Adaptive Responses in Severe Acute Malnutrition: Endocrinology, Metabolomics, Mortality, and Growth

Malnutrition afflicts millions of the world's children and predisposes to death from diarrhea and infectious diseases. Children with severe acute malnutrition (SAM) are at highest risk. Our review of the endocrinology and metabolomics of SAM implicates critical roles for white adipose tissue and its regulatory hormones and growth factors in the adaptation to nutritional deprivation and the restoration of metabolic homeostasis: white adipose provides substrates and energy for hepatic glucose production and cardiopulmonary and central nervous system function, and products of fat metabolism inhibit muscle glucose uptake and utilization and spare muscle protein. Collectively, these effects maintain glucose availability for the brain, red blood cells, and renal medulla and conserve muscle mass. White adipose tissue also secretes leptin, which facilitates the immune response and may protect against mortality from infection. Euglycemia and survival in SAM are thereby prioritized over linear growth, which is suppressed owing to inhibition of insulin-like growth factor 1 production and action. Diversion of energy from growth serves to maintain essential bodily functions in critically ill malnourished children, who have limited energy reserves. Thus, short-term reductions in growth rate have adaptive benefits in SAM. Under favorable conditions, clinical and metabolic recovery are accompanied by catch-up growth, which can mitigate, and in many cases reverse, the stunting of growth in childhood. Nevertheless, clinical recovery can be complicated by preferential accrual of central fat and a relative deficiency of lean/skeletal mass, with potential long-term complications including insulin resistance, glucose intolerance, and metabolic syndrome.