Additive effect of leptin and palm-LEAP2(1–14) ameliorates obesity-induced metabolic stress in ob/ob mice

Liver-enriched antimicrobial peptide 2 (LEAP2) can act as a natural antagonist or inverse agonist of the growth hormone secretagogue receptor, also known as the ghrelin receptor. In our previous studies, palm-LEAP2(1–14), a truncated palmitoylated analogue of LEAP2, proved highly stable and exerted an acute anorexigenic effect. Ghrelin, the endogenous agonist of the ghrelin receptor, and the anorexigenic hormone leptin have opposing effects on appetite. We hypothesized that leptin supplementation combined with long-term antagonism of the ghrelin receptor using palm-LEAP2(1–14) might have a beneficial and potentially additive effect on obesity-related metabolic stress in leptin-deficient ob/ob mice, influencing diabetes, liver steatosis, impaired locomotor activity, and hypothermia. Here, we demonstrated a clear additive effect of combined leptin and palm-LEAP2(1–14) treatment, which increased locomotor activity, reduced plasma cholesterol, liver steatosis, and mRNA expression of the metabolic stress marker Fgf21 , and upregulated hypothalamic Pomc gene expression – outcomes not achieved by either treatment alone. Additionally, leptin, palm-LEAP2(1–14), and both treatments combined each reduced cumulative food intake and circulating FGF21 levels. Only leptin reduced body weight, elevated rectal temperature, increased Ucp1 and Pgc1 mRNA expression in brown adipose tissue, and attenuated hyperinsulinemia, indicating that the weight-reducing and antidiabetic effects were attributable to leptin – not palm-LEAP2(1–14). Liver metabolic stress was further alleviated by decreases in plasma FGF21 and hepatic expression of the lipogenic enzymes. Our study demonstrated the beneficial effects of palm-LEAP2(1–14) on obesity-induced metabolic stress, which were further attenuated when palm-LEAP2(1–14) was coadministered with leptin in ob / ob mice. • Palm-LEAP2(1–14) is a truncated, palmitoylated analogue of LEAP2. • Palm-LEAP2(1–14) combined with leptin showed additive effects in ob/ob mice. • The treatment elevated hypothalamic Pomc mRNA expression and reduced food intake. • Cholesterol levels, liver steatosis and hepatic Fgf21 mRNA expression were reduced. • The treatment showed therapeutic potential for obesity-induced metabolic stress.