Neuronal surface P antigen (NSPA) as a novel regulator of energy homeostasis and adipose tissue metabolism.

Regulation of body weight and glucose homeostasis includes the coordinated activity of hypothalamic neurons and adipocytes within a neuroendocrine network whose dysfunctions underlie obesity, insulin resistance, and type 2 diabetes (T2D). The neuronal surface P antigen (NSPA) is a plasma membrane protein with characteristics of an E3 ubiquitin ligase encoded by the unique gene Zzef1, which has been linked to T2D. NSPA's original discovery in neurons, as a cell-surface cross-reacting autoantigen of anti-P antibodies that associate with cognitive dysfunctions in patients with systemic lupus erythematosus, focused its study on hippocampal-mediated memory processes. Anti-P effects and NSPA-KO mice revealed that NSPA contributes to glutamatergic transmission and synaptic plasticity through mechanisms involving ubiquitylation processes coupled to the stability of NMDAR at the synaptic density. However, NSPA is also expressed in hypothalamic neurons, where glutamatergic synapses and NMDAR function are pivotal to the neuroendocrine control of metabolic and energy balance. Transcriptomics suggests an extended expression of NSPA in metabolically relevant peripheral tissues, including the adipose tissue. Here, we investigated whether body weight regulation and energy homeostasis involve NSPA. We characterized the phenotype of NSPA-KO mice under standard chow and high-fat/high-sugar (HFHS) obesogenic diet conditions, monitoring metabolic parameters and WAT's expression of enzymes and transporters of the glucose metabolism and lipolysis. NSPA-KO mice exhibit: (i) Increased body weight gain, despite similar food intake and higher horizontal locomotion activity; (ii) A shift towards a glycolytic metabolism reflected in an increased RER, accompanied by an increased WAT mass indicating higher lipogenesis; (iii) Improved early glycemic response to glucose challenge, attenuating the acute glycemic rise induced by HFHS feeding; (iv) Reduced insulin sensitivity at 20 weeks of age; (v) Elevated Glut1 and LDH, with decreased Glut4, and HSL S563 phosphorylation in WAT, indicating altered glucose uptake, glycolysis and lipolysis; (vi) Decreased levels of phosphorylated STAT3 in the hypothalamus, suggesting attenuated leptin signaling. This study identifies NSPA as a novel regulator of energy homeostasis, body weight, glucose metabolism, insulin sensitivity, and adipose tissue accumulation, presumably acting at both the hypothalamus and WAT, with potential implications for obesity and metabolic disorders.