Tissue-specific knockout models for AMPKα1/α2, SIRT1, or PGC-1α can delineate causal roles in immunometabolic remodeling, while disease-specific animal models (e.g., high-fat diet–induced obesity, streptozotocin-induced diabetes, or APP/PS1 Alzheimer’s models) can evaluate physiological relevance. This evidence concerns the gene PRKAA1 and obesity due to melanocortin 4 receptor deficiency.