GDF15 regulates its anorexic effects through the hindbrain area postrema (AP) and nucleus of the solitary tract (NTS) neurons where its receptor, glial-derived neurotrophic factor receptor alpha-like (GFRAL), is expressed. The actions of GDF15 may interact with other appetite regulators elevated in obesity, such as leptin. Here, we report that in mice with high-fat-diet-induced obesity (HFD), the combined infusion of GDF15 and leptin causes significantly greater weight and adiposity loss than either treatment alone, indicating potentiation between GDF15 and leptin. Furthermore, obese, leptin-deficient ob/ob mice are less responsive to GDF15, as are normal mice treated with a competitive leptin antagonist. GDF15 and leptin induce more hindbrain neuronal activation in HFD mice than either treatment alone does. We report extensive connections between GFRAL- and LepR-expressing neurons and find LepR knockdown in the NTS to reduce the GDF15-mediated activation of AP neurons. Overall, these findings suggest that leptin signaling pathways in the hindbrain increase GDF15's metabolic actions.
Keywords: GDF15; GFRAL; adiposity; appetite; area postrema; body weight; hindbrain; leptin; nucleus of solitary tract; obesity.
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