Alterations along the neuroendocrine axis of leptin homeostasis: white adipose tissue and hypothalamus in a severe SMA mouse model.

Spinal Muscular Atrophy (SMA) is characterized by a reduction of survival of motoneuron (SMN) protein, resulting in proximal muscle atrophy. SMA is a multi-system disease involving patients with alterations in multiple organs and metabolic pathways. Approved therapies focus on increasing SMN protein level either in the central nervous system or systemically. However, none of these therapies result in a cure. Patients show perturbations in several organs, including altered lipid metabolism such as leptin proteohormone levels, dicarboxylic aciduria and altered β-oxidation. In this study, we describe alterations along the neuroendocrine axis of leptin homeostasis in white adipose tissue (WAT) and hypothalamus of the severe Taiwanese SMA mouse model. Body weight was significantly decreased in SMA mice accompanied by significantly changed leptin protein levels in WAT of pre-symptomatic (P3) mice. Additionally, transcriptome and proteome analyses of WAT and hypothalamus revealed alterations in lipid and glucose metabolic pathways. We also identified several altered targets associated with appetite regulation. Our findings emphasize dysregulations in lipid and glucose metabolism and reinforce the need for research on metabolism in a disease with a predominant neuromuscular phenotype.