The thrifty ‘catch-up fat’ phenotype: its impact on insulin sensitivity during growth trajectories to obesity and metabolic syndrome

Abstract

The analyses of large epidemiological databases have suggested that infants and children who show catch-up growth, or adiposity rebound at a younger age, are predisposed to the development of obesity, type 2 diabetes and cardiovascular diseases later in life. The pathophysiological mechanisms by which these growth trajectories confer increased risks for these diseases are obscure, but there is compelling evidence that the dynamic process of catch-up growth per se, which often overlaps with adiposity rebound at a younger age, is characterized by hyperinsulinemia and by a disproportionately higher rate in the recovery of body fat than lean tissue (i.e. preferential 'catch-up fat'). This paper first focuses upon the almost ubiquitous nature of this preferential 'catch-up fat' phenotype across the life cycle as a risk factor for obesity and insulin-related complications -not only in infants and children who experienced catch-up growth after earlier fetal or neonatal growth retardation, or after preterm birth, but also in adults who show weight recovery after substantial weight loss owing to famine, disease-cachexia or periodic dieting. It subsequently reviews the evidence indicating that such preferential catch-up fat is primarily driven by energy conservation (thrifty) mechanisms operating via suppressed thermogenesis, with glucose thus spared from oxidation in skeletal muscle being directed towards de novo lipogenesis and storage in white adipose tissue. A molecular-physiological framework is presented which integrates emerging insights into the mechanisms by which this thrifty 'catch-up fat' phenotype crosslinks with early development of insulin and leptin resistance. In the complex interactions between genetic constitution of the individual, programming earlier in life, and a subsequent lifestyle of energy dense foods and low physical activity, this thrifty 'catch-up fat' phenotype -which probably evolved to increase survival capacity in a hunter-gatherer lifestyle of periodic food shortages -is a central event in growth trajectories to obesity and to diseases that cluster into the insulin resistance (metabolic) syndrome.

Postnatal catch-up fat after late preterm birth

“…Moreover, amino acid delivery immediately after birth does not match the high fetal protein intake (16). In addition, it has been suggested that catch-up growth may lead to a state of skeletal muscle insulin resistance, which seems to be strictly associated with an accelerated rate of deposition of fat mass rather than fatfree mass (FFM) (17). The adipose tissue appears to exert a specific control of thermogenesis, i.e., thermogenesis is suppressed by the depleted adipose fat stores during starvation, to spare energy.…”

“…Instead of being used in the skeletal muscle glucose is redistributed for lipogenesis and storage in the adipose tissue. This preferential "catch-up fat" can eventually lead to an increased adiposity that, in association with adipose tissue hyper-responsiveness and hyperinsulinemia, may represent an additional risk factor for the development of the metabolic syndrome in young adulthood (17). On the basis of these experimental studies, the rapid catch-up fat shown by the late preterm infants could be partially explained by the fact that the infants enrolled in this study were relatively "underfed" in the first days of life.…”

“…There is evidence that monitoring not only the quantity but also the quality of growth, in terms of body composition changes, may play an important role in gaining further insight into the relationship between birth weight and time in utero on early growth pattern and future health (4)(5)(6). Indeed, extremely preterm infants, assessed at term-corrected age, have been found to be at increased risk for developing increased and/or aberrant adiposity, which is a known risk marker for cardiovascular disease (7,8).…”

Thrifty energy metabolism in catch-up growth trajectories to insulin and leptin resistance

“…More direct evidence for the occurrence of preferential catch-up fat early in life can be derived from a recent longitudinal study of body composition -assessed by dual energy x-ray absorptiometry (DEXA) scan -in infants between the ages of 2 and 5 years born SGA in Spain. 32 A re-analysis of these data 30 reveals that already between ages of 2 and 4.5 years, children born SGA gained more total body fat and less lean tissue, and hence a markedly higher ratio of fat mass to lean tissue mass, than children born AGA, despite similar gains in weight and BMI (Figure 1). By about 4 years of age, those children born SGA had greater total adiposity and abdominal fat, and showed lower insulin sensitivity, than children born AGA.…”

Weight fluctuations and risk for metabolic syndrome in an adult cohort

“…4,5 Although there is a general agreement that modest weight loss has beneficial health effects in obese patients, 6 there are some hypotheses that suggest that weight cycling could be damaging particularly for CVD risk. 7,8 However, studies investigating the effect of weight variability on CVD risk have shown controversial results. Some studies indicated that the overall weight trend had a greater deleterious effect on CVD risk than weight fluctuation (WF) (that is the WF effect was not significant after adjustment for weight change), [9][10][11] whereas others concluded that WF had an independent effect.…”