Leptin stimulates bone formation in ob/ob mice at doses having minimal impact on energy metabolism

Abstract

Leptin, the protein product of the ob gene, is essential for normal bone growth, maturation, and turnover. Peripheral actions of leptin occur at lower serum levels of the hormone than central actions because entry of leptin into the central nervous system (CNS) is limited due to its saturable transport across the blood brain barrier (BBB). We performed a study in mice to model the impact of leptin production associated with different levels of adiposity on bone formation and compared the response with well-established centrally-mediated actions of the hormone on energy metabolism. Leptin was infused (0, 4, 12, 40, 140, or 400 ng/h) for 12 days into 6-week-old female ob/ob mice (n=8/group) using sc implanted osmotic pumps. Treatment resulted in a dose-associated increase in serum leptin. Bone formation parameters were increased at EC50 infusion rates of 7–17 ng/h whereas higher levels (EC50, 40–80 ng/h) were required to similarly impact indices of energy metabolism. We then analyzed gene expression in tibia and hypothalamus at dose rates of 0, 12 and 140 ng/h; the latter dose resulted in serum leptin levels similar to WT mice. Infusion with 12 ng/h leptin increased expression of genes associated with Jak/Stat signaling and bone formation in tibia with minimal effect on Jak/Stat signaling and neurotransmitters in hypothalamus. The results suggest that leptin acts peripherally to couple bone acquisition to energy availability and that limited transport across the BBB insures that the growth promoting actions of peripheral leptin are not curtailed by the hormone’s CNS-mediated anorexigenic actions.

Role of estrogen receptor signaling in skeletal response to leptin in female ob/ob mice

“…Thus, it is possible that oestrogen deficiency contributes to the skeletal phenotype observed in leptin signaling-deficient rodents and restoration of oestrogen receptor signaling following leptin administration may influence the physiological response of ob/ob mice to leptin. This possibility is consistent with the results of a recent leptin dose response study conducted in ob/ob mice (Philbrick, et al 2017). Specifically, a pronounced dose-dependent stimulatory effect of leptin on bone accrual plateaued at a dose rate that increased uterine weight (an index of oestrogen levels).…”

“…Additionally, sc infusion of leptin revealed that the stimulatory effects of leptin on bone formation occur at leptin levels that have minimal effects on energy metabolism (Philbrick et al 2017). These findings provide strong evidence that leptin acts peripherally to stimulate bone formation.…”

Aging human body: changes in bone, muscle and body fat with consequent changes in nutrient intake

“…This effect was attributed to increased angiogenesis, osteogenesis and chondrogenesis (Liu & Cai 2017). Moreover, a recent study showed that different lower dose-infusions of leptin (4-12-40 ng/h) in ob/ob mice resulted in increased bone formation and trabecular thickness, with a minimal impact on energy metabolism (Philbrick et al 2017).…”

Reflections on Cancer in the Bone Marrow: Adverse Roles of Adipocytes

“…On the other hand, evidence also suggests that adipokines, such as leptin, can increase osteoblast differentiation [59,60]. Moreover, in certain diseases with increased MAT and bone disease, decreasing MAT using a PPARγ antagonist was not able to prevent bone loss [61].…”