Dietary protein restriction increases plasma soluble leptin receptor levels and suppresses the appetite-reducing effect of administered leptin

Background and objectives: Leptin, a hormone secreted by the adipose tissue, suppresses appetite and regulates body fat mass. We found that the liver leptin receptor (Ob-R) mRNA and plasma soluble Ob-R (sOb-R) levels increased in mice fed a low-protein diet. In this study, we investigated the physiological function of increased plasma sOb-R on leptin action by administering leptin to low-protein diet-fed C57BL/6J and ob/ob mice. Methods: Four-week-old C57BL/6J mice and 7-week-old ob/ob mice were fed a control diet with 20 % protein or a low-protein diet (with 5 % protein for C57BL/6J mice or 1 % protein for ob/ob mice) for 11 days. On the last four days, 2 mg/kg leptin was intraperitoneally injected into half of the mice in each diet group, and the vehicle was injected into the other half. Five hours after the last injection, the mice were dissected, and blood and organ samples were retrieved. Results: Hepatic Ob-R mRNA levels were increased, and Ob-R protein levels were decreased by protein restriction in both C57BL/6J and ob/ob mice. Plasma sOb-R concentration was increased by protein restriction in C57BL/6J mice but not in ob/ob mice. The appetite-suppressing effect of leptin was decreased in mice fed a low-protein diet in C57BL/6J mice, but not in ob/ob mice. The mRNA levels of genes involved in appetite regulation were altered in response to leptin administration in both diet groups in ob/ob mice, whereas alterations in the expression of these genes could not be detected in C57BL /6J mice. Conclusions: Plasma sOb-R levels did not increase in ob/ob mice, which demonstrates that the presence of normal leptin was required to increase plasma sOb-R levels during protein deficiency. The absence of increased sOb-R levels may be responsible for the lack of suppression of leptin action in ob/ob mice, indicating that increased sOb-R levels may suppress leptin action.