Role of T Regulatory Lymphocytes in the Pathogenesis of High-Fructose Diet–Induced Metabolic Syndrome

Abstract

Abstract-We recently showed that T regulatory lymphocytes (Treg), which are immune suppressors of inflammatory responses, play a role blunting the development of hypertension-induced injury. Treg are unchanged or decreased in children with metabolic syndrome, and therefore, their role in metabolic syndrome remains unclear. We hypothesized that Treg number or function would be depressed in a high-fructose diet-induced metabolic syndrome-like model in rats. Sprague-Dawley rats were fed normal chow or a high-fructose diet for 5 weeks. The high-fructose diet-induced a 3.8-fold increase in plasma triglycerides and a 14% reduction in high-density lipoprotein cholesterol (P<0.001). The high-fructose diet increased reactive oxygen species in aorta and periaortic adipose tissue 2.8-fold (P<0.05), and reduced nicotinamide adenine dinucleotide phosphate oxidase activity 1.9-fold in aorta, and 2.5-fold in the heart (P<0.05). It also increased plasma nitric oxide metabolite levels 6.4-fold (P<0.001). Western blots showed that the high-fructose diet increased ≥2.3-fold vascular and in platelet endothelial cell adhesion molecule 1 in aorta (P<0.01). It did not affect monocyte/macrophage aortic infiltration but caused a 2.4-fold increase in collagen deposition in the aortic media (P<0. 01 FoxP3+ cells was observed in children with metabolic syndrome (2.5 versus 3.1%). 15To determine the role of Treg in the metabolic syndrome, vascular oxidative stress and inflammation and the number and function of Treg were studied in high-fructose diet-fed SpragueDawley rats, a well-established model mimicking some features of the western diet-induced metabolic syndrome. 16,17 These rats exhibit hypertension, insulin resistance, and abnormal lipid profile resembling the human metabolic syndrome better than a monogenic model. We hypothesized that vascular oxidative stress and inflammation and changes in the immune response, including Treg activity and response, participate in the mechanisms leading to the metabolic syndrome. Materials and MethodsAdditional materials and methods are described in the online-only Data Supplement. Experimental DesignEight-week-old Sprague-Dawley male rats (Harlan Laboratories, Indianapolis, IN) were fed a high-fructose diet (TD.89247, Harlan Laboratories) composed of 60% fructose, 21% protein, 5% fat, 8% cellulose, and standard vitamins and mineral mix or normal chow diet (control) for 5 weeks. Systolic BP (SBP) was measured by the tailcuff method after 4 weeks on the diet. SBP was also determined by telemetry together with heart rate and animal activity every 5 minutes for 10 seconds for 2 consecutive days at baseline and at the end of every week during the 5 weeks of treatment. Three days before the end of the protocol, blood was collected from the saphenous vein on heparin for triglycerides, and high-density lipoprotein cholesterol was determined after 5 hours of fasting. At the end of the protocol, body weight was evaluated, and rats were anesthetized with 3% isoflurane mixed with O 2 at 1 L/min (depth of ane...

Caffeine Intake Improves Fructose-Induced Hypertension and Insulin Resistance by Enhancing Central Insulin Signaling

“…21,22 Our findings extend these observations to fructose-fed rats, which show similar metabolic disturbances. 14,23 In the present study, fructose intake caused increased levels of serum norepinephrine, serum triglycerides, insulin, and fasting serum glucose and reduced high-density lipoprotein but resulted in no change in body weight or cholesterol compared with control rats.…”

“…3,24 In particular, most studies have found that administering rats 10% fructose in drinking water induces a more severe metabolic disorder compared with providing 60% fructose in food. 22,24 In this study, we used 10% fructose in drinking water as a fructose-induced hypertension model. Our data revealed the presence of hypertension in fructose-fed rats.…”

Aging, Arterial Stiffness, and Hypertension

“…T regulatory lymphocytes suppress inflammatory responses and attenuate hypertension-associated organ damage. It was reported that high fructose diet-induced metabolic syndrome decreased the number and function of the T regulatory lymphocytes, 27 which may promote metabolic syndrome-associated arterial stiffening and hypertension.…”

Potential Clinical Application of Recently Discovered Brain Mechanisms Involved in Hypertension

“…92 In contrast, T regulatory cells, which are immune suppressors having anti-inflammatory activity, are decreased in angiotensin II-induced hypertension and high-fructose diet-induced metabolic syndrome. 88,97 A recent study demonstrated that immunosenescent CD8 + T cells are increased in human hypertension. 98 Thus, low-grade inflammation and oxidative stress play a role in above-mentioned abnormalities, including the brain mechanisms of hypertension.…”