Is metabolic flexibility determined by early life nutrition?

Abstract

The environment during development has a strong influence on metabolism in later life. In particular, reduced nutrition in early development is associated with obesity in later adulthood. However, the causal mechanisms and processes underlying the phenomenon are not fully defined. The primary objective of this thesis was therefore to identify and investigate mechanisms underlying the above association. My experimental studies focussed on structure and function of skeletal muscle, regulation of gene transcription, and postnatal outcomes for prenatally undernourished rats relative to their controls. The outcome of the study is that undernourished rats follow a developmental pathway characterised by efficient energy use and storage together with capacity for metabolic flexibility that differs from dietary-induced obesity. A well-established rat model of reduced maternal nutrition during pregnancy consistently produces offspring that become obese as adults. These offspring are metabolically distinct from the offspring of adequately nourished mothers and this thesis contributes to understanding their unique metabolic phenotype. My experiments investigated: (1) the capacity for metabolic flexibility from birth through to weaning and adulthood; (2) factors integral to pathways that regulate metabolic plasticity; and (3) interactions between the prenatal environment, varied postnatal environmental conditions, the outcomes for body composition and skeletal muscle metabolism. My study demonstrated changes in skeletal muscle structure and metabolic function for offspring of undernourished mothers compared with their controls. The impact of prenatal undernutrition on postnatal skeletal muscle development became apparent as the offspring matured. In particular, mechanisms may include altered patterns of gene expression for mitochondrial biogenesis and calcium signalling pathways. The altered regulation of these genetic factors highlights mechanisms for the observed fibre type composition and oxidative capacity of skeletal muscle, even in a sedentary postnatal environment. In sum, this thesis demonstrates that the consequences for adult rats of growth restriction in utero are substantially different from dietary obesity in control adult rats despite superficial similarity between the two conditions. This difference arises from under-nourished foetuses following a developmental pathway that prepares them for survival under conditions where food may be scarce. The difference was recognised from the structure and function of muscles, retained insulin sensitivity, deposition and use of stored fat, and at the level of gene transcription. These results support the hypothesis that offspring of undernourished mothers have increased flexibility of energy storage and use by way of enhanced oxidative metabolism.