The prevalence of metabolic syndrome including central obesity, insulin resistance, impaired glucose tolerance, hypertension, and dyslipidemia is increasing. Development of adequate therapy for metabolic syndrome requires an animal model that mimics the human disease state. Therefore, we have characterized the metabolic, cardiovascular, hepatic, renal, and pancreatic changes in male Wistar rats (8-9 weeks old) fed on a high-carbohydrate, high-fat diet including condensed milk (39.5%), beef tallow (20%), and fructose (17.5%) together with 25% fructose in drinking water; control rats were fed a cornstarch diet. During 16 weeks on this diet, rats showed progressive increases in body weight, energy intake, abdominal fat deposition, and abdominal circumference along with impaired glucose tolerance, dyslipidemia, hyperinsulinemia, and increased plasma leptin and malondialdehyde concentrations. Cardiovascular signs included increased systolic blood pressure and endothelial dysfunction together with inflammation, fibrosis, hypertrophy, increased stiffness, and delayed repolarization in the left ventricle of the heart. The liver showed increased wet weight, fat deposition, inflammation, and fibrosis with increased plasma activity of liver enzymes. The kidneys showed inflammation and fibrosis, whereas the pancreas showed increased islet size. In comparison with other models of diabetes and obesity, this diet-induced model more closely mimics the changes observed in human metabolic syndrome.

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Rodents are widely used to mimic human diseases to improve understanding of the causes and progression of disease symptoms and to test potential therapeutic interventions. Chronic diseases such as obesity, diabetes and hypertension, together known as the metabolic syndrome, are causing increasing morbidity and mortality. To control these diseases, research in rodent models that closely mimic the changes in humans is essential. This review will examine the adequacy of the many rodent models of metabolic syndrome to mimic the causes and progression of the disease in humans. The primary criterion will be whether a rodent model initiates all of the signs, especially obesity, diabetes, hypertension and dysfunction of the heart, blood vessels, liver and kidney, primarily by diet since these are the diet-induced signs in humans with metabolic syndrome. We conclude that the model that comes closest to fulfilling this criterion is the high carbohydrate, high fat-fed male rodent.

Survival of multicellular organisms depends on their ability to fight infection, metabolize nutrients, and store energy for times of need. Unsurprisingly, therefore, immunoregulatory and metabolic mechanisms interact in human conditions such as obesity. Both infiltrating immunoinflammatory cells and adipocytes play critical roles in the modulation of metabolic homeostasis, so it is important to understand factors that regulate both adipocyte and immune cell function. A currently favored paradigm for obesity-associated metabolic dysfunction is that chronic macronutrient and/or lipid overload (associated with adiposity) induces cellular stress that initiates and perpetuates an inflammatory cycle and pathophysiological signaling of immunoinflammatory cells and adipocytes. Many lipid mediators exert their biological effects by binding to cognate receptors, such as G-protein-coupled receptors and Toll-like receptors. This process is tightly regulated under normal physiological conditions, and any disruption can initiate disease processes. Observations that cellular lipid loading (associated with adiposity) initiates inflammatory events has encouraged studies on the role of lipid mediators. In this review, we speculate that lipid mediators act on important immune receptors to induce low-grade tissue inflammation, which leads to adipocyte and metabolic dysfunction.

Olive oil, an important component of the Mediterranean diet, produces cardioprotective effects, probably due to both oleic acid and the polyphenols such as oleuropein and hydroxytyrosol. Our aim in this study was to assess whether a polyphenol-enriched extract from the leaves of Olea europaea L. with oleuropein as the major component attenuated the cardiovascular, hepatic, and metabolic signs of a high-carbohydrate, high-fat (HCHF) diet (carbohydrate, 52%; fat, 24%, 25% fructose in drinking water) in rats. Male Wistar rats were fed either a cornstarch diet (CS) or a HCHF diet for a total of 16 wk. Diets of the treatment groups [CS+olive leaf extract (OLE) and HCHF+OLE] were supplemented with 3% OLE after 8 wk of being fed their respective CS or HCHF diets for a further 8 wk. After 16 wk, HCHF rats developed signs of metabolic syndrome, including elevated abdominal and hepatic fat deposition, collagen deposition in heart and liver, cardiac stiffness, and oxidative stress markers (plasma malondialdehyde and uric acid concentrations), with diminished aortic ring reactivity, abnormal plasma lipid profile, impaired glucose tolerance, and hypertension. Compared with HCHF rats, those in the HCHF+OLE group had improved or normalized cardiovascular, hepatic, and metabolic signs with the exception of elevated blood pressure. These results strongly suggest that an OLE containing polyphenols such as oleuropein and hydroxytyrosol reverses the chronic inflammation and oxidative stress that induces the cardiovascular, hepatic, and metabolic symptoms in this rat model of diet-induced obesity and diabetes without changing blood pressure.

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Metabolic syndrome is a risk factor for cardiovascular disease and nonalcoholic fatty liver disease (NAFLD). We investigated the responses to the flavonol, quercetin, in male Wistar rats (8-9 wk old) divided into 4 groups. Two groups were given either a corn starch-rich (C) or high-carbohydrate, high-fat (H) diet for 16 wk; the remaining 2 groups were given either a C or H diet for 8 wk followed by supplementation with 0.8 g/kg quercetin in the food for the following 8 wk (CQ and HQ, respectively). The H diet contained ~68% carbohydrates, mainly as fructose and sucrose, and ~24% fat from beef tallow; the C diet contained ~68% carbohydrates as polysaccharides and ~0.7% fat. Compared with the C rats, the H rats had greater body weight and abdominal obesity, dyslipidemia, higher systolic blood pressure, impaired glucose tolerance, cardiovascular remodeling, and NAFLD. The H rats had lower protein expressions of nuclear factor (erythroid-derived 2)-related factor-2 (Nrf2), heme oxygenase-1 (HO-1), and carnitine palmitoyltransferase 1 (CPT1) with greater expression of NF-κB in both the heart and the liver and less expression of caspase-3 in the liver than in C rats. HQ rats had higher expression of Nrf2, HO-1, and CPT1 and lower expression of NF-κB than H rats in both the heart and the liver. HQ rats had less abdominal fat and lower systolic blood pressure along with attenuation of changes in structure and function of the heart and the liver compared with H rats, although body weight and dyslipidemia did not differ between the H and HQ rats. Thus, quercetin treatment attenuated most of the symptoms of metabolic syndrome, including abdominal obesity, cardiovascular remodeling, and NAFLD, with the most likely mechanisms being decreases in oxidative stress and inflammation.