The Starving Cell: Metabolic Syndrome as an Adaptive Process

Metabolic syndrome (MetS) is commonly presumed to stem from obesity, with both propelled by energy surfeit: positive balance of calories consumed to energy expended. A complementary thesis is proposed: that episodes of cell energy deficit (not expressly calorie deficit) drive MetS – the “Starving Cell.” Risk factors for MetS include hypoxemia from sleep apnea, severe calorie debt, mitochondrial dysfunction, oxidative stress; and sleep restriction, illness, surgery, trauma, cold. Each fosters inadequate cell energy, hampering production or boosting demand. MetS factors support energy: glucose, triglycerides, abdominal/visceral fat – and blood pressure, sustaining perfusion. Additional energy-supportive adaptations co-occur in MetS: e.g. increased free fatty acids and deposition of metabolically active ectopic fat. Indeed, increased appetite/calories and reduced activity – features of the energy surfeit model – also arise as adaptations to cell energy deprivation. Among persons who are overweight, the risk for MetS remains determined by energy deprivation contributors. The Thrifty Gene hypothesis, and MetS promotion by fetal energy deprivation, prefigure the Starving Cell thesis. However, evidence is vastly more comprehensive in connecting cell energy deprivations to MetS elements: generalizing the sources of energy deficit that dispose to MetS; the populations vulnerable to their impact; and the forms of adaptation implemented to protect energy. This clarifies why MetS factors cohere; and why other energy-supportive adaptations attend them. It explains bidirectional MetS associations; and why MetS factors appear “paradoxically” protective in some populations. It generates predictions, and suggests approaches to MetS mitigation that complement and modify existing approaches, and may augment their efficacy. N at ur e P re ce di ng s : h dl :1 01 01 /n pr e. 20 11 .6 53 5. 1 : P os te d 15 O ct 2 01