Coupling factor 6-induced activation of ecto-F1F(o) complex induces insulin resistance, mild glucose intolerance and elevated blood pressure in mice.
OBJECTIVE
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
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.
Department of Cardiology, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki 036-8562, Japan. osanait@cc.hirosaki-u.ac.jp
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T
Osanai
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M
Tanaka
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K
Magota
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Tomita
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Okumura
D000138:Acidosis / Q000378:metabolism; D000818:Animals; D001794:Blood Pressure; D003593:Cytoplasm / Q000378:metabolism; D004195:Disease Models, Animal; D018149:Glucose Intolerance / Q000378:metabolism*; D005951:Glucose Tolerance Test; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D006863:Hydrogen-Ion Concentration; D006973:Hypertension / Q000235:genetics / Q000378:metabolism*; D007333:Insulin Resistance; D051379:Mice; D008822:Mice, Transgenic; D025261:Mitochondrial Proton-Translocating ATPases / Q000378:metabolism*; D009479:Neuropeptides / Q000378:metabolism; D010086:Oxidative Phosphorylation Coupling Factors / Q000378:metabolism*; D006180:Proton-Translocating ATPases / Q000378:metabolism*; D020744:rac GTP-Binding Proteins / Q000378:metabolism; D020830:rac1 GTP-Binding Protein / Q000378:metabolism
D009479:Neuropeptides; D010086:Oxidative Phosphorylation Coupling Factors; C107953:RAC1 protein, human; C484602:Rac1 protein, mouse; C000628217:F(6) ATPase; D025261:Mitochondrial Proton-Translocating ATPases; D006180:Proton-Translocating ATPases; D020744:rac GTP-Binding Proteins; D020830:rac1 GTP-Binding Protein