Different genes for obesity are associated with insulin loss of regulation of the membrane (Ca2+ + Mg2+)-ATPase in the obesity syndrome. Lessons from animal models.
Intracellular Ca2+ homeostasis is impaired in tissues from obese humans and rats and insulin loses its regulatory effect on the plasma membrane (Ca2+ + Mg2+)-ATPase in kidney basolateral membranes (BLM) from the genetically obese fa/fa rats. We have demonstrated that loss of insulin regulation of the ATPase may impair insulin biologic effects and may therefore contribute to the insulin resistance in the obese rodents. To test whether the defect is restricted to one species or to one gene of obesity, studies were extended to an additional genetically obese rodent of another species the C57BL/6J ob/ob mice. Twelve-weeks-old obese and control male mice were used and (Ca2+ + Mg2+)-ATPase activity and its regulation by insulin were evaluated in their kidney BLM. The obese mice were heavier (56.4 +/- 2.5 vs 30.5 +/- 1.2 g P < 0.05), were hyperinsulinemic (6.32 +/- 1.87 vs 0.59 +/- 0.13 ng/ml P < 0.05) and had decreased (by 80%) specific binding of insulin to their epididymal fat cells compared with their non-obese littermates controls (ob/+, +/+). Yet, non-fasting plasma glucose levels were similar in the obese and control mice (227.0 +/- 19.3 vs 226.8 +/- 13.7 mg/dl N.S.). Basal activity of the (Ca2+ + Mg2+)-ATPase was similar in membranes from the ob/ob and control mice. However, while insulin (1-40 ng/ml) stimulated the ATPase activity in BLM form controls in a dose dependent manner (15-52%), no effect of insulin on the enzyme was seen in BLM from the obese mice even in the presence of the highest (40 ng/ml) concentration of insulin.(ABSTRACT TRUNCATED AT 250 WORDS)
Levy
J
J
Department of Medicine, Wayne State University School of Medicine, Detroit, Michigan 48201, USA.
Gavin
J R
JR
D017667:Adipocytes / Q000378:metabolism; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D017301:Ca(2+) Mg(2+)-ATPase / Q000378:metabolism*; D002462:Cell Membrane / Q000187:drug effects / Q000201:enzymology*; D004195:Disease Models, Animal; D004822:Epididymis / Q000378:metabolism; D007328:Insulin / Q000097:blood / Q000378:metabolism / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D009765:Obesity / Q000201:enzymology / Q000235:genetics*; D013577:Syndrome
D001786:Blood Glucose; D007328:Insulin; D017301:Ca(2+) Mg(2+)-ATPase