Animal and Human Tissue Na,K-ATPase in Obesity and Diabetes: A New Proposed Enzyme Regulation

Background:Na,K-ATPase is a membrane enzyme that energizes the Na-pump, hydrolyzing ATP and wasting energy as heat. It may play a role in thermogenesis, energy balance, and obesity development. Regulation of the enzyme by insulin is controversial. Methods:In animal and human obesity, tissue Na,K-ATPase was assayed by colorimetric measurement of released Pi. Results:Na,K-ATPase of hyperglycemic-hyperinsulinemic ob/ob mice (compared with lean control animals) was reduced in liver (−63%) and in kidney (−47%) (P < 0.001 in both instances). In contrast, in streptozotocin-treated hypoinsulinemic-diabetic Swiss mice, versus untreated animals, we found an increase of liver (+54%, P < 0.01) and kidney (+94%, P < 0.001) Na,K-ATPase. The enzyme was also increased (+99%, P < 0.05) in kidney from ob/ob mice made diabetic-hypoinsulinemic with streptozotocin (versus untreated obese animals). This is contrary to the occurrence of a genetic enzymatic defect and suggests regulation by hyperinsulinemia, present in ob/ob mice. A positive correlation between tissue enzyme activity and glycemia existed in both ob/ob and Swiss mice. In adipose tissue from obese patients (compared with lean subjects), Na,K-ATPase was reduced (−65%, P < 0.001) and negatively correlated with body mass index, oral glucose tolerance test—insulinemic area, and mean blood pressure. In vitro, in human liver tissue, 3 &mgr;g/mL glucagon exerted a statistically inhibitory effect on Na,K-ATPase (−44%). Conclusion:We hypothesize that animal and human obesity is associated with reduction of tissue Na,K-ATPase, linked to hyperinsulinemia, which may repress or inactivate the enzyme, influencing thermogenesis and energy balance.

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