Leptin is a pleiotropic cytokine hormone known to influence numerous physiological processes such as growth, appetite, energy expenditure, stress, reproduction, and immunity in vertebrates. In mammals, leptin is produced by adipose tissue and is thought to work primarily as an adipostat. It circulates in proportion to fat deposition and inhibits appetite while stimulating lipolysis and fatty acid oxidation to prevent excessive lipid accumulation. Its function on energy homeostasis in fish is poorly understood despite leptin’s well-conserved anorexigenic actions. The liver is typically the predominate site of production in fishes and data suggests that leptin may act to regulate carbohydrate catabolism in these and other ectothermic vertebrates. Our prior work in the tilapia (Oreochromis mossambicus) determined that recombinant tilapia leptin A, the predominant paralog in fishes, induces hyperglycemia and depletes hepatic glycogen suggesting the hormone induces glycogenolysis. We have also found that hepatic lepa and/or circulating hormone levels increase in tilapia in response to various stressors, including fasting and seawater challenge, while others show the hormone rises with hypoxia. Both insulin and the classical stress hormones, epinephrine and cortisol, play roles in regulating glucose availability and interact with leptin in tilapia to maintain glucose homeostasis under normal anabolic states as well as during stress-associated catabolic states.
Additionally, in a transcriptomic study of the tilapia pituitary we identified numerous metabolic pathways regulated by leptin. Orthogonal testing showed the hormone induces glycolysis by increasing the activity of key glycolytic enzymes and their transcript levels. The hormone also affected hypoxic responsive pathways likely associated with enhanced anaerobic glycolysis. This led us to hypothesize that leptin may act to decrease oxygen consumption by promoting anaerobic glycolysis and suppressing aerobic respiration.
To this end oxygen consumption rates were measured in perifused pituitary RPDs using intermittent flow respirometry. Recombinant tilapia leptin caused an immediate decline in oxygen consumption rate (mO2) that was sustained over the course of leptin exposure. The rate of oxygen consumption was reduced by 12% with leptin treatment. Upon removal of leptin, mO2 slowly recovered to pre-treatment levels. We then evaluated oxygen consumption and mitochondrial function using the Agilent Seahorse platform. Again, we found that leptin caused an immediate 15% reduction of pituitary basal mO2. This reduction was accompanied by decreased mitochondrial ATP production and spare respiratory capacity. Collectively, these results indicate that leptin may suppress cellular respiration or energy expenditure. This may represent a novel function of leptin in facilitating adaptation and survival in the face of physiologic and environmental stressors like hypoxia, infection, and osmotic stress.