Metabolic programming effects initiated in the suckling period predisposing for adult-onset obesity cannot be reversed by calorie restriction

Srinivasan, Malathi; Mahmood, Saleh; Patel, Mulchand S.

doi:10.1152/ajpendo.00519.2012

Cited by 18 publications

(19 citation statements)

References 39 publications

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“…Decreased Stat3 and no change in Socs3 in mRNA levels were also observed in a previous study (31); however, no difference was observed in these two genes between NL and SL rats in the present study. Similar results on Lepr mRNA levels were observed in the HC, HC/PF, and HC/ PF/AL rats (37). Upon resumption of ad libitum feeding, reduction in Lepr mRNA expression was observed in SL/PF/AL rats, representing a negative correlation with the higher serum leptin levels and the SL phenotype in these rats.…”

Section: Discussionsupporting

confidence: 82%

“…A similar observation was recently reported in an obese rat model in which metabolic programming was induced by feeding a milk formula high in carbohydrate-derived calories (HC) during the suckling period (37). Pair-feeding (mild CR) of SL rats from the time of weaning resulted in normalization of body weight, food intake, and serum hormonal levels in SL/PF rats, culminating in an NL-like metabolic phenotype in these rats.…”

Section: Discussionsupporting

confidence: 73%

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Adult-onset obesity induced by early life overnutrition could be reversed by moderate caloric restriction

Liu

Srinivasan

Mahmood

et al. 2013

American Journal of Physiology-Endocrinology and Metabolism

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Overnutrition during the suckling period (small litter, SL) results in the development of adult-onset obesity. Our aim was to investigate whether two levels of caloric restriction (CR) in the early postweaning period can reverse obese phenotype in SL rats. The normal litter (NL) had 12 pups/dam and SL had 3 male pups/dam from the postnatal day 3 until day 21. After weaning, rats consumed lab chow as indicated: 1) NL and SL groups were on ad libitum regimen up to day 140, 2) another SL group was pair-fed (SL/PF) to NL(∼14% reduction), 3) SL/PF/AL group was pair-fed up to day 94 and then switched to ad libitum feeding, 4) SL/CR group received 24% reduction (moderate CR) in food intake compared with SL, and 5) SL/CR/AL group was on 24% CR up to day 94 and then switched to ad libitum feeding. Pair-feeding reduced body weight gains and serum insulin and leptin levels compared with SL rats, but these parameters were restored to SL levels in the SL/PF/AL rats after switching to ad libitum feeding. Interestingly, the moderate CR normalized these parameters in SL/CR and SL/CR/AL rats compared with NL. The expression of neuropeptide Y, proopiomelanocortin, and leptin receptor returned to control levels in hypothalami from SL/CR and SL/CR/AL rats. These results indicate that appropriate manipulation of energy intake during the early postweaning period could lead to longer-lasting effects on the regulation of body weight homeostasis via reversal of the early preweaning programming effects on the hypothalamic appetite regulation mechanism.

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Section: Discussionsupporting

confidence: 82%

Section: Discussionsupporting

confidence: 73%

Adult-onset obesity induced by early life overnutrition could be reversed by moderate caloric restriction

Liu

Srinivasan

Mahmood

et al. 2013

American Journal of Physiology-Endocrinology and Metabolism

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“…Even in utero, the source of fetal hyperinsulinemia is endogenous: maternal glucose can cross the placenta, but maternal insulin cannot [116]. Importantly, central dysregulation of appetite induced in perinatal life by isocaloric high-carbohydrate formulas cannot be undone by subsequent periods of caloric restriction, even though whole-body metabolic status improves [772]. This dreadful pattern mimics the most common approaches for caloric restriction of obese humans, who quickly improve their metabolic status (Section 2.3) but often remain hungry (Section 7).…”

Section: Experimental Systems To Study the Atherometabolic Syndrome Amentioning

confidence: 99%

Imbalanced insulin action in chronic over nutrition: Clinical harm, molecular mechanisms, and a way forward

Williams

2016

Atherosclerosis

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The growing worldwide prevalence of overnutrition and underexertion threatens the gains that we have made against atherosclerotic cardiovascular disease and other maladies. Chronic overnutrition causes the atherometabolic syndrome, which is a cluster of seemingly unrelated health problems characterized by increased abdominal girth and body-mass index, high fasting and postprandial concentrations of cholesterol- and triglyceride-rich apoB-lipoproteins (C-TRLs), low plasma HDL levels, impaired regulation of plasma glucose concentrations, hypertension, and a significant risk of developing overt type 2 diabetes mellitus (T2DM). In addition, individuals with this syndrome exhibit fatty liver, hypercoagulability, sympathetic overactivity, a gradually rising set-point for body adiposity, a substantially increased risk of atherosclerotic cardiovascular morbidity and mortality, and--crucially--hyperinsulinemia. Many lines of evidence indicate that each component of the atherometabolic syndrome arises, or is worsened by, pathway-selective insulin resistance and responsiveness (SEIRR). Individuals with SEIRR require compensatory hyperinsulinemia to control plasma glucose levels. The result is overdrive of those pathways that remain insulin-responsive, particularly ERK activation and hepatic de-novo lipogenesis (DNL), while carbohydrate regulation deteriorates. The effects are easily summarized: if hyperinsulinemia does something bad in a tissue or organ, that effect remains responsive in the atherometabolic syndrome and T2DM; and if hyperinsulinemia might do something good, that effect becomes resistant. It is a deadly imbalance in insulin action. From the standpoint of human health, it is the worst possible combination of effects. In this review, we discuss the origins of the atherometabolic syndrome in our historically unprecedented environment that only recently has become full of poorly satiating calories and incessant enticements to sit. Data are examined that indicate the magnitude of daily caloric imbalance that causes obesity. We also cover key aspects of healthy, balanced insulin action in liver, endothelium, brain, and elsewhere. Recent insights into the molecular basis and pathophysiologic harm from SEIRR in these organs are discussed. Importantly, a newly discovered oxide transport chain functions as the master regulator of the balance amongst different limbs of the insulin signaling cascade. This oxide transport chain--abbreviated 'NSAPP' after its five major proteins--fails to function properly during chronic overnutrition, resulting in this harmful pattern of SEIRR. We also review the origins of widespread, chronic overnutrition. Despite its apparent complexity, one factor stands out. A sophisticated junk food industry, aided by subsidies from willing governments, has devoted years of careful effort to promote overeating through the creation of a new class of food and drink that is low- or no-cost to the consumer, convenient, savory, calorically dense, yet weakly satiating. It is past time for the rest of us ...

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“…The stimulatory effect of the PNS is exerted via acetylcholine, whereas the inhibitory effect of the SNS is exerted via norepinephrine. In vivo and in vitro studies on the insulin secretory capacity of islets from HC rats indicated an augmented response to cholinergic stimulation and a reduced sensitivity to adrenergic inhibition, suggesting that an altered ANS regulation contributes to the hypersecretory capacity of the HC islet cells [82].…”

Section: Overnutrition By Early Overfeedmentioning

confidence: 96%

“…High carbohydrate milk formula until the time of weaning resulted in chronic hyperinsulinemia and adult-onset obesity (HC phenotype) in these rats supported by hypersecretory capacity of HC islets and hypothalamic alterations predisposing to hyperphagia [82]. Insulin secretion by pancreatic islets is under the control of peripheral (circulating blood glucose concentrations) and central Autonomic Nervous System (ANS) mechanisms.…”

Section: Overnutrition By Early Overfeedmentioning

confidence: 99%

Can Insulin Resistance or Secretion be Programmed Earlier in Life?

Oliveira¹,

Lisboa²,

Moura³

2013

J Diabetes Metab

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Diabetes and its complications occur at high rates in the world population. Several epidemiological studies have associated perinatal adversities, such as nutritional disturbances or diseases during gestation and lactation, with the development of insulin resistance or failure on insulin secretion in the adult progeny. Only recently the mechanism by which this phenomenon occurs is being delineated through series of experimental studies and implies epigenetics changes as a main initializing event. In this review, the authors give a comprehensive report of the different models of fetal and developmental programming that can result either in insulin resistance or insulin inappropriate secretion, with the possible mechanistic explanation for these alterations. The changes in the female workforce, which implies in profound nutritional and hormonal changes, exposure to endocrine disruptor or addictive compounds during gestation and lactation, including the reduction of lactation period creates conditions that, are obesogenic for their progenies, increasing the risk of type 2 diabetes mellitus. Finally, neonatal insults might be an important ethiopathogenic factor for the development of metabolic disturbances in adulthood, including obesity and diabetes, contributing to the considerable increase in chronic diseases incidence in society.

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Metabolic programming effects initiated in the suckling period predisposing for adult-onset obesity cannot be reversed by calorie restriction

Cited by 18 publications

References 39 publications

Adult-onset obesity induced by early life overnutrition could be reversed by moderate caloric restriction

Adult-onset obesity induced by early life overnutrition could be reversed by moderate caloric restriction

Imbalanced insulin action in chronic over nutrition: Clinical harm, molecular mechanisms, and a way forward

Can Insulin Resistance or Secretion be Programmed Earlier in Life?

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