Are we eating more than we think? Illegitimate signaling and xenohormesis as participants in the pathogenesis of obesity.

Resource utilization may represent a central force driving evolution. A tight link between sensing energy availability and managing energy acquisition and utilization constitutes a common feature among all organisms. While such a link was likely adaptive during prehistoric evolution, modern lifestyles may decouple perceived cues from actual energy availability so as to promote obesity in humans. A particular illegitimate signal is chronic stress, which may shift body phenotype to suit a more conservative state of energy management. In prehistoric times, such a response likely aided survival during periods of low resource availability. However, new sources of chronic stress have emerged that bear little relationship to contextual energy, which is generally abundant in the modern world. In addition, modern techniques of husbandry and agriculture can produce stress in the food chain, such that food itself can act as an illegitimate signal of chronic stress. Obese livestock and unusual fat profiles in farmed fish, meat, and eggs may reflect stress phenotypes. Consumers of stressed foods may sense those signals--a phenomenon known as xenohormesis--and assume the stressed phenotype. This maladaptive process may promote obesity by erroneously biasing hosts towards caloric accumulation in the context of energy abundance. Regional tissue accumulation of fat may indicate local tissue stress. Atherosclerosis may result from stress signals that induce sympathetic bias and regional fat accumulation in vessel adventitia. Medications such as neuroleptics and foods such as diet drinks may generate illegitimate signals by mimicking molecules used for energy management. Implications for the prevention and treatment of dysfunctions related to these derangements are discussed. New strategies for manufacturing biologics by manipulating stress conditions or controlling fatty acid attachments to proteins are envisioned.