Gangliosides, complex membrane glycosphingolipids, engage in a variety of inter- and intracellular interactions, and play a crucial role in the pathogenesis of various neurological and neurodegenerative diseases. Another membrane constituent, leptin receptor (LepR), modulates feeding behavior by influencing signaling and integration in many regions of the central nervous system. Studies show that a-series gangliosides alter leptin activity by interacting with LepR The redistribution of gangliosides can also influence the regulation of the Na⁺,K⁺-ATPase (NKA) function, whereas leptin pathways can inhibit NKA. Our aim was to deepen the understanding of how altered ganglioside profile impacts abundance and activity of LepR and NKA in mouse thalamus. We used St8sia1 null mouse model, which lacks GD3 synthase and consequently does not synthesize b-series gangliosides, but instead synthesizes more a-series gangliosides compared to wild-type (WT) mice. Both isoforms, 125 kDa and 100 kDa of LepR, were explored. We used protein expression analysis by Western blotting for LepR and NKA in thalamus samples. In addition, enzyme activity of NKA was measured in null compared to WT mice. Results revealed higher amounts of NKA and lower amount of both LepR isoforms in thalamus samples of the null mice compared to their WTs. Enzyme activity of NKA was lower in thalamus samples of null mice compared to their WTs. Therefore, altered ganglioside composition differentially affects NKA and LepR abundance, accompanied by lower NKA enzyme activity in the mouse thalamus, suggesting a noteworthy connection between leptin receptor and NKA ion transporter in a diverse glycolipid milieu.