Early life origins of metabolic disease: Developmental programming of hypothalamic pathways controlling energy homeostasis.

A wealth of animal and human studies demonstrate that perinatal exposure to adverse metabolic conditions - be it maternal obesity, diabetes or under-nutrition - results in predisposition of offspring to develop obesity later in life. This mechanism is a contributing factor to the exponential rise in obesity rates. Increased weight gain in offspring exposed to maternal obesity is usually associated with hyperphagia, implicating altered central regulation of energy homeostasis as an underlying cause. Perinatal development of the hypothalamus (a brain region key to metabolic regulation) is plastic and sensitive to metabolic signals during this critical time window. Recent research in non-human primate and rodent models has demonstrated that exposure to adverse maternal environments impairs the development of hypothalamic structure and consequently function, potentially underpinning metabolic phenotypes in later life. This review summarizes our current knowledge of how adverse perinatal environments program hypothalamic development and explores the mechanisms that could mediate these effects.SEO receives funding from the British Heart Foundation and is a member of the MRC Metabolic Diseases Unit. LD is a Sir Henry Wellcome Post-Doctoral Fellow.This is the author accepted manuscript. The final version is available from Elsevier via http://dx.doi.org/10.1016/j.yfrne.2015.08.00

Mechanisms mediating the impact of maternal obesity on offspring hypothalamic development and later function

As obesity rates have risen around the world, so to have pregnancies complicated by maternal obesity. Obesity during pregnancy is not only associated with negative health outcomes for the mother and the baby during pregnancy and birth, there is also strong evidence that exposure to maternal obesity causes an increased risk to develop obesity, diabetes and cardiovascular disease later in life. Animal models have demonstrated that increased weight gain in offspring exposed to maternal obesity is usually preceded by increased food intake, implicating altered neuronal control of food intake as a likely area of change. The hypothalamus is the primary site in the brain for maintaining energy homeostasis, which it coordinates by sensing whole body nutrient status and appropriately adjusting parameters including food intake. The development of the hypothalamus is plastic and regulated by metabolic hormones such as leptin, ghrelin and insulin, making it vulnerable to disruption in an obese in utero environment. This review will summarise how the hypothalamus develops, how maternal obesity impacts on structure and function of the hypothalamus in the offspring, and the factors that are altered in an obese in utero environment that may mediate the permanent changes to hypothalamic function in exposed individuals

Sex and gender differences in developmental programming of metabolism.

BACKGROUND: The early life environment experienced by an individual in utero and during the neonatal period is a major factor in shaping later life disease risk-including susceptibility to develop obesity, diabetes, and cardiovascular disease. The incidence of metabolic disease is different between males and females. How the early life environment may underlie these sex differences is an area of active investigation. SCOPE OF REVIEW: The purpose of this review is to summarize our current understanding of how the early life environment influences metabolic disease risk in a sex specific manner. We also discuss the possible mechanisms responsible for mediating these sexually dimorphic effects and highlight the results of recent intervention studies in animal models. MAJOR CONCLUSIONS: Exposure to states of both under- and over-nutrition during early life predisposes both sexes to develop metabolic disease. Females seem particularly susceptible to develop increased adiposity and disrupted glucose homeostasis as a result of exposure to in utero undernutrition or high sugar environments, respectively. The male placenta is particularly vulnerable to damage by adverse nutritional states and this may underlie some of the metabolic phenotypes observed in adulthood. More studies investigating both sexes are needed to understand how changes to the early life environment impact differently on the long-term health of male and female individuals.Wellcome Trust, MRC, NIH, Foundation for Prader-Willi Research, The Saban Research Institut

Decreased ovarian reserve, dysregulation of mitochondrial biogenesis, and increased lipid peroxidation in female mouse offspring exposed to an obesogenic maternal diet.

Maternal diet during pregnancy influences the later life reproductive potential of female offspring. We investigate the molecular mechanisms underlying the depletion of ovarian follicular reserve in young adult females following exposure to obesogenic diet in early life. Furthermore, we explore the interaction between adverse maternal diet and postweaning diet in generating reduced ovarian reserve. Female mice were exposed to either maternal obesogenic (high fat/high sugar) or maternal control dietin uteroand during lactation, then weaned onto either obesogenic or control diet. At 12 wk of age, the offspring ovarian reserve was depleted following exposure to maternal obesogenic diet (P< 0.05), but not postweaning obesogenic diet. Maternal obesogenic diet was associated with increased mitochondrial DNA biogenesis (copy numberP< 0.05; transcription factor A, mitochondrial expressionP< 0.05), increased mitochondrial antioxidant defenses [manganese superoxide dismutase (MnSOD)P< 0.05; copper/zinc superoxide dismutaseP< 0.05; glutathione peroxidase 4P< 0.01] and increased lipoxygenase expression (arachidonate 12-lipoxygenaseP< 0.05; arachidonate 15-lipoxygenaseP< 0.05) in the ovary. There was also significantly increased expression of the transcriptional regulator NF-κB (P< 0.05). There was no effect of postweaning diet on any measured ovarian parameters. Maternal diet thus plays a central role in determining follicular reserve in adult female offspring. Our observations suggest that lipid peroxidation and mitochondrial biogenesis are the key intracellular pathways involved in programming of ovarian reserve.-Aiken, C. E., Tarry-Adkins, J. L., Penfold, N. C., Dearden, L., Ozanne, S. E. Decreased ovarian reserve, dysregulation of mitochondrial biogenesis, and increased lipid peroxidation in female mouse offspring exposed to an obesogenic maternal diet.This study was funded jointly by grants from the Academy of Medical Sciences, the Addenbrooke’s Charitable Trust, an Isaac Newton Trust/Wellcome Trust ISSF/University of Cambridge Joint Research Grant and the MRC (MRC_MC_UU_12012/4).This is the final version of the article. It first appeared from the Federation of American Societies for Experimental Biology via http://dx.doi.org/10.1096/fj.15-28080

Exploring Telomere Dynamics in Aging Male Rat Tissues: Can Tissue-Specific Differences Contribute to Age-Associated Pathologies?

INTRODUCTION: Due to increasing lifespan, global aging rates are rising rapidly and age-associated diseases are increasing. To ensure that health span is concomitant with life span, a greater understanding of cellular mechanisms of aging is important. METHODS: Telomere length analysis from a wide range of tissues from weaning, young adult, and middle-aged (3, 12 and 52 week) male Wistar rats were conducted using Southern blotting. Telomere lengths were compared between tissues and ages using regression models based on the ratios of longest-to-shortest telomere fragments. RESULTS: Robust linear age-dependent telomere attrition was observed in the liver; 3 versus 12 weeks, 3 versus 52 weeks (p < 0.01), 12 versus 52 weeks (p < 0.05) and the heart; 3 versus 12 weeks (p < 0.05) and 3 versus 52 weeks (p < 0.001). More subtle shortening was observed in aorta and epididymal fat; 3 and 12 versus 52 weeks (p < 0.001) and in skeletal muscle; 3 versus 52 weeks (p < 0.05), 12 versus 52 weeks (p < 0.01). Young thymus telomeres increased in length (3 vs. 12 weeks) and then shortened between 12 and 52 weeks (p < 0.001). We also reported disparity in telomere shortening within tissues: telomeres in aging brain cortex significantly shortened; 3 versus 52 weeks (p < 0.05), 12 versus 52 weeks (p < 0.01). This was not seen in the hypothalamic region. A robust stepwise shortening was observed in the renal cortex; 3 versus 12 weeks, 12 versus 52 weeks (p < 0.05), and 3 versus 52 weeks (p < 0.001), which was not as apparent in the renal medulla; 3 versus 12 weeks (p < 0.01) and 3 versus 52 weeks (p < 0.01). The vastus lateralis skeletal muscle demonstrated the shortest telomere length at weaning and underwent robust age-associated attrition; 3 versus 52 weeks (p < 0.05), 12 versus 52 weeks (p < 0.01). We demonstrated that specific tissues exhibit unique telomere attrition profiles which may partially explain why certain diseases are more prevalent in aged individuals. DISCUSSION/CONCLUSION: We show wide variations between tissues in vulnerability to the aging process. In the future, this may help target potential interventions to improve health span

Enhanced SUMOylation and SENP-1 protein levels following oxygen and glucose deprivation in neurones

Here, we show that oxygen and glucose deprivation (OGD) causes increased small ubiquitin-like modifier (SUMO)-1 and SUMO-2/3 conjugation to substrate proteins in cultured hippocampal neurones. Surprisingly, the SUMO protease SENP-1, which removes SUMO from conjugated proteins, was also increased by OGD, suggesting that the neuronal response to OGD involves a complex interplay between SUMOylation and deSUMOylation. Importantly, decreasing global SUMOylation in cultured hippocampal neurones by overexpression of the catalytic domain of SENP-1 increased neuronal vulnerability to OGD-induced cell death. Taken together, these results suggest a neuroprotective role for neuronal SUMOylation after OGD

Programming of central and peripheral insulin resistance by low birthweight and postnatal catch-up growth in male mice.

AIMS: Intra-uterine growth restriction (IUGR) followed by accelerated postnatal growth is associated with an increased risk of obesity and type 2 diabetes. We aimed to determine central and peripheral insulin sensitivity in mice that underwent IUGR followed by postnatal catch-up growth and investigate potential molecular mechanisms underpinning their physiology. METHODS: We used a C57BL/6J mouse model of maternal diet-induced IUGR (maternal diet, 8% protein) followed by cross-fostering to a normal nutrition dam (maternal diet, 20% protein) and litter size manipulation to cause accelerated postnatal catch-up growth. We performed intracerebroventricular insulin injection and hyperinsulinaemic-euglycaemic clamp studies to examine the effect of this early nutritional manipulation on central and peripheral insulin resistance. Furthermore, we performed quantitative real-time PCR and western blotting to examine the expression of key insulin-signalling components in discrete regions of the hypothalamus. RESULTS: IUGR followed by accelerated postnatal growth caused impaired glucose tolerance and peripheral insulin resistance. In addition, these 'recuperated' animals were resistant to the anorectic effects of central insulin administration. This central insulin resistance was associated with reduced protein levels of the p110β subunit of phosphoinositide 3-kinase (PI3K) and increased serine phosphorylation of IRS-1 in the arcuate nucleus (ARC) of the hypothalamus. Expression of the gene encoding protein tyrosine phosphatase 1B (PTP1B; Ptpn1) was also increased specifically in this region of the hypothalamus. CONCLUSIONS/INTERPRETATION: Mice that undergo IUGR followed by catch-up growth display peripheral and central insulin resistance in adulthood. Recuperated offspring show changes in expression/phosphorylation of components of the insulin signalling pathway in the ARC. These defects may contribute to the resistance to the anorectic effects of central insulin, as well as the impaired glucose homeostasis seen in these animals