METABOLIC PLASTICITY

Markers of prenatal metabolic plasticity and assessment of their reversibility by postnatal interventions

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 Obiettivo del progetto (Objective)

'Inactivity and nutritional aberrations result in an expanding population of individuals with compromised metabolic function including obesity and insulin resistance. From this pool of individuals an increasing percentage develops overt diabetes leading to vast personal and social burden. Natural interventions are beneficial and exercise accompanied by weight loss can reverse insulin resistance, at least partially. Metabolic stress history has significant impact on the long-term organization of metabolic adaptive responses, especially during early stages of life (intrauterine and early postnatal). Individual variability of genetic background and metabolic-stress history coincides with the need for diverse interventions, in order to optimize metabolic control. Linking distinct markers of metabolic aberrations with genetic and metabolic stress history components will provide tools for individualized approaches for treating patients, which will facilitate our efforts to “normalize” a maladaptive metabolic profile in the context of a sedentary/hypercaloric life style. The general aim of the proposed study is to define the experimental tools that will shape a model animal system for the study of the metabolic impact of interventions that may be used therapeutically in states of compromised metabolism. The specific aims include (a) the identification of serum and tissue markers that specifically characterize the metabolic derangements associated with distinct mouse models of in utero metabolic risk and (b) the examination of the effects of nutritional, medicinal, hormonal and physical activity interventions on these markers and their association with changes in insulin resistance and metabolic balance. Establishing an experimental model that will facilitate the assessment of the metabolic effects of medicinal and, primarily, life-style measures, such as exercise and nutritional/caloric modifications, will help the study of debilitating states such as diabetes and cachexia.'

Introduzione (Teaser)

Poor physical activity and sub-optimal nutrition as well as what happens in the womb may induce obesity, metabolic syndrome and diabetes. Predisposed individuals require early intervention strategies to prevent onset of such conditions .

Descrizione progetto (Article)

The EU-funded METABOLIC PLASTICITY project worked on identifying markers of metabolic aberrations to monitor metabolic profiles in high-risk individuals during pharmaceutical and lifestyle interventions.

Multiple human epidemiological studies have linked our metabolic adaptive responses and susceptibility to diabetes to our prenatal exposure to over-nutrition, under-nutrition or other stressors. Project members used in utero mouse models to study effects of low birth weight due to maternal under-nutrition (UN) on offspring. Comparison of maternally undernourished mice with normal mice showed that maternal UN produces offspring with aberrant metabolism and predisposition to obesity.

The 5' adenosine monophosphate-activated protein kinase (AMPK) and the mammalian target of rapamycin (mTOR) pathway are known regulators of cellular energy and nutrition. Protein phosphatase 2A (PP2A) helps regulate cell homeostasis by fine-tuning energy and nutrient sensing in cells of normal mice.

Analysis of mice tissue samples showed that the amount of PP2A-A is altered in the offspring of undernourished mice. Its knockdown in cultured cells confirmed that PP2A acts as a controller in the AMPK/mTOR sensor system.

Such developmental metabolic plasticity may be reflected in non-linear correlation patterns between birth weight and metabolic markers.

Predicting biological variability and response to interventions using markers and mathematical modelling could be the key to normalising compromised metabolic profiles in high-risk individuals.