Chromium (d‐Phenylalanine)₃ Improves Obesity‐Induced Cardiac Contractile Defect in ob/ob Mice

Abstract

DONG, FENG, XIAOPING YANG, NAIR SREEJAYAN, AND JUN REN. Chromium (D-phenylalanine) 3 improves obesity-induced cardiac contractile defect in ob/ob mice. Obesity. 2007;15:2699 -2711. Objective: Low-molecular weight chromium compounds, such as chromium picolinate [Cr(pic) 3 ], improve insulin sensitivity, although toxicity is a concern. We synthesized a novel chromium complex, chromium (D-phenylalanine) 3 [Cr(D-phe) 3 ], in an attempt to improve insulin sensitivity with reduced toxicity. The aim of this study was to compare the two chromium compounds on cardiac contractile function in ob/ob obese mice. Research Methods and Procedures: C57BL lean and ob/ob obese mice were randomly divided into three groups: H 2 O, Cr(D-phe) 3 , or Cr(pic) 3 (45 g/kg per day orally for 6 months). Results:The glucose tolerance test displayed improved glucose clearance by Cr(D-phe) 3 but not Cr(pic) 3 . Myocytes from ob/ob mice exhibited depressed peak shortening (PS) and maximal velocity of shortening/relengthening (ϮdL/ dt), prolonged time-to-PS and time-to-90% relengthening (TR90), reduced electrically stimulated rise in intracellular Ca 2ϩ (⌬fura-2 fluorescence intensity), and slowed intracellular Ca 2ϩ decay. Although a 3-month Cr(D-phe) 3 treatment for a separate group of ob/ob and lean 2-month-old mice only rectified reduced ϮdL/dt in ob/ob mice, all mechanical and intracellular Ca 2ϩ abnormalities were significantly attenuated or ablated by 6 months of Cr(D-phe) 3 but not Cr(pic) 3 treatment (except TR90). Sarco(endo)plasmic reticulum Ca 2ϩ ATPase activity and Na ϩ -Ca 2ϩ exchanger expression were depressed in ob/ob mice, which were reversed by both Cr(D-phe) 3 and Cr(pic) 3 , with a more pronounced effect from Cr(D-phe) 3 . Cr(D-phe) 3 corrected reduced insulin-stimulated glucose uptake and improved basal phosphorylation of Akt and insulin receptor, as well as insulin-stimulated phosphorylation of Akt and insulin receptor in ob/ob myocytes. Heart homogenates from ob/ob mice had enhanced oxidative stress and protein carbonyl formation compared with the lean group, which were attenuated by both Cr(D-phe) 3 and Cr(pic) 3 . Discussion: Our data suggest that the new Cr(D-phe) 3 compound possesses better cardio-protective and insulin-sensitizing properties against obesity.

Akt2 knockout mitigates chronic iNOS inhibition-induced cardiomyocyte atrophy and contractile dysfunction despite persistent insulin resistance

“…Adult age- and gender-matched Akt2 knockout mice and their littermates without Akt2 knockout (used as controls) were injected with either the iNOS inhibitor 1400W (2 mg/kg/d, s.c.) or saline for 7 consecutive days (Nagareddy et al , 2005; Nagareddy et al , 2009). Intraperitoneal glucose tolerance test (IPGTT) was performed (Dong et al , 2007). In brief, following the drug or saline treatment, mice fasted overnight were given an injection of glucose (2 mg/kg, i.p.).…”

Effects of chromium picolinate on vascular reactivity and cardiac ischemia-reperfusion injury in spontaneously hypertensive rats

“…Second, Cr(pic)3 could beneficially influence dysregulation of calcium homeostasis in the ischemic reperfused myocardium. This notion is supported by a) the demonstration that the myocardium accumulates trivalent chromium following Cr(pic)3 treatment [18] and b) Cr(pic)3 treatment reverses depressed sarcoplasmic reticulum Ca 2+ ATPase activity and Na + /Ca 2+ exchanger expression in cardiac myocytes from ob/ob mice [14]. Third, Cr(pic)3 purportedly possesses antioxidant property that could be beneficial to the myocardium subjected to IRI [14, 25].…”

“…While Cr(pic)3 has been extensively investigated in relation to carbohydrate metabolism, there are only a few studies devoted to its effects on the cardiovascular system [14, 17, 19, 24–27, 29]. The consideration of the cardiovascular effects of the supplement becomes more relevant in view of the documented association between type 2 diabetes/glucose intolerance and cardiovascular disorders such as abnormal vascular function, increased blood pressure and augmented susceptibility to ischemic heart disease [3, 4, 11, 28].…”

Molecular mechanisms of chromium in alleviating insulin resistance

“…In addition, chromium inhibited hydrogen peroxide-mediated oxidation of thiols and lipid peroxidation [78]. Chromium supplementation in obese mice significantly attenuated the obesity-associated elevated ratio of oxidized glutathione to reduced glutathione and the formation of protein carbonyl [79]. Similar effects of chromium on elevated oxidative stress in diabetic subjects have been reported from randomized clinical trials in which serum thiobarbituric acid reactive substances were used as a marker for the end-product of lipid peroxidation and total serum antioxidative status and glutathione peroxidase activity were used to assess oxidative stress [80, 81].…”

“…The chromium complex attenuated the streptozotocin-induced left ventricular dysfunction, infarct size and cardiomyocyte apoptosis. Chromium also improved cardiac contractile functions and cardiomyocyte calcium handling in obese mice [79]. In addition, chromium treatment resulted in an increased Glut-4 translocation to the lipid raft fractions, reduced Cav-1, and increased Cav-3 expression, together with phosphorylation of Akt, eNOS and AMPK.…”