Chronic metabolic diseases are widely understood as disorders of excess — excess calories, excess adiposity, excess glucose, excess inflammation. However, converging evidence across mitochondrial biology, adipose immunology, hepatic lipid metabolism, autonomic physiology, microbiome signaling, and circadian regulation indicates that the primary pathology is not excess activation, but impaired resolution.
Metabolic health depends on the capacity to transition between energetic states — to shift flexibly between glucose and lipid utilization, sympathetic activation and parasympathetic recovery, inflammatory initiation and resolution. This capacity for state-transition is governed by an integrated network linking mitochondrial dynamics, adipose endocrine signaling, immune tone, vagal modulation, and circadian control. When these systems become synchronized in rigidity, metaflammation, adipose overflow, mitochondrial fragmentation, and autonomic threat-lock emerge, forming the shared mechanistic substrate of diabetes, hypertension, NAFLD, cardiovascular disease, autoimmune vulnerability, and neurodegeneration.
This work presents a unified, physiology-first framework for understanding the onset, progression, and potential reversibility of chronic disease. It clarifies how recovery occurs when the conditions for resolution are restored — not through intensification, restriction, or control, but through re-enabling the organism’s innate capacity to return to repair.
