Animal and human tissue Na,K-ATPase in normal and insulin-resistant states: regulation, behaviour and interpretative hypothesis on NEFA effects

Summary The sodium(Na)‐ and potassium(K)‐activated adenosine‐triphosphatase (Na,K‐ATPase) is a membrane enzyme that energizes the Na‐pump by hydrolysing adenosine triphosphate and wasting energy as heat, so playing a role in thermogenesis and energy balance. Na,K‐ATPase regulation by insulin is controversial; in tissue of hyperglycemic‐hyperinsulinemic ob/ob mice, we reported a reduction, whereas in streptozotocin‐treated hypoinsulinemic‐diabetic Swiss and ob/ob mice we found an increased activity, which is against a genetic defect and suggests a regulation by hyperinsulinemia. In human adipose tissue from obese patients, Na,K‐ATPase activity was reduced and negatively correlated with body mass index, oral glucose tolerance test‐insulinemic area and blood pressure. We hypothesized that obesity is associated with tissue Na,K‐ATPase reduction, apparently linked to hyperinsulinemia, which may repress or inactivate the enzyme, thus opposing thyroid hormones and influencing thermogenesis and obesity development. Insulin action on Na,K‐ATPase, in vivo, might be mediated by the high level of non‐esterified fatty acids, which are circulating enzyme inhibitors and increase in obesity, diabetes and hypertension. In this paper, we analyse animal and human tissue Na,K‐ATPase, its level, and its regulation and behaviour in some hyperinsulinemic and insulin‐resistant states; moreover, we discuss the link of the enzyme with non‐esterified fatty acids and attempt to interpret and organize in a coherent view the whole body of the exhaustive literature on this complicated topic.