Adipose Tissue Plasticity in Catch-Up–Growth Trajectories to Metabolic Syndrome

In the midt a time when the concept of Syndrome X was being introduced by Reaven (1) to draw attention to the cardiovascular risks associated with insulin resistance and compensatory hyperinsulinemia, Tanner (2) was emphasizing a fundamental property of human growth as a targetseeking function: Children, no less than rockets, have their trajectories, governed by control systems of their genetic constitution and powered by the energy absorbed from the environment. Deflect the child from its natural growth trajectory (by acute malnutrition or a sudden lack of a hormone), and a restoring force develops, so that as soon as the missing food or the absent hormone is supplied again, the child hastens to catch-up towards its original growth curve. When it gets there, the child slows again, to adjust its path onto the old trajectory once more. How the child does this we do not know. What was also unknown (and unforeseen) then was that drives catch-up growth long viewed as an essential feature of recovery from the deleterious effects of poor growth on development and health could emerge as a major risk factor for disease entities of syndrome X, now more commonly known as the insulin resistance syndrome or metabolic syndrome. There are now compelling evidence, from both epidemiological and clinical studies, which suggest that people who had low birth weight (often a marker for foetal growth constraints) or who showed reduced growth rate during infancy and childhood, but who subsequently showed catch-up growth, have higher susceptibility for abdominal obesity, glucose intolerance, type 2 diabetes or cardiovascular diseases later in life (3-7). The risks for later obesity and type 2 diabetes seem particularly high when catch-up growth occurs early in postnatal life (4, 6, 7) a pattern of accelerated growth that is common in individuals born small-for-gestational-age. Independently of the timing of catch-up growth, however, the dynamic process of catch-up growth is characterized by a disproportionately faster rate of fat deposition relative to that of lean tissue, with this phenomenon of preferential catch-up fat being intimately associated with hyperinsulinemia (8, 9). The development of insulin resistance interlinked with catch-up fat could thus be an early feature of the mechanisms by which catch-up growth confers increased risk for metabolic syndrome later in life. Of central importance to our understanding of the pathophysiology of catch-up fat, therefore, is the issue of whether (and how) processes that regulate fat storage during catch-up fat may lead to a state of insulin resistance and impaired glucose tolerance. From a standpoint of systems physiology, three fundamental autoregulatory control systems could be implicated in preferential catch-up fat: (i) compensatory hyperphagia, (ii) an increase in fat mass at the expense of lean body mass, and (iii) an increase in metabolic efficiency, i.e. energy conservation mechanisms operating through suppressed thermogenesis, and which are embodied in the concept of a thrifty energy metabolism . The fact that the phenomenon of preferential catch-up fat persists in the absence of hyperphagia or altered lean body mass (9, 10) underscores a central role for suppressed thermogenesis as a fundamental physiological reaction to growth retardation and consequential body fat depletion or delayed adipose tissue development. It has been proposed (8, 9) that as skeletal muscle is a major site for both thermogenesis and insulin-mediated glucose disposal, a reduction in muscle metabolic rate will result in diminished glucose utilization and glucose sparing, thereby leading to compensatory hyperinsulinaemia. As depicted schematically in Figure 1, this in turn, would serve to redirect the spared glucose towards de-novo lipogenesis and fat storage in adipose Published in "Diabetes 58(5): 1037-1039 , 2009" which should be cited to refer to this work.