Effects Of Overnutrition Research Articles

Glucose-induced CRL4COP1-p53 axis amplifies glycometabolism to drive tumorigenesis

The diabetes-cancer association remains underexplained. Here, we describe a glucose-signaling axis that reinforces glucose uptake and glycolysis to consolidate the Warburg effect and overcome tumor suppression. Specifically, glucose-dependent CK2 O-GlcNAcylation impedes its phosphorylation of CSN2, a modification required for the deneddylase CSN to sequester Cullin RING ligase 4 (CRL4). Glucose, therefore, elicits CSN-CRL4 dissociation to assemble the CRL4COP1 E3 ligase, which targets p53 to derepress glycolytic enzymes. A genetic or pharmacologic disruption of the O-GlcNAc-CK2-CSN2-CRL4COP1 axis abrogates glucose-induced p53 degradation and cancer cell proliferation. Diet-induced overnutrition upregulates the CRL4COP1-p53 axis to promote PyMT-induced mammary tumorigenesis in wild type but not in mammary-gland-specific p53 knockout mice. These effects of overnutrition are reversed by P28, an investigational peptide inhibitor of COP1-p53 interaction. Thus, glycometabolism self-amplifies via a glucose-induced post-translational modification cascade culminating in CRL4COP1-mediated p53 degradation. Such mutation-independent p53 checkpoint bypass may represent the carcinogenic origin and targetable vulnerability of hyperglycemia-driven cancer.

The Effect of Overnutrition on Mediated Collagen in Drosophila Melanogaster Physiology

Obesity affects approximately 13% of the adult population, resulting in excessive fat cell deposition and metabolic dysfunction. Collagen, a protein that supports skin regeneration, muscle building, and pain relief, is studied in Drosophila melanogaster under different diet conditions. This experiment aims to test whether overnutrition affects physiology and collagen due to any anatomical changes in Drosophila Melanogaster, more commonly known as fruit flies. The research conducted over several weeks utilizes two diets: an obesity-inducing diet containing excessive glucose and coconut oil and a traditional diet of blue food medium, yeast, and water. The study groups include a wild-type, collagen-mutated, and obesity-mutated group, with multiple assays measuring how the obesity-inducing diet affects each population and their collagen levels. The results reveal that the obese group experienced higher food consumption levels but had lower locomotive ability than the other test groups. Hydroxyproline, the building amino acid for collagen, and collagen levels were higher in the obesity mutant than in the wild-type and collagen mutated group. The study shows that anatomical changes in organisms are influenced by both diet and movement. The obesity group, on an obesity-inducing diet, experienced decreased movement related to increased food intake and decreased neural activity. The high-fat and high-sugar diet suppressed neuronal autophagy, created inaccurate hunger and satiety perceptions, and increased collagen deposition. Anatomical changes were observed in collagen-heavy tissue areas, whereas decreased neural activity and increased feeding rates were behavioral changes. The study emphasized the importance of a healthy diet and exercise in promoting overall health.

The immediate effect of overnutrition and fluoxetine treatment during the critical period of development on the hippocampus

It is well known that overnutrition, overweight, and obesity in children can modulate brain mechanisms of plasticity, monoaminergic systems, and mitochondrial function. The immediate effect of overnutrition during the developmental period has not been thoroughly examined in rats until the present. This study sought to evaluate the impact on adult rats of early life overfeeding and fluoxetine treatment from post-natal day 1 (PND1) to post-natal day 21 (PND21) relative to mitochondrial function, oxidative balance, and expression of specific monoaminergic genes in the hippocampus. The following were evaluated: mitochondrial function markers, oxidative stress biomarkers, dopamine-and serotonin-related genes, and BDNF mRNA levels. Overfeeding during the lactation period deregulates cellular metabolism and the monoaminergic systems in the hippocampus. Strikingly, serotonin modulation by fluoxetine treatment protected against some of the effects of early overnutrition. We conclude that overfeeding during brain development induce detrimental effects in mitochondria and in the genes that regulate homeostatic status that can be the molecular mechanisms related to neurological diseases.

Пищевой статус и продолжительность жизни человека

Social factors such as bad living conditions, harmful labor conditions, low quality of medicine, loss of social contacts, etc., and lifestyle factors such as mal- and over-nutrition, hypodynamia, bad habits, etc. are the main issues of premature ageing. In this article, the alimentary factor such as the risk of premature ageing has been considered from the point of view of over- and malnutrition (protein-e nergy undernutrition) and its influence on the rate of ageing. The effect of overnutrition has been examined in the literature review of Russian and foreign investigators. Scientific publications show that one alimentary factor can be used to produce a significant influence on life span and frequency of some degenerative diseases. The relationship between malnutrition in the older population and biological age has been evaluated. 408 those surveyed from the city of Voronezh aged 55 to 70 were included into the study. The examination was nonrecurrent. The biological age of those surveyed was determined using the method by V. P. Voitenko. Malnutrition was assessed with the MNA (Mini Nutritional Assessment) tool. Malnutrition is observed among 2.2% of elderly patients, 58.8% of those surveyed are at risk for malnutrition, whereas 39% of them have a normal alimentary status. It is established that the biological age is correlated with the alimentary status. Statistically significant differences are found in the mean group values of the biological age in the subgroup of people with a normal alimentary status in relation to the subgroup of people with a risk for malnutrition (p<0.05): the values were 56±1.7 and 64±1.4, respectively. The publication shows a direct and indirect influence of the alimentary status (both overnutrition, and malnutrition) on the rate of senescence.

SSTEAP4 regulates cellular homeostasis and improves high-fat-diet-caused oxidative stress in hepatocytes

AimNonalcoholic fatty liver disease (NAFLD) has become a global epidemic, but its pathogenesis is unclear. STEAP4, a member of six transmembrane protein family, integrates inflammatory and metabolic responses. Our present aim is to explore the roles of STEAP4 in maintaining cellular homeostasis and improving high-fat-diet (HFD)-caused oxidative stress in hepatocytes. Main methodsNAFLD model was established by HFD-feeding mice. The effects of over-nutrition on liver were detected by serum biochemical analysis and bulk RNA-seq. The levels of gene expression were measured by QPCR and Western Blot. Immunofluorescent staining was applied to determine the localization of STEAP4. AMPK agonist was employed to investigate the link between STEAP4 and AMPK pathway. Key findingsSus scrofa STEAP4 (sSTEAP4) relieved oxidative stress and rescued the viability of hepatocytes. sSTEAP4 increased AKT phosphorylation and SOD2 level in hepatocytes, whether or not treated with H2O2, suggesting sSTEAP4 has regulatory effects on insulin signaling and antioxidant pathways. However, sSTEAP4 inhibited AMPK phosphorylation and Beclin1/LC3 expression under H2O2-deficiency situation, but the results were conversed with H2O2 stimulation. The cellular ER stress was aggravated with the increased energy during oxidative stress, indicating that sSTEAP4 might regulate the energetic communication between ER and mitochondria by intervening mitochondrial energy production. In addition, sSTEAP4 was demonstrated to localize in the membranes of plasma and ER in HepG2 hepatocytes. SignificanceOur results reveal that sSTEAP4 based on the needs of cell itself to improve hepatic oxidative stress and HFD-caused NAFLD, which might provide a new therapeutic scheme for NAFLD.

Global associations between macronutrient supply and age-specific mortality

Animal experiments have demonstrated that energy intake and the balance of macronutrients determine life span and patterns of age-specific mortality (ASM). Similar effects have also been detected in epidemiological studies in humans. Using global supply data and 1,879 life tables from 103 countries, we test for these effects at a macrolevel: between the nutrient supplies of nations and their patterns of ASM. We find that macronutrient supplies are strong predictors of ASM even after correction for time and economic factors. Globally, signatures of undernutrition are evident in the effects of low supply on life expectancy at birth and high mortality across ages, even as recently as 2016. However, in wealthy countries, the effects of overnutrition are prominent, where high supplies particularly from fats and carbohydrates are predicted to lead to high levels of mortality. Energy supplied at around 3,500 kcal/cap/d minimized mortality across ages. However, we show that the macronutrient composition of energy supply that minimizes mortality varies with age. In early life, 40 to 45% energy from each of fat and carbohydrate and 16% from protein minimizes mortality. In later life, replacing fat with carbohydrates to around 65% of total energy and reducing protein to 11% is associated with the lowest level of mortality. These results, particularly those regarding fats, accord both with experimental data from animals and within-country epidemiological studies on the association between macronutrient intake and risk of age-related chronic diseases.

Fetal programming in sheep: effects on pre- and postnatal development in lambs.

This systematic review and meta-analysis aim to summarize the effects of maternal undernutrition or overnutrition during pregnancy on fetal weight and morphometric measurements during pregnancy, at birth, and postnatal period in sheep. After completing the search, selection, and data extraction steps, the measure of effect was generated by the individual comparison of each indicator with the average of the control and treated group (undernutrition or overnutrition) using the DerSimonian and Laird method for random effects. Subgroup analyses were also performed for lambing order, litter size, sex, as well as level, timing, and duration of the intervention. Fetal weight during the first third of pregnancy was not affected by maternal undernutrition or overnutrition. On the other hand, undernutrition in the second and last third of gestation reduces the weight of the lamb both during pregnancy, at birth, and during the postnatal period, requiring at least 120 postnatal days to achieve the same weight as its contemporaries in the control treatment. However, this reduction in weight is not accompanied by reductions in morphometric measurements, demonstrating that the animals were lighter, but of equal size. In overnutrition, there is an increase in fetal weight in the second third of gestation. However, in the last third of the gestational period, there are no differences in fetal weight for the multiparous subgroup, but it was reduced in primiparous ewes. There are no effects of overnutrition on birth weight; however, this result is highly heterogeneous. Thus, maternal nutrition of ewe during pregnancy has effects on fetal and postnatal weight, but not on size. Furthermore, the effects of undernutrition are more homogeneous while overnutrition showed heterogeneous responses.

Alarming evidence: high fat diet alters brainstem circuits prior to the development of obesity.

The prevalence of obesity and its associated diseases, including type 2 diabetes mellitus, has substantially increased worldwide, placing a significant burden both on individuals and society as a whole. This healthcare crisis requires the development of novel interventions and effective obesity prevention strategies. Alarmingly, numerous recent studies have emphasized the importance of gestational and perinatal periods, which have a critical influence on the offspring's weight and metabolism in the development of obesity (Kubo et al. 2014; Sullivan & Grove 2010; Sullivan et al. 2011). Considering the high incidence of obesity in the general population, including women of child-bearing age, studies investigating the effect of overnutrition and a high fat diet (HFD) during gestational and perinatal periods on the health of offspring have particular relevance and importance for global health and economy. It has been demonstrated that maternal hyperglycaemia or gestational diabetes is associated with a higher risk of childhood obesity and this risk increases if the mother is overweight or obese (Kubo et al. 2014). Studies using rodent models showed that maternal HFD consumption or overnutrition contributes to the development of hyperphagia (Sullivan et al. 2011). Upregulation of orexigenic peptides, decreased sensitivity to leptin, and abnormalities of the central melanocortin, serotonin and dopamine systems have also been reported and associated with maternal HFD consumption (Chang et al. 2008; Sullivan & Grove, 2010; Sullivan et al. 2011). These findings have been linked to changes in hypothalamic pathways controlling feeding circuits and disruption of these circuits contributes to the development of obesity. The hypothalamus works in concert with brainstem autonomic centres to maintain homeostatic functions. A variety of studies have demonstrated that diet-induced obesity causes multiple changes in vagal neural circuits, which compromise the function of both the vagal afferents and efferents; however, in these studies it is difficult to differentiate the effect of diet and/or obesity. Therefore, the following question arises: does HFD alone modulate vagal neural circuits and if it does, when do the changes occur? Previous studies demonstrated the vulnerability of the brainstem autonomic neural circuits to exposure to HFD and postulated that HFD dysregulates the vagal reflex control independently of obesity (Covasa & Ritter, 2000; Swartz et al. 2010; Browning et al. 2013); however, direct evidence demonstrating the effect of perinatal HFD on neuronal excitability remained unknown. Bhagat and his coworkers have designed an elegant study, reported in this issue of The Journal of Physiology (Bhagat et al. 2015), to investigate the consequences of perinatal HFD consumption on vagal motor neurons using electrophysiological, pharmacological and morphological approaches. Their study focuses on gastric-related motor neurons and demonstrates that perinatal HFD consumption dysregulates neurotransmitter release from synaptic inputs and reduces the excitability of gastric-projecting neurons in the dorsal motor nucleus of the vagus. These changes were accompanied by increased size and dendritic arborization of gastric-projecting vagal motor neurons, and were observed prior to the development of obesity. The observation that the changes occur before the development of obesity gives a particular importance to these novel findings, because it points out that the attenuation of the vago-vagal reflex signalling exists before the development of obesity. In agreement with previous findings that show the vulnerability of autonomic circuits, the authors’ data demonstrate that the perinatal period is a critical time, which may determine the weight and/or metabolism of the offspring. On the other hand, further studies are needed to establish the particular time frame (e.g. in utero or pre-weaning phrases) responsible for these changes to answer the question: are these changes in vagal neural circuits caused by perinatal HFD exposure reversible or not, and what are the underlying mechanisms? Taken together, increasing evidence, including the current study by Bhagat et al., demonstrates that maternal and perinatal diet has a significant effect on the central nervous system, including the autonomic pathways that regulate homeostatic functions. Furthermore, these changes in vagal circuitry may define the susceptibility to obesity and metabolic disorders; however, further detailed studies are needed to delineate the underlying mechanisms.

Animal Models and Better Understanding of “One Medicine”

Medical science has long been informed by the study of animal physiology and pathophysiology, both spontaneous and induced. Physiologist Claude Bernard studied dogs to better understand pancreatic, hepatic and cardiovascular homeostasis [1,2]. Best and Banting uncovered the function of insulin through studies in experimental dogs [3]. More recent studies of obesity in cats have found similarities and interesting differences in the manifestation of the adverse effects of overnutrition between cats and humans [4]. The complete sequencing of the human and mouse genomes, and deep sequencing of pig, cattle, dog and cat have opened up the opportunity to systematically compare genetic similarities and differences [5,6]. [...]

To be predisposed to insulin resistance and type 2 diabetes

It has long been recognized that some people in some families are predisposed to insulin resistance and type 2 diabetes from birth, and because insulin resistance consistently has been found in first degree relatives and offspring of patients with type 2 diabetes, the prevailing view has been that insulin resistance is an at least partly genetically determined trait playing a key role in the development of type 2 diabetes (Beck-Nielsen & Groop, 1994). Zhu et al. report in this issue of The Journal of Physiology that obesity in pregnant sheep (ewes) induced by over-nutrition from 60 days before to 75 days after conception was associated with the development of whole-body insulin resistance and glucose intolerance in the ewes, and most importantly with impaired signalling of the crucial AMP-activated protein kinase 8AMPK, as well as insulin receptor substrate-1 (IRS-1)-associated phospho-inositide-3 kinase (PI3K) pathways in fetal skeletal muscle (Zhu et al. 2008). Insulin signalling through PI3K mediates the majority of the metabolic effects of insulin including membrane glucose transport and glycogen synthesis, and AMPK acts as an intracellular sensor that once activated, promotes membrane glucose uptake and mitochondrial energy (ATP) production. The implications for our current understanding of the origin of insulin resistance and type 2 diabetes are numerous. Firstly, the study provides further evidence that under-nutrition in utero and low birth weight are not the only metabolic and nutritional challenges operating early in life increasing risk of later development of insulin resistance and type 2 diabetes (Hales & Barker, 2001). While under-nutrition in utero may be relevant to some current and historical life circumstances and populations, the propagation of Western life style, over-nutrition and obesity in virtually all parts of the world has gradually changed the focus and quantitative relevance away from under-nutrition and over to the potential deleterious effects of over-nutrition and obesity in pregnancy. Thus, it is most likely that the consequences of programming induced by over-nutrition in utero may contribute significantly to the enormous burden of disease associated with type 2 diabetes and the metabolic syndrome in countries like the United States. As mentioned by Zhu et al. (2008), Warram et al. reported almost two decades ago that insulin resistance predicts the development of type 2 diabetes in the offspring of diabetes parents (Warram et al. 1990). Indeed, young and otherwise healthy offspring of diabetic parents commonly exhibit insulin resistance and impaired muscle insulin signalling and glycogen synthesis many decades before onset of overt type 2 diabetes (Vaag et al. 1992), and it has for a long time been thought that muscle insulin resistance may represent an inherited or genetic trait in type 2 diabetes (Beck-Nielsen & Groop, 1994). Much to the surprise of many investigators in the field, recent large-scale genome-wide association (GWA) studies failed to identify any polymorphisms of genes involved in insulin action or insulin signalling contributing to the development of type 2 diabetes (Frayling, 2007). Instead, a number of genes thought to be involved in the control of insulin secretion showed polymorphisms that conferred marginally but statistical significantly increased susceptibility to type 2 diabetes (Frayling et al. 2007). With the report by Zhu et al. it may now be speculated that insulin resistant offspring of diabetic mothers to some unknown extent may be due to obesity and/or mild glucose intolerance during pregnancy per se, and not necessarily to genetics. Indeed, it is likely that the women who later develop type 2 diabetes may have been obese many years before onset of overt disease, and/or that they due to genetics (including genetic beta cell dysfunction) may have had glucose intolerance or overt (gestational) diabetes during pregnancy (even without knowing it) decades before they had the diagnosis of type 2 diabetes. Although many genes involved in the development of type 2 diabetes are yet to be discovered, the possibility that ‘genetic insulin resistance’ to some extent may be due to intrauterine programming should be kept in mind in the future. Similarly, heritability estimates of insulin resistance and related diseases inherent in the metabolic syndrome including besides type 2 diabetes (abdominal) obesity, hypertension, dyslipidaemia and even premature cardiovascular disease, as obtained from family studies should keep the possibility open that the trait in focus may not necessarily have a genetic origin, in particular if the criteria of a positive family history includes having a mother as a – or the – proband.

The DONALD Study. History, current status and future perspectives.

Nutrition during childhood and adolescence is an important determinant of development and health, both for the child and the later adult. In industrialised countries as well as in many countries of economic transition, emphasis has moved from combating nutrient deficiencies to research on the effects of overnutrition and food selection. Prevention of chronic diseases including obesity have become a major focus in research. However, the complex relation between infant growth and its related endocrine and metabolic changes on the one hand and the influence of nutrition and nutritional status on the other hand still need to be understood in detail. Studies aiming to elucidate this have to follow children and adolescents during their growth period. The following pages display the features of the German DONALD Study ( DOrtmund Nutritional and Anthropometric Longitudinally Designed Study) which was specifically designed to address these complex research questions. Finally, comparisons to other studies are made and the specific strength and weaknesses of this study are discussed. As the DONALD study offers unique research opportunities and due to its long follow-up an abundance of data, collaborative research is encouraged.

Caloric restriction and experimental carcinogenesis

Concern over effects of over-nutrition on carcinogenesis is not new. Almost 70 years ago Hoffman1,2 attributed the rise in cancer incidence of the time to an excess of caloric intake.

Obesity-induced hyperplastic lung growth.

The effects of overnutrition on lung growth were studied in newborn male Long-Evans rats made obese by nursing in small litters with subsequent feeding of a high fat diet. Control rats were nursed in normal-sized litters and then fed standard rat chow. The animals were killed at 8 wk of age. When compared with control rats, obese rats had significant increases in body weight (24%); fat pad weight (118%); fat pad weight/body weight ratio (77%); snout-to-anus length (11%); total lung weight (11%); lung content of DNA (19%), protein (22%), RNA (22%), total lipids (31%), cholesterol (20%), and triglycerides (141%); and the lung triglyceride/DNA ratio (217%). Serum levels of insulin (71%), total lipids (60%), cholesterol (64%), and triglycerides (90%) were also elevated in obese rats as compared with those in control rats. Unchanged were the ratios of lung protein/DNA, RNA/DNA, lipid/DNA, and cholesterol/DNA; lung phospholipid content; and serum concentrations of glucose and phospholipids. The results indicate the presence of cellular hyperplasia in lungs of young rats made obese by diet. Lipid deposition in the obese lungs suggests metabolic alterations in pulmonary composition occurring with obesity.

Some aspects of obesity in childhood.

In 1950 Otto Wolff set up one of the first clinics in the United Kingdom specifically for the study and treatment of obesity in children. His original observations on the effects of over-nutrition on the development of children and of the outcome of hospital treatment (Wolff, 1955; Lloyd et al., 1961) have never been surpassed. His continuing interest in the subject has promoted work into many aspects cellular, biochemical, psychological and epidemiological and, together with the studies of numerous workers in many countries, has greatly enhanced our knowledge of this important nutritional disorder. Nevertheless many questions wait for answers and many problems for solutions. This review will discuss some of them. Because obesity in children is only rarely associated with endocrine diseases or other syndromes, these will not be considered here and the topic remains that of 'simple obesity' in itself a grave misnomer!

Overnutrition, overgrowth and hormones (with special reference to the infant born of the diabetic mother).

It is the purpose of this paper to consider the effects of overnutrition on changes in body composition and cell growth and to discuss such changes in relationship to hormone secretion. The role of insulin secretion on cell growth is of importance especially with respect to cell growth in the primate fetus.