The early origins of obesity and insulin resistance: timing, programming and mechanisms.

Maternal obesity is associated with an increased risk of developing gestational diabetes mellitus and it also results in an increased risk of giving birth to a large baby with increased fat mass. Furthermore, it is also contributes to an increased risk of obesity and insulin resistance in the offspring in childhood, adolescence and adult life. It has been proposed that exposure to maternal obesity may therefore result in an 'intergenerational cycle' of obesity and insulin resistance. There is significant interest in whether exposure to maternal obesity around the time of conception alone contributes directly to poor metabolic outcomes in the offspring and whether dieting in the obese mother before pregnancy or around the time of conception has metabolic benefits for the offspring. This review focusses on experimental and clinical studies that have investigated the specific impact of exposure to maternal obesity during the periconceptional period alone or extending beyond conception on adipogenesis, lipogenesis and on insulin signalling pathways in the fat, liver and muscle of the offspring. Findings from these studies highlight the need for a better evidence base for the development of dietary interventions in obese women before pregnancy and around the time of conception to maximize the metabolic benefits and minimize the metabolic costs for the next generation.

Acute inhibition of casein kinase 1δ/ε rapidly delays peripheral clock gene rhythms.

Circadian rhythms are generated through a transcription-translation feedback loop involving clock genes and the casein kinases CSNK1D and CSNK1E. In this study, we investigated the effects of the casein kinase inhibitor PF-670462 (50 mg/kg) on rhythmic expression of clock genes in the liver, pancreas and suprachiasmatic nucleus (SCN) as well as plasma corticosterone, melatonin and running behaviour in rats and compared them to the responses to a 4 h extension of the light phase. PF-670462 acutely phase delayed the rhythmic transcription of Bmal1, Per1, Per2 and Nr1d1 in both liver and pancreas by 4.5 ± 1.3 and 4.5 ± 1.2 h, respectively, 1 day after administration. In the SCN, the rhythm of Nr1d1 and Dbp mRNA expression was delayed by 4.2 and 4 h, respectively. Despite these changes, the time of peak plasma melatonin secretion was not delayed, although the plasma corticosterone rhythm and onset of wheel-running activity were delayed by 2.1 and 1.1 h, respectively. These changes are in contrast to the effects of the 4 h light extension, which resulted in delays in peak expression of the clock genes of less than 1 h and no change in the melatonin or corticosterone rhythms. The ability of the casein kinase inhibitor to bring about large phase shifts in the rhythms of major metabolic target tissues may lead to new drugs being developed to rapidly phase adjust circadian rhythms to alleviate the metabolic impact of shift work.

Early origins of heart disease: low birth weight and determinants of cardiomyocyte endowment.

1. World-wide epidemiological and experimental animal studies demonstrate that adversity in fetal life, resulting in intrauterine growth restriction, programmes the offspring for a greater susceptibility to ischaemic heart disease and heart failure in adult life. 2. After cardiogenesis, cardiomyocyte endowment is determined by a range of hormones and signalling pathways that regulate cardiomyocyte proliferation, apoptosis and the timing of multinucleation/terminal differentiation. 3. The small fetus may have reduced cardiomyocyte endowment owing to the impact of a suboptimal intrauterine environment on the signalling pathways that regulate cardiomyocyte proliferation, apoptosis and the timing of terminal differentiation.

Periconceptional nutrition and the early programming of a life of obesity or adversity.

Women entering pregnancy with a high body weight and fat mass have babies at increased risk of becoming overweight or obese in childhood and later life. It is not known, whether exposure to a high level of maternal nutrition before pregnancy and exposure to a high transplacental nutrient supply in later pregnancy act through similar mechanisms to program later obesity. Using the pregnant sheep we have shown that maternal overnutrition in late pregnancy results in an upregulation of PPARγ activated genes in fetal visceral fat and a subsequent increase in the mass of subcutaneous fat in the postnatal lamb. Exposure to maternal overnutrition during the periconceptional period alone, however, results in an increase in total body fat mass in female lambs only with a dominant effect on visceral fat depots. Thus the early programming of later obesity may result from 'two hits', the first occurring as a result of maternal overnutrition during the periconceptional period and the second occurring as a result of increased fetal nutrition in late pregnancy. Whilst a short period of dietary restriction during the periconceptional period reverses the impact of periconceptional overnutrition on the programming of obesity, it also results in an increased lamb adrenal weight and cortisol stress response, together with changes in the epigenetic state of the insulin like growth factor 2 (IGF2) gene in the adrenal. Thus, not all of the effects of dietary restriction in overweight or obese mother in the periconceptional period may be beneficial in the longer term.

Impact of maternal periconceptional overnutrition on fat mass and expression of adipogenic and lipogenic genes in visceral and subcutaneous fat depots in the postnatal lamb.

Women entering pregnancy with a high body weight and fat mass have babies who are at increased risk of becoming overweight or obese in later life. We investigated whether maternal overnutrition in the periconceptional period results in an increased fat mass and expression of adipogenic and lipogenic genes in offspring and whether dietary restriction can reverse these changes. Nonpregnant donor ewes (n = 23) were assigned to one of four groups: control-control fed at 100% maintenance energy requirements (MER) for at least 5 months, control-restricted fed 100% MER for 4 months and 70% MER for 1 month, high-high (HH) fed ad libitum (170-190% MER) for 5 months, or high-restricted (HR) fed ad libitum for 4 months and 70% MER for 1 month. Single embryos were transferred to nonobese recipient ewes, and lamb fat depots were weighed at 4 months. Peroxisome proliferator-activated receptor-γ, glyceraldehyde-3-phosphate dehydrogenase, lipoprotein lipase, leptin, and adiponectin mRNA expression was measured in the lamb fat depots. Total fat mass was higher in female lambs in the HH but not HR group than controls. There was a relationship between donor ewe weight and total fat mass and G3PDH mRNA expression in perirenal fat in female lambs. There was no effect of periconceptional nutritional treatment on peroxisome proliferator-activated receptor-γ, glyceraldehyde-3-phosphate dehydrogenase, lipoprotein lipase, leptin, and adiponectin mRNA expression in any fat depot. Thus, exposure to maternal overnutrition in the periconceptional period alone results in an increased body fat mass in the offspring and that a short period of dietary restriction can reverse this effect.