Attenuated glucose uptake promotes catabolic metabolism through activated AMPK signaling and impaired insulin signaling in zebrafish

Abstract

Glucose metabolism in fish remains a controversial area of research as many fish species are traditionally considered glucose-intolerant. Although energy homeostasis remodeling has been observed in fish with inhibited fatty acid β-oxidation (FAO), the effects and mechanism of the remodeling caused by blocked glucose uptake remain poorly understood. In this study, we blocked glucose uptake by knocking out <i>glut2</i> in zebrafish. Intriguingly, the complete lethality, found in <i>Glut2</i>-null mice, was not observed in <i>glut</i>2^-/- zebrafish. Approxiamately 30% of <i>glut</i>2^-/- fish survived to adulthood and could reproduce. The maternal zygotic mutant <i>glut2</i> (MZ<i>glut2</i>) fish exhibited growth retardation, decreased blood and tissue glucose levels, and low locomotion activity. The decreased pancreatic β-cell numbers and <i>insulin</i> expression, as well as liver <i>insulin receptor a</i> (<i>insra</i>), fatty acid synthesis (<i>chrebp, srebf1, fasn, fads2</i>, and <i>scd</i>), triglyceride synthesis (<i>dgat1a</i>), and muscle mechanistic target of rapamycin kinase (<i>mtor</i>) of MZ<i>glut2</i> zebrafish, suggest impaired insulin-dependent anabolic metabolism. Upregulated expression of lipolysis (<i>atgl</i> and <i>lpl</i>) and FAO genes (<i>cpt1aa</i> and <i>cpt1ab</i>) in the liver and proteolysis genes (<i>bckdk, glud1b</i>, and <i>murf1a</i>) in muscle were observed in the MZ<i>glut2</i> zebrafish, as well as elevated levels of P-AMPK proteins in both the liver and muscle, indicating enhanced catabolic metabolism associated with AMPK signaling. In addition, decreased amino acids and elevated carnitines of the MZ<i>glut2</i> zebrafish supported the decreased protein and lipid content of the whole fish. In summary, we found that blocked glucose uptake impaired insulin signaling-mediated anabolism <i>via</i> β-cell loss, while AMPK signaling-mediated catabolism was enhanced. These findings reveal the mechanism of energy homeostasis remodeling caused by blocked glucose uptake, which may be a potential strategy for adapting to low glucose levels.