Amyotrophic lateral sclerosis (ALS) is a motor neuron disease leading to paralysis and death within 2-5 years from disease onset. Other hallmark features include weight loss and metabolic dysfunction. Several lines of clinical evidence indicated that higher energy expenditure (hypermetabolism) is associated with weight loss in ALS patients. Recent clinical evidence showed that the hypothalamus, which governs whole-body energy metabolism, is compromised in ALS and that hypothalamic volume correlates with body weight. However, little is known whether hypermetabolism contributes to disease progression and how the hypothalamus is compromised in ALS. Our newly established ALS mouse model, MATR3 S85C knock-in (Matr3S85C/S85C) mouse, exhibits motor features and neurodegeneration reminiscent of ALS. Matr3S85C/S85C mice also display inability to gain body weight, browning of white fat, higher energy expenditure, and signs of hypothalamic defects, implicating a potential link between hypothalamic dysfunction, hypermetabolism and weight loss. In this proposal, we will determine whether hypermetabolism is associated with weight loss in Matr3S85C/S85C mice (Aim 1). In addition, we will identify which hypothalamic nuclei are affected in the mutant mice (Aim 2). These studies will provide invaluable evidence to illuminate the pathophysiology and the mechanism underlying weight loss in ALS. Understanding the mechanisms of weight loss would be a key step toward developing novel and innovative therapeutic modalities for ALS.