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Background: LEAP2 is a recently discovered endogenous growth hormone secretagogue receptor (GHSR) antagonist that blocks the actions of the hormone Ghrelin. Not only is ghrelin a potent orexigen, but also its administration increases blood glucose while mouse models lacking ghrelin function exhibit lower blood glucose levels after overnight fasting. This escalates to life-threatening hypoglycemia in the setting of an acute-on-chronic caloric restriction protocol in which a mouse's adipose stores are depleted by several days of 60% caloric restriction followed by a 23 h fast. Recently, we have shown that genetic LEAP2 deletion in mice enhances ghrelin's actions to increase food intake and growth hormone secretion. In the current study, we investigated the potential of LEAP2 deletion to protect against hypoglycemia during severe chronic caloric restriction Methods: Eight-week-old (n=12-20) male Ghrelin-KO, LEAP2-KO, LEAP2-KO/Ghrelin-KO (lacking both LEAP2 and ghrelin) and their wild-type littermates were subjected to a 6-day long 60% chronic caloric restriction using standard chow (Teklad 7001 diet) followed by a 23 h fast. Daily body weight and blood glucose levels from tail nicks were measured at 6:30 PM (30 minutes prior to the start of the dark phase). Results: The acute-on-chronic caloric restriction reduced body weight to a similar degree in all four genotypes (by 25% in Wild-type controls, 24% in Ghrelin-KO, 23% in LEAP2-KO, and 26% in LEAP2/Ghrelin-KO; p=n.s.). Blood glucose levels were significantly reduced (p <0.0001) in Ghrelin-KO mice (by 53%) compared to wild-type controls (by 31%) and LEAP2-KO mice (by 22%). Notably, blood glucose levels in LEAP2-KO mice remained similar to those in wild-type littermates (86 ± 7 mg/dL in LEAP2-KO vs. 96 ± 6 mg/dL in WTs on the sixth day of caloric restriction; p=n.s.). Nor did LEAP2 deletion in ghrelin-KO mice affect blood glucose levels (61 ± 9 mg/dL in LEAP2-KO/Ghrelin-KO mice vs. 67 ± 10 mg/dL in ghrelin-KO mice; p=n.s.). Conclusions: These data suggest that in the setting of an acute-on-chronic chronic restriction protocol modeling starvation, LEAP2 does not impact the protective effects of ghrelin in defending against severe hypoglycemia.