Coupling factor 6-induced activation of ecto-F1F(o) complex induces insulin resistance, mild glucose intolerance and elevated blood pressure in mice.

Abstract

AIMS/HYPOTHESIS:

Despite advances in pharmacological treatments, diabetes with hypertension continues to be a major public health problem with high morbidity and mortality rates. We recently identified a circulating peptide coupling factor 6 (CF6), which binds to the plasma membrane ATP synthase (ecto-F(1)F(o) complex), resulting in intracellular acidosis. We investigated whether overexpression of CF6 contributes to diabetes and hypertension by intracellular acidosis.

METHODS:

Transgenic mice overexpressing CF6 (also known as ATP5J) were generated, and physiological, biochemical and molecular biology studies were performed.

RESULTS:

CF6 overexpression elicited a sustained decrease in intracellular pH in tissues (aorta, kidney, skeletal muscle and liver, with the exception of adipose tissue) that express its receptor, the β-subunit of ecto-F(1)F(o) complex. Consistent with the receptor distribution, phospho-insulin receptor β, phosphoinositide 3-kinase activity and the phospho-Akt1:total Akt1 ratio were all decreased in the skeletal muscle and the liver in transgenic compared with wild-type mice, resulting in a decrease of plasma membrane-bound GLUT4 and an increase in hepatic glucose production. Under a high-sucrose diet, transgenic mice had insulin resistance and mild glucose intolerance; under a high-salt diet, they had elevated blood pressure with increased renal RAS-related C3 botulinum substrate 1 (RAC1)-GTP, which is an activator of mineralocorticoid receptor.

CONCLUSIONS/INTERPRETATION:

Through its action on the β-subunit of ecto-F(1)F(o) complex, which results in intracellular acidosis, CF6 plays a crucial role in the development of insulin resistance and hypertension. This finding might advance our understanding of the mechanisms underlying diabetes and hypertension, possibly also providing a novel therapeutic target against cardiovascular disease.

• Authors: T Osanai, M Tanaka, K Magota, H Tomita, K Okumura
• Journal: Diabetologia (Diabetologia) Vol. 55 Issue 2 Pg. 520-9 (Feb 2012) ISSN: 1432-0428 [Electronic] Germany
• PMID: 22038518 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Neuropeptides
• Oxidative Phosphorylation Coupling Factors
• RAC1 protein, human
• Rac1 protein, mouse
• F(6) ATPase
• Mitochondrial Proton-Translocating ATPases
• Proton-Translocating ATPases
• rac GTP-Binding Proteins
• rac1 GTP-Binding Protein

Topics

• Acidosis (metabolism)
• Animals
• Blood Pressure
• Cytoplasm (metabolism)
• Disease Models, Animal
• Glucose Intolerance (metabolism)
• Glucose Tolerance Test
• Hepatocytes (metabolism)
• Humans
• Hydrogen-Ion Concentration
• Hypertension (genetics, metabolism)
• Insulin Resistance
• Mice
• Mice, Transgenic
• Mitochondrial Proton-Translocating ATPases (metabolism)
• Neuropeptides (metabolism)
• Oxidative Phosphorylation Coupling Factors (metabolism)
• Proton-Translocating ATPases (metabolism)
• rac GTP-Binding Proteins (metabolism)
• rac1 GTP-Binding Protein (metabolism)