Development and Use of Leptin Receptor Antagonists to Increase Appetite and Adaptive Metabolism in Ruminants
Authors: Boisclair Yves R. , Gertler Arieh 
Published: March 2022

Objectives The original project had 2 major objectives: (1) To determine the effects of centrally administered leptin antagonist on appetite and adaptive metabolism in the sheep; (2) To develop and prepare second-generation leptin antagonists combining high binding affinity and prolonged in vivo half-life. Background Periods of suboptimal nutrition or exaggerated metabolic activity demands lead to a state of chronic energy insufficiency. Ruminants remain productive for a surprisingly long period of time under these circumstances by evoking adaptations sparing available energy and nutrients. The mechanism driving these adaptations in ruminant remains unknown, but could involve a reduction in plasma leptin, a hormone acting predominantly in the brain. In laboratory animals, reduced leptin signaling promotes survival during nutritional insufficiency by triggering energy sparing adaptations such as reduced thyroid hormone production and insulin resistance. Our overall hypothesis is that similar adaptations are triggered by reduced leptin signaling in the brain of ruminants. Testing of this hypothesis in ruminants has not been possible due to inability to block the actions of endogenous leptin and access to ruminant models where leptin antagonistic therapy is feasible and effective. Major achievements and conclusions The Israeli team had previously mutated 3 residues in ovine leptin, with no effect on receptor binding. This mutant was renamed ovine leptin antagonist (OLA) because it cannot activate signaling and therefore antagonizes the ability of wild type leptin to activate its receptor. To transform OLA into an effective in vivo antagonist, the Israeli made 2 important technical advances. First, it incorporated an additional mutation into OLA, increasing its binding affinity and thus transforming it into a super ovine leptin antagonist (SOLA). Second, the Israeli team developed a method whereby polyethylene glycol is covalently attached to SOLA (PEG-SOLA) with the goal of extending its half-life in vivo. The US team used OLA and PEG-SOLA in 2 separate animal models. First, OLA was chronically administered directly into the brain of mature sheep via a cannula implanted into the 3rdcerebroventricule. Unexpectedly, OLA had no effect of voluntary feed intake or various indicators of peripheral insulin action but reduced the plasma concentration of thyroid hormones. Second, the US team tested the effect of peripheral PEG-SOLA administration in an energy sensitive, rapidly growing lamb model. PEG-SOLA was administered for 14 consecutive days after birth or for 5 consecutive days before sacrifice on day 40 of life. Plasma PEG-SOLA had a half-life of over 16 h and circulated in 225- to 288-fold excess over endogenous leptin. PEG-SOLA administration reduced plasma thyroid hormones and resulted in a higher fat content in the carcass at slaughter, but had no effects on feed intake, body weight, plasma glucose or insulin. These results show that the team succeeded in developing a leptin antagonist with a long in vivo half-life. Moreover, in vivo results show that reduced leptin signaling promotes energy sparing in ruminants by repressing thyroid hormone production. Scientific and agricultural implications The physiological role of leptin in ruminants has been difficult to resolve because peripheral administration of wild type leptin causes little effects. Our work with leptin antagonists show for the first time in ruminants that reduced leptin signaling induces energy sparing mechanisms involving thyroid hormone production with little effect on peripheral insulin action. Additional work is needed to develop even more potent leptin antagonists, to establish optimal administration protocols and to narrow down phases of the ruminant life cycle when their use will improve productivity.