Glucose Signaling in Naked Mole-rats during Hypoxia

Abstract

In hypoxic conditions, glucose metabolism plays an essential role in energy production in most mammals, as many tissues shift toward anaerobic glycolysis to meet cellular energy demands. However, some hypoxia-tolerant species maintain partial aerobic metabolism or utilize alternative metabolic pathways to sustain ATP production. Of particular interest are mechanisms that regulate metabolic rate and energy balance, as hypoxia suppresses aerobic pathways, potentially leading to cell death in hypoxia-intolerant species. Naked mole-rats (NMRs, Heterocephalus glaber) are among the most hypoxia-tolerant mammals and significantly suppress their metabolic rate under hypoxic conditions. NMRs also switch from primarily lipid-based metabolism during normoxia to carbohydrate-based metabolism during hypoxia. Despite their exceptional hypoxia tolerance, how NMRs regulate glucose metabolism and energy balance across developmental stages remains unclear. It is also unknown whether adult NMRs retain neotenic traits that contribute to their hypoxia tolerance, suggesting a potential evolutionary adaptation. The goal of my thesis is to examines how different developmental stages of NMRs regulate their metabolic rate and glucose metabolism in normoxia and hypoxia. We hypothesize that NMRs exhibit abnormal glucose metabolism regulation that varies across developmental stages and caste roles within the colony, influencing their ability to conserve energy under hypoxia. We predict that all groups of NMRs will suppress their metabolic rate and downregulate glucose metabolism pathways to conserve energy, with this suppression being more pronounced in younger animals. To address these questions, newborns, juveniles, and adults (subordinates and queens) were exposed to normoxia (21% O₂) or acute hypoxia (7%, 5%, or 3% O₂) to measure metabolic rate, body temperature, and blood glucose levels. Glucose, insulin, and insulin-like growth factor-1 (IGF-1) were administered to assess glucose handling in NMRs during normoxia and sever acute hypoxia (3% O2). Molecular analysis focused on normoxia and severe hypoxia (3% O₂) to examine blood lactate levels, glycolytic enzyme activity, glycogen metabolism, gluconeogenesis, IGF signaling, and glucose transporter expression. Our findings reveal several novel insights into NMR glucose metabolism: 1) All age groups reduce metabolic rate and body temperature across all hypoxia levels. Subordinates and juveniles primarily metabolize lipids in normoxia but switch to carbohydrates in hypoxia, whereas queens rely on carbohydrate metabolism under all conditions. 2) Blood glucose increases in hypoxia across all groups but with differing thresholds. Blood glucose rises in moderate hypoxia for queens and pups but only in severe hypoxia for subordinates and juveniles. While glucose tolerance remains similar across groups in normoxia, clearance times following a bolus glucose challenge are 2-3 times longer in juveniles and subordinates than in queens or pups under hypoxia. Administration of insulin or IGF-1 lower blood glucose in subordinates in all conditions, but only IGF-1 impacts blood glucose in hypoxic queens. 3) Blood lactate accumulation and anaerobic pathways show tissue-specific adaptations. Hypoxia elevates blood lactate levels in all groups, reflecting increased anaerobic metabolism. Gene and protein analyses reveal that subordinates and juveniles enhance glucose mobilization for energy, while queens prioritize ATP conservation for prolonged hypoxic survival. Overall, these findings highlight metabolic adaptations across tissues, developmental stages, and castes in NMRs, enabling their survival in hypoxia. Subordinates and juveniles exhibit metabolic flexibility, supporting their energy-intensive roles in tunneling, foraging, and caretaking. In contrast, queens prioritize ATP conservation to sustain reproduction. These caste- and age-specific strategies optimize survival and efficiency within the colony, reinforcing the exceptional hypoxia tolerance and resilience of NMRs.