Caloric restriction (CR) life span of animals, while in humans excess nutrient intake is associated with the "syndrome of insulin resistance". This syndrome represents a constellation of metabolic defects that are important risk factors for age-related diseases. Under normal circumstances, the deleterious effects of the excessive availability of nutrients are countered by the prompt activation of nutrient "counterregulatory" systems. The latter include (but is not limited to) hypothalamic neuro-circuitries partly under the control of leptin. The activation of these nutrient "counterregulatory" systems should prevent the excessive storage of energy and the onset of insulin resistance. We will demonstrate that the hexosamine biosynthesis pathway (HBP) is a central nutrient-sensing mechanism. Activation of HBP induces insulin resistance and regulates the secretion of several adipose-derived peptides through (but is not limited to) glycolysation of transcription factor SP1. We will demonstrate that: 1) Aging muscle, independent of body fat, expresses higher levels of the end products of HBP, supporting increased activation of this nutrient sensing pathway. 2) Challenging this pathway directly by glucosamine administration leads to rapid peripheral insulin resistance in aging rats. 3) In parallel, activation of the HBP increases the expression, in particular in visceral fat, of potentially harmful fat-derived peptides associated with insulin resistance and its syndrome. Because a chronic increase in nutrients can directly increase carbon flux through HBP, it may have a potential role in the metabolic syndrome of aging and on the mechanisms mediating the beneficial effects of CR.
hexosamine biosynthetic pathway