The continuum of disrupted metabolic tempo, mitochondrial substrate congestion, and metabolic gridlock toward the development of non-communicable diseases

Non-communicable diseases (NCD) are the slow-motion disasters with imminent global health care burden. The current dietary management for NCD is dominated by the calorie balance model. Apart from the quantitative balance of calorie, healthy bioenergetics requires temporal eating and fasting rhythms, and the subsequent switching for different metabolic fuels. We herein term these three bioenergetic attributes, i.e., caloric balance, diurnal eating-fasting rhythm, and metabolic flexibility, as the metabolic tempo. These three attributes are intertwined with each other; alteration of one attribute affects one or more other attributes. Lifestyle-induced disrupted metabolic tempo presents a high flux of mixed carbon substrates to mitochondria, with the resulting congestion and indecisiveness of metabolic switches. Such indecisiveness impairs metabolic flexibility, promotes anabolism, and accumulates the energy storage pools. The triggers from hypoxic inducible factor expression could further promote the metabolic gridlock and adipocyte maladaptation. The maladaptive adipocytes lead to ectopic fat deposition, increased circulating lipid levels, insulin resistance, and chronic systemic inflammation. These continuum set stages for clinical NCDs. We propose that the restoration of all tempo attributes through the combined diet-, time-, and calorie-restricted interventions could be the preferred strategy for NCD management.