosteatosis with tissue fibrosis and inflammation, as well as myocardial hypertrophy, fibrosis, and steatosis (60–62, 64).

Whereas the Lanyu minipig does not develop MetS, the Lee-Sung breed fed an “atherogenic” diet accurately reproduces every central feature of the disease along with hepatic and cardiac pathological changes.

Bama Minipig

Originating from Southern China, the Bama is a miniature pig purposely bred for meeting the needs of biomedical research (145). The Bama minipig is highly inbred, inexpensive, and maintains a small size at maturity with an average weight of 40 to 50 kg when maintained on a standard diet (10, 146). In addition, the Bama is a model of choice for infectious diseases and pharmacological studies (147). However, the application of Bama minipigs is limited on an international stage since it is a breed local to China and rarely found beyond borders of the country.

The Bama minipig fed a high-fat-fructose diet developed most core features of MetS with consistent induction of hypertriglyceridemia, hypercholesterolemia, and glucose intolerance (9, 10, 14). However, no evidence of hypertension has been reported in this model and, although Chen et al. (148) described the Bama breed as susceptible to developing type 2 diabetes, reports of hyperglycemia in this model remain contradictory (9, 10, 14). This miniature breed can reach 50 kg after 6 mo of high-fat-fructose diet and up to 140 kg after 2.5 yr of intervention (10). In addition, Xia et al. (10) reported that a 23-mo-long high-fat-fructose diet induced hepatic steatosis and inflammation. In the same model, authors reported cardiac sequelae with myocardial hypertrophy and steatosis as well as transcriptomic alterations in metabolic, apoptosis, and inflammatory signaling-related pathways (11). These results suggest that the Bama minipig may be a relevant translational model for NASH and cardiovascular research. Finally, this model also developed renal injury with lipid deposition, cellular apoptosis, tissue inflammation, and glomerular hypertrophy (15).

To date only mid- to long-term studies have been conducted on the Bama model, with durations ranging from 6 to 23 mo. Nonetheless, Zhu et al. (9) reported marked dyslipidemia, hyperglycemia, and hyperinsulinemia as early as 3 mo of high-fat-sucrose diet. Therefore, mid-term studies may produce satisfactory reproduction of MetS in the Bama model.

The Bama minipig stands out as a standardized and affordable breed of convenient size that emulates MetS core components and several of its secondary comorbidities, including nonalcoholic fatty liver disease and cardiac remodeling upon a “Western” diet.

Yucatan Minipig

The Yucatan minipig was imported from the Mexican peninsula of the same name in the 1960s (149). This hairless breed found use as an experimental model primarily due to its docile temperament and substantial tolerance to human handling and restraint. In a direct comparison with the Ossabaw miniature swine model, the Yucatan swine displayed a less severe phenotype with lower blood pressure, reduced body fat accumulation as well as more moderate glucose intolerance and insulin resistance (90). In spite of this, Huang et al. (129, 130) demonstrated the potential of Yucatan animals as a model of MetS, using a high-fat-fructose diet to induce hypertriglyceridemia, hypercholesterolemia, and insulin resistance and investigate contractile recovery after myocardial ischemia. However, this model developed only moderate hypertension with elevated systolic but unchanged diastolic blood pressure. Naturally, this high-fat-fructose diet-fed model did not exhibit severe myocardial sequelae, but instead only modest LV hypertrophy and unchanged contractile function. These results suggest that the diet-induced Yucatan MetS model poorly reproduces the cardiovascular consequences of MetS. Marshall et al. (132) demonstrated that this model can be improved by artificially inducing MetS components such as hypertension when they replicated HF-pEF in aortic-banded Yucatan minipigs. Interestingly, LV hypertrophy was detectable in this model as early as 2 mo after banding. More recently, Curtasu et al. (128) performed a comparison between ad libitum and restricted feeding patterns with a high-fat-sugar diet. Yucatan minipigs with restricted food access gained ∼30 kg in a 20 wk intervention, whereas animals fed ad libitum gained over 50 kg. Ad libitum feeding pattern also resulted in more severe hypercholesterolemia; however, serum triglycerides and glucose levels did not differ between groups. Finally, Pop et al. (131) used the Yucatan model to examine gut hormone signaling in MetS following embolization of gastroduodenal arteries. This procedure was successful in attenuating ghrelin secretion and substantially altered expression of key glucose transporters, sodium-glucose-linked transporter-1, and glucose transporter-2, in the porcine foregut mucosa.

Overall, each core feature of MetS has been achieved in varying combinations in the different porcine models presented herein. A dietary intervention with variable feeding patterns was applied for inducing MetS in each porcine model discussed. These diets were generally categorized as “Western”-type, with increased fat, carbohydrate, cholesterol, and salt content to promote hypertension and metabolic dysfunction. However, although most “Western” diets were similar, their precise composition varied across studies. On top of this, diets also differed in the quantity of food that was distributed to animals. Researchers must consider that nutrient source and feeding pattern have been shown to considerably influence MetS progression (83, 150). Consistent design of dietary interventions would improve porcine model reproducibility.

The chemical or surgical induction of hypertension in combination with the “Western” diet intervention reliably replicated the cardiovascular sequelae of MetS and HF-pEF, such as cardiac hypertrophy, fibrosis, and LV contractile dysfunction in several models. By artificially promoting certain components of MetS, researchers can accelerate disease progression, which facilitates the replication of advanced MetS comorbidities within the allocated study duration. However, although requiring increased amounts of resources, long-term studies may more accurately replicate the long-term “natural” progression of the human MetS (6).

CHARACTERISTICS, ADVANTAGES, AND LIMITATIONS OF PORCINE MODELS OF METABOLIC SYNDROME AND EMERGING AREAS OF INVESTIGATION

Overall, porcine models fall into two major categories: livestock breeds and miniature breeds. Livestock breeds are large and lean animals that have been purposely selected for building up muscle mass. These breeds are affordable and available; however, their excessive size often necessitates the use of juvenile animals over short-term interventions. In addition, livestock species are generally outbred with a certain degree of heterozygosity and inter-individual genetic variability (151). Outbred animals better approximate the human diversity than homozygous inbred models (152); however, increased inter-individual variability implicates the use of larger cohorts to detect significant experimental outcomes.

On the other hand, miniature breeds are small and more suited to biomedical research, several of them such as the Ossabaw and Göttingen being naturally predisposed to obesity. Although coming at increased cost, these breeds have the major advantage of greatly facilitating long-term experiments, which can more reliably induce MetS core and secondary components.

In a recent review, Sturek et al. have extensively compared the Yucatan, Ossabaw, and Göttingen miniature models for their fidelity in reproducing MetS, type 2 diabetes, and atherosclerosis, as well as their respective contribution to cardiovascular device development (6). Since numerous other breeds of the Sus scrofa species have been used to emulate and explore MetS pathophysiology, we propose extending the comparison by including every model that has been characterized in any detail to date. Although highly similar, each porcine model presents specific advantages and limitations that are inherent to the breed itself and to the specific disease induction methods. It is also important to consider that porcine models differ in their MetS baseline parameters, such as blood pressure and body weight. Therefore, disease characterization is breed-specific and must be performed by comparing MetS versus lean animals instead of referring to preestablished threshold values as in humans. Here we collected representative MetS parameters for each porcine model to facilitate model comparison and characterization (Table 1). Moreover, we also propose consideration of MetS pathology with its cardiac and hepatic comorbidities (Fig. 2), as well as discussing emerging concepts such as gut microbiota alteration, intestinal permeability, and neurological disorders.

Metabolic Syndrome Core Components

Truncal obesity, hypertension, hypertriglyceridemia hypercholesterolemia, type 2 diabetes, and insulin resistance constitute the core components of MetS (1). The reliable induction of these parameters is essential for an accurate reproduction of the disease. Importantly, core parameter severity can influence the development of secondary organ sequelae and therefore the relevance of certain porcine models for specific aspects of MetS. In this section, we discuss the notable differences between porcine models and between porcine and human MetS.

Obesity.

Although every porcine model reliably reproduced the obesity component of MetS, differences in breeds’ phenotype were found to affect disease progression. Livestock breeds such as the domestic, Iberian, Landrace, Duroc, and the Yorkshire tended to exhibit a leaner phenotype than miniature breeds. Indeed, these MetS models generally exhibited moderate obesity, with a 10% to 30% increase in body weight compared with lean animals (Table 1). This may be explained by years of selective breeding of livestock animals in favor of muscle growth rather than fat accumulation. Meanwhile, miniature breeds including the Bama, Gottingen, Lee-Sung, Ossabaw, and Yucatan model of MetS developed severe obesity by building up to twice the body weight of control animals.

Hypertension.

Hypertension has been successfully induced in most porcine models of MetS via “Western” diets alone or in combination with pharmaceutical or surgical procedures. Although the normotensive and hypertensive parameters of most porcine MetS models closely resembled human criteria, the Iberian (53, 54) and Tibetan (133) models exhibited higher arterial pressures than other breeds, and Yucatan minipigs presented low diastolic blood pressure (129). These differences have to be considered when defining MetS in these models; this may also affect the severity of secondary comorbidities, especially cardiac sequelae.

Hypertriglyceridemia and hypercholesterolemia.

Although hypertriglyceridemia and hypercholesterolemia have been systematically reproduced in every porcine MetS model, it is important to consider that porcine HDL-C levels exhibit a pattern that is opposite to the human syndrome. Whereas low HDL-C constitute a MetS criteria in patients, porcine models of MetS exhibit higher HDL-C levels than their lean counterparts. This may be explained by the fact that MetS is generally induced with diets rich in cholesterol that results in severe hypercholesterolemia, with increased content in every lipoprotein fraction.

Type 2 diabetes and insulin resistance.

It is important to consider that, although most porcine models of MetS presented glucose intolerance and insulin resistance, they did not reliably exhibit type 2 diabetes with increased fasting blood glucose upon a dietary intervention. This may be due to the fact that pigs have increased pancreatic β cell capacity, resulting in improved glycemic control, which has been promoted over years of selective breeding for improved growth and thus energy accumulation (153). The use of juvenile animals may also have accounted for the poor reproduction of diabetes; indeed, young pigs have better glycemic control than adults (72). Consequently, the reproduction of a diabetic phenotype in porcine models generally required the induction of pancreatic dysfunction using toxic compounds such as streptozotocin or alloxan (43, 154). However, since the chemical induction of diabetes also impedes energy storage, it may result in an inaccurate reproduction of the obesity component of MetS (155). Most importantly, streptozotocin directly affects hepatic (156), cardiac (157), and renal function (158), and therefore influences the development of MetS secondary comorbidities. Investigators must also consider that pigs are resistant to streptozotocin toxicity, with no visible effect at low dose (50 mg/kg) and a partially reversible diabetic phenotype at higher dose (150 mg/kg) (159). Nonetheless, Hara et al. (160) reported that a 200 mg/kg dose induced stable diabetes over 20 wk without renal and hepatic dysfunction in Large White sows. However, a high dose of streptozotocin resulted in the rapid induction of pancreatic dysfunction that approximated the insulin-dependent type 1 diabetes phenotype (161).

Nonalcoholic Steatohepatitis

The most accurate reproductions of NASH were obtained in the Ossabaw miniature swine (83, 97) and Microminipig (65) (Table 2). Although both models reflected the full disease complexity, the Ossabaw fidelity was supported by independent studies, whereas the Microminipig has only recently started to emerge. The Göttingen (43, 50), Iberian (56), Lee-Sung (61, 64,) and Bama (10, 12, 13) remain satisfactory models that recapitulated most features of NASH. Intriguingly, different studies using the same breed did not consistently report similar NASH features. These discrepancies may be explained by differences between study parameters and design such as diet composition and intervention length. Identifying the parameters that are key for the induction of MetS comorbidities would improve the fidelity of porcine models as well as our grasp of disease pathogenesis.

Table 2. Reproduction of nonalcoholic steatohepatitis in porcine models of metabolic syndrome
NASH Criterion Microminipig Ossabaw Göttingen Iberian Lee-Sung Bama
Steatosis Yes (65) Yes (83, 97)
No (84, 101)		 Yes (42)
No (43)		 Yes (56) Yes (61, 64) Yes (10, 13)
Inflammation Yes (65, 66) Yes (83, 97)
No (84)		 Yes (43) Yes (56) Yes (64) Yes (10)
Ballooning Yes (65) Yes (83, 84, 97) No (43) Yes (56) na na
Fibrosis Yes (65) Yes (83, 84, 88, 97) Yes (43, 47) No (56) Yes (64) na

na, not assessed or not reported; NASH, nonalcoholic steatohepatitis.

Cardiac Remodeling and Pathological Signaling in the Heart

When subjected to a “Western” diet challenge, most porcine models of MetS did not reliably develop features of cardiac remodeling. It is arguable that diet-induced models of MetS only reflected the early pathological changes that preceded the manifestation of cardiovascular sequelae; therefore, more pronounced comorbidities would have required longer interventions to develop. In line with this, the Bama minipig fed high-fat-sucrose diet for an extended period of 23 mo effectively developed severe cardiac hypertrophy with evidence of fibrosis and steatosis (10, 11). Although authors did not assess LV function, this study may constitute the only satisfactory reproduction of myocardial sequelae in a porcine model of MetS subjected to a dietary intervention alone. Therefore, the induction of additional components of MetS appears to be essential for accurately reproducing advanced states of cardiovascular diseases within short intervention periods. Indeed, the surgical or pharmaceutical induction of hypertension in domestic (17, 22, 37), Göttingen (47), Landrace (57–59) and Ossabaw (88) models of MetS successfully recapitulated the cardiovascular secondary comorbidities of MetS. Importantly, these models exhibited pathological features that were analogous to human HF-pEF, which demonstrated the translatability of these porcine models in cardiovascular research. Therefore, the induction of hypertension in addition to a dietary challenge stands out as the most robust method for reproducing the complexity of structural heart diseases in varied porcine MetS models. These findings closely mirror human pathology where the mechanical stress induced by hypertension appears to contribute greatly to cardiac remodeling (162). Finally, although the myocardial sequelae of MetS have been shown to promote an atrial fibrillation substrate (163), this aspect remains unexplored in porcine models of MetS.

Emerging Concepts of Gut Microbiota Alteration, Intestinal Permeability, and Neurological Disorders

Recent research suggests the involvement of intestinal barrier disruption and gut mucosal inflammation in MetS pathophysiology (164). In line with this, the gut microbiota constitutes a major source of environmental factors and may be a key regulator of MetS progression. Indeed, several large-scale clinical studies have now demonstrated the metabolically influential role of microbiome-derived metabolites, such as branched-chain fatty acids (165), short-chain fatty acids (166), and modified bile acids (167). With dietary habits and digestive tract anatomy that are highly similar to humans, pigs represent excellent translational models for gastrointestinal research (5). Pigs are also excellent responders to dietary interventions as suggested by several studies reporting improvements in intestinal barrier function following prebiotic and probiotic supplementation (168–170). Indeed, porcine MetS models exhibited alterations in gut microbiota that were consistent with those observed in human patients (51, 56, 58, 97, 102). Importantly, authors reported changes in key influential bacterial species that are involved in host metabolism, inflammatory-signaling, and bile acid modification (171). However, it is of note that although pigs and humans host similar bacterial populations, Bifidobacterium genera were found in lower abundance in the porcine gut microbiome (172). In addition, microbiota composition varied between porcine breeds and models. For instance, Pedersen et al. (51) reported that, compared with Göttingen minipigs, the gut microbiota of Ossabaw miniature swine was richer in Actinobacteria and Bacteroides. Interestingly, white pigs such as the Landrace have been shown to host more abundant cellulolytic communities than black-colored breeds (173).

In regard to intestinal homeostasis, only the Ossabaw (97, 98) and Iberian (56) models were examined for pathological changes in the gut mucosa during MetS. In these models, authors reported structural, cellular, and molecular intestinal changes that were consistent with decreased barrier function. However, no study so far has performed in vivo or ex vivo assessments of intestinal permeability in a porcine MetS model. The fidelity of porcine models in reproducing changes in intestinal homeostasis during MetS should be further explored.

Remarkably, the alterations in the gut microbiota that occur during MetS have been associated with neuroinflammation and neuroendocrine system deregulation during MetS (174). In a Duroc pig model of obesity, Valent et al. (39) evaluated the effects of the probiotic Bifidobacterium breve and omega-3 fatty acids over hypothalamic neurotransmitters. In this study, pigs fed a diet enriched in fat presented alterations in hypothalamic and hippocampal dopaminergic neurotransmitters that were reversed upon supplementation of B. breve and omega-3 fatty acids to diet. In addition, Olver et al. investigated the neurological sequelae of MetS and HF-pEF in the aortic-banded “Western” diet-fed Ossabaw minipig model. Authors reported impaired brain blood supply and alterations in cerebral vascular endothelium that were associated with transcriptomic signatures of neurological and behavioral disorders, including dementia and Alzheimer’s disease (175). Interestingly, cerebral vasoconstriction and reduced blood flow were attributed to impaired insulin-dependent vasodilatation (175, 176). These data strongly encourage the use of porcine models for investigating the neurological sequelae of MetS.

Overall, the swine stands out as a powerful model for studying MetS development with multiple end-organ sequelae. The strength of this model mainly lies in its similarities to human physiology and its accuracy in reproducing disease phenotype. However, some differences between porcine and human MetS have to be considered, the major one being the pig’s natural resistance to diabetes. Finally, researchers have to bear in mind that this large animal model comes with size and breed-related limitations (Table 3).

Table 3. Major strengths and limitations of the porcine models of metabolic syndrome
Strengths Limitations

  • Pig size allows large sample collection and human-tailored interventions

  • Gastrointestinal, immune, and cardiovascular systems similar to human

  • Livestock breeds are cost-efficient and readily available

  • Miniature breeds can be studied over long-term interventions

  • Pig size implies costly husbandry needs as well as specific equipment and expertise

  • The pig is a suboptimal model for diabetes

  • Large breeds generally studied over juvenile stages only

  • Certain models remain poorly standardized with conflicting studies

STRENGTHS AND LIMITATIONS

This review has applied a comprehensive search strategy that has outlined in detail the metabolic features reported in 127 articles and synthesized a condensed view of each distinct porcine model available. However, it is important to note that the authors may not have classified their model as MetS, but rather by the individual risk factors (i.e., obese, insulin resistant, hypertensive, etc.). The result of this potential misclassification could be that studies may have been erroneously excluded or missed during the initial search phase. In line with this, an additional informal review of the literature conducted using “pig model” and “risk factors” as search keywords revealed several additional porcine models of metabolic dysfunction. Although this uncovered several additional important citations, it is possible that other relevant studies have been omitted. Despite this limitation, this review has covered in detail the most complete and commonly applied porcine models of MetS.

CONCLUDING REMARKS

Herein, we have identified the individual characteristics of MetS that are associated with each porcine model, thereby providing researchers in the gastrointestinal and cardiometabolic fields with a comprehensive reference material from which to select the model most appropriate to their study design and objectives. In addition, this review indicates that there is currently no single model that perfectly recapitulates the human syndrome. Nevertheless, several porcine models pose highly satisfactory representations of MetS for translational research. The Ossabaw miniature swine is the most commonly used porcine MetS model and it also represents the most promising recapitulation of MetS due to its high fidelity in reproducing NASH and HF-pEF. The “Western” diet and mineralocorticoid-induced Landrace model represents a more affordable alternative that successfully reproduces intestinal and cardiovascular MetS comorbidities. Finally, miniature breeds such as the Göttingen and Bama allow researchers to investigate the progression of MetS over long-term studies. Future efforts should focus on further optimizing and characterizing currently available MetS models, while exploring adjacent parameters, such as the composition of the gut microbiome and development of the important extrametabolic sequelae commonly observed in patients with MetS.

GRANTS

This work was supported by Science Foundation of Ireland Grant R18769.

DISCLOSURES

No conflicts of interest, financial or otherwise, are declared by the authors.

AUTHOR CONTRIBUTIONS

G.L.C., P.M.R., F.M.H., and N.M.C. conceived and designed research; G.L.C., P.M.R., F.M.H., and N.M.C. prepared figures; G.L.C., P.M.R., and F.M.H. drafted manuscript; G.L.C., P.M.R., F.M.H., and N.M.C. edited and revised manuscript; N.M.C. approved final version of manuscript.

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