Chromium (D-phenylalanine)3 improves obesity-induced cardiac contractile defect in ob/ob mice.

Abstract

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 mug/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 (+/-dL/dt), prolonged time-to-PS and time-to-90% relengthening (TR90), reduced electrically stimulated rise in intracellular Ca(2+) (Deltafura-2 fluorescence intensity), and slowed intracellular Ca(2+) 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 +/-dL/dt in ob/ob mice, all mechanical and intracellular Ca(2+) 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(2+) ATPase activity and Na(+)-Ca(2+) 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.

• Authors: Feng Dong, Xiaoping Yang, Nair Sreejayan, Jun Ren
• Journal: Obesity (Silver Spring, Md.) (Obesity (Silver Spring)) Vol. 15 Issue 11 Pg. 2699-711 (Nov 2007) ISSN: 1930-7381 [Print] United States
• PMID: 18070761 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Homeodomain Proteins
• Organometallic Compounds
• Picolinic Acids
• Sodium-Calcium Exchanger
• Tlx2 protein, mouse
• chromium (D-Phenylalanine)3
• chromium tripicolinate
• Phenylalanine
• Receptor, Insulin
• Proto-Oncogene Proteins c-akt
• Sarcoplasmic Reticulum Calcium-Transporting ATPases
• Glucose

Topics

• Animals
• Disease Models, Animal
• Dose-Response Relationship, Drug
• Glucose (metabolism)
• Homeodomain Proteins (metabolism)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Obese
• Myocardial Contraction (drug effects, physiology)
• Myocytes, Cardiac (drug effects, metabolism, pathology)
• Obesity (metabolism, physiopathology)
• Organometallic Compounds (pharmacology)
• Oxidative Stress (drug effects)
• Phenylalanine (analogs & derivatives, pharmacology)
• Picolinic Acids (pharmacology)
• Proto-Oncogene Proteins c-akt (metabolism)
• Receptor, Insulin (metabolism)
• Sarcoplasmic Reticulum Calcium-Transporting ATPases (metabolism)
• Sodium-Calcium Exchanger (metabolism)
• Thinness (metabolism, physiopathology)