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

Abstract

Catch-up growth early in life (after fetal, neonatal or infantile growth retardation) is a major risk factor for later obesity, type-2 diabetes and cardiovascular diseases. These risks are generally interpreted alongside teleological arguments that environmental exposures which hinder growth early in life lead to programming of 'thrifty mechanisms' that are adaptive during the period of limited nutrient supply (or growth constraint), but which increase risks for diseases during improved nutrition and catch-up growth later in life. This paper addresses this notion of 'thrifty mechanisms' in the light of evidence that catch-up growth is characterized by a disproportionately higher rate of fat gain relative to lean tissue gain, and that such preferential catch-up fat is in part driven by energy conservation mechanisms operating via suppressed thermogenesis. It provides a molecular-physiological framework which integrates emerging insights into mechanisms by which this thrifty 'catch-up fat' phenotype cross-links with insulin and leptin resistance.

Hepatic mitochondrial energetics during catch-up fat after caloric restriction

“…In addition, the findings from indirect calorimetry of NPRQ values greater than 1 suggest that the increased lipid deposition typical of refed rats is partly the result of the occurrence of a higher rate of de novo lipogenesis in refed rats than in controls. This result is well in agreement with the "glucose redistribution hypothesis" [7,21], according to which the insulin-resistant state of skeletal muscle found in refed rats is of central importance in sparing glucose that can be diverted toward de novo lipogenesis and fat storage in adipose tissue. Indeed, a higher FAS activity-and hence de novo lipogenic capacity-has been reported in white adipose tissues of refed rats relative to controls [7,21].…”

“…This result is well in agreement with the "glucose redistribution hypothesis" [7,21], according to which the insulin-resistant state of skeletal muscle found in refed rats is of central importance in sparing glucose that can be diverted toward de novo lipogenesis and fat storage in adipose tissue. Indeed, a higher FAS activity-and hence de novo lipogenic capacity-has been reported in white adipose tissues of refed rats relative to controls [7,21]. Given the importance of the liver a site for de novo lipogenesis, our results showing that hepatic FAS activity is also significantly higher after 1 week of refeeding suggest that the liver could also be contributing importantly to the enhanced whole-body de novo lipid synthesis in refed rats.…”

Ontogenesis of muscle and adipose tissues and their interactions in ruminants and other species

“…Programming of foetal lean-to-fat ratio by maternal nutrition during pregnancy The relationships between maternal nutrient intake during pregnancy and the growth of the foetus help to ensure successful pregnancy and the life-long health and productivity of offspring, partly as the result of controlled lean-to-fat ratio (Wu et al, 2006;Cottrell and Ozanne, 2008;Dulloo, 2008). In ruminants, several strategies have been used to study the effects of maternal nutrition: (i) changes in maternal energy intake to modify the nutrient availability for the foetus, (ii) experimental restriction of nutrient delivery through placental carunclectomy, and (iii) reduction in the uterine blood flow to induce small birth weight as a model for human intrauterine growth retardation (Redmer et al, 2004;Cottrell and Ozanne, 2008;Forhead and Fowden, 2009).…”

“…However, foetal metabolic adaptations to maternal undernutrition exist at least in sheep that will favour a disproportionately higher rate of fat gain relative to muscle gain in a post-natal environment providing plentiful nutrition. These adaptations, also called 'thrifty mechanism' (Cottrell and Ozanne, 2008;Dulloo, 2008), result partly from cross-talk between muscle and WAT (see 'Interactions' below).…”

“…In monogatrics, a 'thrifty mechanism' was proposed to sustain the compensatory growth and preferential deposition of WAT in the post-natal period (Dulloo, 2008). A decrease in plasma level of leptin or other adipose-specific signal(s) that sense the state of AT store depletion leads to a decrease in PI3K-and AMPK-stimulated energy expenditure in muscle.…”