Abstract
We assessed if leptin, a cytokine hormone known to enhance energy expenditure by promoting lipid and carbohydrate catabolism in response to physiologic stress, might directly regulate cellular glycolysis. A transcriptomic analysis of prolactin cells in the tilapia (Oreochromis mossambicus) pituitary rostral pars distalis (RPD) revealed that recombinant leptin (rtLep) differentially regulates 1,995 genes, in vitro. Machine learning algorithms and clustering analyses show leptin influences numerous cellular gene networks including metabolism; protein processing, transport, and metabolism; cell cycle and the hypoxia response. Leptin stimulates transcript abundance of the glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase (gapdh) in a covariate manner to the hypoxic stress gene network. Orthogonal tests confirm that rtLepA dose-dependently increases gapdh gene expression in the RPD along with transcript abundance of 6-phosphofructo-1-kinase (pfk1), the rate limiting glycolytic enzyme. Functional testing demonstrated that leptin stimulates PFK activity and glycolytic output, while Stattic (a STAT3 blocker) was sufficient to suppress these responses, indicating leptin stimulates glycolysis through a STAT3-dependent mechanism. Leptin also stimulated pfk1 gene expression and lactate production in primary hepatocyte incubations in a similar manner to those shown for the pituitary RPD. This work characterizes a critical metabolic action of leptin to directly stimulate glycolysis across tissue types in a teleost model system, and suggest that leptin may promote energy expenditure, in part, by stimulating glycolysis. These data in a teleost fish, suggest that one of leptin's ancient, highly-conserved functions among vertebrates may be stimulation of glycolysis to facilitate the energetic needs associated with various stressors.
Highlights
Leptin is a pleiotropic cytokine that regulates numerous physiological processes and whose dysfunction is implicated in pathologies including obesity, diabetes, and cancer [1, 2]
To identify functionally interactive gene networks regulated by leptin, a reduction of data dimensionality (RDD) analyses was performed on the most highly significant differentially expressed genes (DEGs) or those with the lowest p-values
The RDD demonstrates that at least 400 highly significant DEG inputs are required to build an artificial neural network model of leptin signaling with optimal predictive accuracy (Figure 1A; Supplemental Table 2)
Summary
Leptin is a pleiotropic cytokine that regulates numerous physiological processes and whose dysfunction is implicated in pathologies including obesity, diabetes, and cancer [1, 2]. Leptin is elevated during hypoxia in a wide range of vertebrates, when metabolic rate is suppressed; the hormone may drive energy production and overall expenditure even when oxidative respiration is less viable, possibly by stimulating fermentation pathways [12,13,14,15]. These findings point toward an emerging paradigm for leptin across vertebrate taxa as a comprehensive promoter of energy expenditure under both normoxic and hypoxic conditions where it mobilizes energy reserves, enhances substrate uptake in peripheral cells, and induces their catabolism. The data illustrate leptin directly stimulates glycolysis by increasing the expression of glycolytic genes, the activity of glycolytic enzymes, and overall glycolytic output through a STAT3 dependent mechanism
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