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Background: Undernutrition and anemia are comorbid conditions. The anemia associated with undernutrition is often attributed to increased rates of infection; however, iron deficiency is also common in areas where undernutrition is prevalent. A limited number of studies have shown that undernutrition reduces dietary iron absorption, which may be mediated by increases in the iron regulatory hormone hepcidin. Findings from these studies suggest that increases in hepcidin with undernutrition are independent of the traditional signaling pathways involved in the control of hepcidin synthesis (dietary iron intake and infection/inflammation) and occur in response to gluconeogenic signals. In situations of undernutrition, gluconeogenesis may be activated as glycogen stores are depleted and hepcidin-mediated declines in ferroportin may inhibit iron recycling and dietary iron from entering portal circulation. Objective: The primary objective of the current study was to determine the effects of varying severities and durations of energy restriction on hepcidin and iron homeostasis in male and female mice. Methods: Fourteen-week-old male and female C57BL/6 mice (n=180) were randomized into 7 diet groups: ad libitum and varying levels of energy restriction (10%, 20%, 40%, 60%, 80%,100% energy restriction, n=10/diet). Feed was split into 2 meals provided in the morning and evening and was calculated based on the feed consumed by the ad libitum males or females, respectively. Mice were fed their respective diets for up to 3 weeks. Results: At 48 h, liver hepcidin mRNA increased 4-fold (P<0.01) and serum hepcidin increased by 55% (P<0.005) with 100% energy restriction compared to mice fed ad libitum. At 3 weeks, there was a similar 4-fold increase in liver hepcidin mRNA with both 10% (P<0.01) and 20% (P<0.01) energy restriction, and serum hepcidin increased by 30% with 10% (P=0.083) and 20% (P=0.099) energy restriction. Exploratory analyses revealed sex differences where serum hepcidin increased by 55% (P=0.01) and 63% (P<0.01) with 10% and 20% energy restriction, respectively, in male mice but not female mice. Serum iron declined with energy restriction at 48 h (P=0.04), but there were no post-hoc differences. At 3 weeks, serum iron was reduced with both 10% (P<0.05) and 20% (P<0.01) energy restriction compared to mice fed ad libitum. At 48 h, serum hepcidin was positively correlated with liver hepcidin mRNA (R=0.361, P=0.005) and c-reactive protein (R=0.286, P=0.031), but was not correlated with liver gluconeogenic enzymes. At 3 weeks, serum hepcidin was positively correlated with liver hepcidin mRNA (R=0.539, P<0.0001), and the liver gluconeogenic enzymes Pck1 (R=0.461, P=0.003), Creb3l3 (R=0.590, P<0.0001), Pygl (R=0.569, P<0.0001), and Ppargc1a (R=0.357, P=0.026); and negatively correlated with change in bodyweight (R= –0.436, P=0.006), lean mass (R= –0.408, P=0.010), fat mass (R= –0.414, P=0.009), liver weight (R= –0.502, P=0.001), and gastrocnemius weight (R= –0.382, P=0.017). Conclusions: These findings provide support for gluconeogenesis as a physiologically significant stimulator of hepcidin, even with mild-to-moderate energy restriction of 10-20%. If mild-to-moderate undernutrition increases hepcidin similarly in humans, these findings may provide a possible mechanism for the increased rates of iron deficiency and iron deficiency anemia observed in undernourished populations.