Overfeeding in the early postnatal period aggravates inflammation and hepatic insulin sensitivity in the 5α-dihydrotestosterone-induced animal model of PCOS.

Background: Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in women of reproductive age and is closely associated with chronic low-grade inflammation and insulin resistance. To clarify the contribution of prepubertal weight gain to the development of insulin resistance in PCOS, we investigated the effects of early postnatal overfeeding on inflammatory and energy-sensing pathways as well as on markers of insulin signaling in the liver of the PCOS rat model. Methods: Obesity induced by overfeeding was achieved by reducing litter size, while the PCOS-like condition was developed by treatment with 5α-dihydrotestosterone (DHT). Western blot and qPCR were used to analyze the expression of pro-inflammatory transcription factors and cytokines, as well as markers of the energy sensing and insulin signaling pathways. Results: The results showed that hepatic insulin sensitivity was impaired only in DHT-treated rats raised in small litters, as evidenced by increased phosphorylation of IRS1 on Ser307 and decreased expression of total IRS1. Postnatal overfeeding stimulated JNK1 activation independent of hyperandrogenemia; nevertheless, the synergistic effect of both factors triggered NLRP3 activation and increased IL1ß expression in the small litter DHT-treated group. This pro-inflammatory state was accompanied by decreased activatory phosphorylation of AMPK and reduced levels of its protein targets. Conclusions: Overfeeding in the early postnatal period leads to a decrease in hepatic insulin sensitivity in the rat model of PCOS, which is associated with decreased activation of AMPK and stimulation of the hepatic NLRP3-IL1ß signaling pathway. Accordingly, the inhibition of NLRP3 activation could provide a basis for the development of new therapeutic strategies for the treatment of insulin resistance in women with PCOS.

Paternal undernutrition and overnutrition modify semen composition and preimplantation embryo developmental kinetics in mice.

BACKGROUND: The importance of parental diet in relation to eventual offspring health is increasing in prominence due to the increased frequency of parents of reproductive age consuming poor diets. Whilst maternal health and offspring outcome have been studied in some detail, the paternal impacts are not as well understood. A father's poor nutritional status has been shown to have negative consequences on foetal growth and development and ultimately impact the long-term adult health of the offspring. In this study, we examined sperm- and seminal vesicle fluid-mediated mechanisms of preimplantation embryo development alterations in response to sub-optimal paternal diets. RESULTS: Male mice were fed a diet to model either under (low-protein diet (LPD)) or over (high-fat/sugar 'Western' diet (WD)) nutrition, LPD or WD supplemented with methyl donors or a control diet (CD) before mating with age-matched females. Male metabolic health was influenced by WD and MD-WD, with significant changes in multiple serum lipid classes and hepatic 1-carbon metabolites. Sperm RNA sequencing revealed significant changes to mRNA profiles in all groups when compared to CD (LPD: 32, MD-LPD: 17, WD: 53, MD-WD: 35 transcripts). Separate analysis of the seminal vesicle fluid proteome revealed a significant number of differentially expressed proteins in all groups (LPD: 13, MD-LPD: 27, WD: 24, MD-WD: 19) when compared to control. Following mating, in vitro time-lapse imaging of preimplantation embryos revealed a significant increase in the timing of development in all experimental groups when compared to CD embryos. Finally, qPCR analysis of uterine tissue at the time of implantation identified perturbed expression of Cd14 and Ptgs1 following mating with WD-fed males. CONCLUSIONS: Our current study shows that paternal nutritional status has the potential to influence male metabolic and reproductive health, impacting on embryonic development and the maternal reproductive tract. This study highlights potential direct (sperm-mediated) and indirect (seminal vesicle fluid-mediated) pathways in which a father's poor diet could shape the long-term health of his offspring.

Overnutrition in persons with cystic fibrosis on modulator therapy and the relationship to obstructive sleep apnea.

Cystic fibrosis (CF) care is evolving with the ubiquitous use of modulator therapy and resultant increase in lifespan. It is important for CF clinicians to monitor the pathologic weight gain that is concomitantly being seen as obesity is a known risk factor for multiple other diseases. In this review we focus on obesity in CF, discuss screening and lifestyle considerations, outline CF-specific concerns with weight loss medications, and describe the vicious cycle of obesity and obstructive sleep apnea (OSA). We discuss screening and treatment for OSA, as it directly correlates with weight fluctuation. We offer interim recommendations for CF teams as they continue to care for this population.

Malnutrition among Children under Age Five in Panama: Results of the ENSPA 2019.

Background: Malnutrition has important short- and long-term consequences in children under age five. Malnutrition encompasses undernutrition, overnutrition, and the coexistence of both of them, known as the double burden of malnutrition (DBM). Objective: The aim of this study was to estimate the prevalence of undernutrition, overnutrition, and the DBM among these children at the national level and by living area in Panama. Methods: Data from the National Health Survey of Panama (ENSPA, Spanish acronym), a population-based, cross-sectional study carried out in 2019 were used. Stunting, wasting, overweight, and obesity were defined according to the cut-off points of the World Health Organization Growth Standards. Undernutrition was defined as being stunted only, wasted only or both; overnutrition was defined as being overweight only or obese only; and the DBM was defined as the co-occurence of stunting and overweight/obesity in the same child. Prevalence and general characteristics at the national level and by living area were weighted. Findings: The prevalence of undernutrition was 15.3% (95% confidence interval (CI) 13.4-17.3) at the national level and 36.6% (CI: 30.1-43.5) in indigenous areas. The prevalence of overnutrition was 10.2% (8.2-12.6) at the national level and 11.9% (CI: 8.5-16.3), 8.4% (CI: 6.5-10.7) and 8.7% (CI: 5.2-14.3) in urban, rural and indigenous areas, respectively. The DBM prevalence was 1.4% (CI: 1.0-2.1) at the national level and 2.7% (CI: 1.4-5.1) in indigenous areas. Conclusions: Undernutrition is still the most prevalent malnutrition condition in our country. Panama has the highest prevalence of overnutrition in Central America. The highest prevalence of undernutrition and DBM was found among children living in indigenous areas.

How much does overnutrition weigh? The environmental and social impacts of Metabolic Food Waste in Italy.

Excess Food Energy Intake (EFEI), namely Metabolic Food Waste (MFW) corresponds to excess calorie intake related to overconsumption of food and is responsible for overweight (OW) and obesity (OB) conditions. Identifying its causes and impacts could be important, so that it can be prevented and reduced, generating health, environmental and societal benefits. Therefore, this research quantifies MFW among OW and OB adult populations (18-75 years) in Italy and its environmental and social implications. Life cycle assessment (LCA) through the Simapro 9.5 software was used and then, the results were monetized according to the Environmental Price Handbook to understand the real environmental cost. Finally, Social LCA (S-LCA) was considered following the Product Social Impact Assessment (PSILCA) guidelines to understand the potential social risks behind the food that ends up on our plates. The results highlight the amount of MFW in Italy is 2696 billion kcal/year corresponding to 1.59 Mtons over-consumed food/year, while the impacts are mainly related to global warming (8.78 Mtons CO2 eq/year, or 2.29 % of the total Italian CO2 emissions), terrestrial ecotoxicity (843,451 tons 1.4-DCB/year), freshwater ecotoxicity (222,483 tons 1.4 DCB eq/year), and land consumption (8 million m2a eq/year), mostly due to the meat, fats and oils and sweets overconsumption. Impacts monetization also shows that MFW could induce an environmental price of € 1340/per capita/year, and finally, the S-LCA reveals how overconsumption of food has the potential to affect gender discrimination, water depletion, trade union, and social discrimination due to the high proportion of labor migrants in the agricultural sector.

Understanding the cause of type 2 diabetes.

Type 2 diabetes has long been thought to have heterogenous causes, even though epidemiological studies uniformly show a tight relationship with overnutrition. The twin cycle hypothesis postulated that interaction of self-reinforcing cycles of fat accumulation inside the liver and pancreas, driven by modest but chronic positive calorie balance, could explain the development of type 2 diabetes. This hypothesis predicted that substantial weight loss would bring about a return to the non-diabetic state, permitting observation of the pathophysiology determining the transition. These changes were postulated to reflect the basic mechanisms of causation in reverse. A series of studies over the past 15 years has elucidated these underlying mechanisms. Together with other research, the interaction of environmental and genetic factors has been clarified. This knowledge has led to successful implementation of a national programme for remission of type 2 diabetes. This Review discusses the paucity of evidence for heterogeneity in causes of type 2 diabetes and summarises the in vivo pathophysiological changes, which cause this disease of overnutrition. Type 2 diabetes has a homogenous cause expressed in genetically heterogenous individuals.

Transcriptomic Analysis of Newborn Hanwoo Calves: Effects of Maternal Overnutrition during Mid- to Late Pregnancy on Subcutaneous Adipose Tissue and Liver.

This study investigated the transcriptomic responses of subcutaneous adipose tissue (SAT) and liver in newborn Hanwoo calves subjected to maternal overnutrition during mid- to late gestation. Eight Hanwoo cows were randomly assigned to control and treatment groups. The treatment group received a diet of 4.5 kg of concentrate and 6.5 kg of rice straw daily, resulting in intake levels of 8.42 kg DMI, 5.69 kg TDN, and 0.93 kg CP-higher than the control group (6.07 kg DMI, 4.07 kg TDN, and 0.65 kg CP), with respective NEm values of 9.56 Mcal and 6.68 Mcal. Following birth, newly born calves were euthanized humanely as per ethical guidelines, and SAT and liver samples from newborn calves were collected for RNA extraction and analysis. RNA sequencing identified 192 genes that were differentially expressed in the SAT (17 downregulated and 175 upregulated); notably, HSPA6 emerged as the most significantly upregulated gene in the SAT and as the singular upregulated gene in the liver (adj-p value < 0.05). Additionally, differential gene expression analysis highlighted extensive changes across genes associated with adipogenesis, fibrogenesis, and stress response. The functional enrichment pathway and protein-protein interaction (PPI) unraveled the intricate networks and biological processes impacted by overnutrition, including extracellular matrix organization, cell surface receptor signaling, and the PI3K-Akt signaling pathway. These findings underscore maternal overnutrition's substantial influence on developmental pathways, suggesting profound cellular modifications with potential lasting effects on health and productivity. Despite the robust insights that are provided, the study's limitations (sample size) underscore the necessity for further research.

Short-Term Postnatal Overfeeding Induces Long-Lasting Cardiometabolic Syndrome in Mature and Old Mice Associated with Increased Sensitivity to Myocardial Infarction.

SCOPE: Perinatal nutritional disturbances may "program" an increased cardio-metabolic risk in adulthood; however, few experimental studies have explored their effects on mature and/or old animal. This study aims to investigate the influence of postnatal overfeeding (PNOF) on cardiac function, sensitivity to ischemia-reperfusion (I-R) injury in vivo, glucose metabolism, and metabolic profile of pericardial adipose tissue (PAT) in young (4 months), adult (6 months), old (12 months), and very old (18 months) male mice. METHODS AND RESULTS: Two days after birth, PNOF is induced by adjusting the litter size of C57BL/6 male mice to three pups/mother, while the normally fed (NF) control group is normalized to nine pups/mother. After weaning, all mice have free access to standard diet. Glucose/insulin tests and in vivo myocardial I-R injury are conducted on mice aged from 2 to 12 months, while echocardiography is performed at all ages up to 18 months. PNOF mice exhibit an early and persistent 10-20% increase in body weight and a 10% decrease in left ventricular ejection fraction throughout their lifespan. In PNOF mice aged 4, 6, and 12 months, glucose intolerance and insulin resistance are observed, as well as a 27-34% increase in infarct size. This is accompanied by a higher PAT mass with increased inflammatory status. CONCLUSION: Short-term PNOF results in nutritional programming, inducing long-lasting alterations in glucose metabolism and cardiac vulnerability in male mice, lasting up to 12 months.

Role of RIPK3 in lipid metabolism and postnatal overfeeding-induced metabolic disorders in mice.

Postnatal overfeeding can increase the long-term risk of metabolic disorders, such as obesity, but the underlying mechanisms remain unclear and treatment approaches are limited. Receptor-interacting protein kinase 3 (RIPK3) is associated with several metabolic diseases. We investigated the effects of RIPK3 on neonatal overfeeding-related metabolic disorders. On postnatal day 3, litter sizes were adjusted to 9-10 (normal litters, NL) or 2-3 (small litters, SL) mice per dam to mimic postnatal overfeeding. After weaning, NL and SL mouse were fed normal diet. We generated an adeno-associated virus (AAV) carrying short hairpin RNA (shRNA) against Ripk3 and an empty vector as a control. The NL and SL groups were treated intravenously with 1×1012 vector genome of AAV vectors at week 6. The SL group showed a higher body weight than the NL group from week 3 of age through adulthood. At weeks 6 and 13, the SL group exhibited impaired glucose and insulin tolerance, RIPK3 up-regulation, and lipid accumulation in liver and adipose tissues. In the SL group, the genes involved in lipid synthesis and lipolysis were increased, whereas fatty acid ß-oxidation-related genes were weakened in adipose tissue and liver. At week 13, AAV-shRNA-Ripk3 ameliorated adipose tissue hypertrophy, hepatic steatosis, insulin resistance, and dysregulated lipid metabolism in the adipose tissue and liver of SL mice. These findings support a novel mechanism underlying the pathogenesis of postnatal overfeeding-related metabolic disorders and suggest potential therapeutic targets.

Deletion of Impdh2 in adipocyte precursors limits the expansion of white adipose tissue and enhances metabolic health with overnutrition.

The equilibrium between the hypertrophic growth of existing adipocytes and adipogenesis is vital in managing metabolic stability in white adipocytes when faced with overnutrition. Adipogenesis has been established as a key player in combating metabolic irregularities caused by various factors. However, the benefits of increasing adipogenesis-mediated white adipose tissue (WAT) expansion for metabolic health regulation remain uncertain. Our findings reveal an increase in Impdh2 expression during the adipogenesis phase, both in vivo and in vitro. Xmp enhances adipogenic potential by fostering mitotic clonal expansion (MCE). The conditional knockout of Impdh2 in adipocyte progenitor cells(APCs) in adult and aged mice effectively curbs white adipose tissue expansion, ameliorates glucose tolerance, and augments energy expenditure under high-fat diet (HFD). However, no significant difference is observed under normal chow diet (NCD). Concurrently, the knockout of Impdh2 in APCs significantly reduces the count of new adipocytes induced by HFD, without affecting adipocyte size. Mechanistically, Impdh2 regulates the proliferation of APCs during the MCE phase via Xmp. Exogenous Xmp can significantly offset the reduction in adipogenic abilities of APCs due to Impdh2 deficiency. In summary, we discovered that adipogenesis-mediated WAT expansion, induced by overnutrition, also contributes to metabolic abnormalities. Moreover, the pivotal role of Impdh2 in regulating adipogenesis in APCs offers a novel therapeutic approach to combat obesity.

Overnutrition, Hyperinsulinemia and Ectopic Fat: It Is Time for A Paradigm Shift in the Management of Type 2 Diabetes.

The worldwide incidence of prediabetes/type 2 has continued to rise the last 40 years. In the same period, the mean daily energy intake has increased, and the quality of food has significantly changed. The chronic exposure of pancreatic ß-cells to calorie excess (excessive energy intake) and food additives may increase pancreatic insulin secretion, decrease insulin pulses and/or reduce hepatic insulin clearance, thereby causing chronic hyperinsulinemia and peripheral insulin resistance. Chronic calorie excess and hyperinsulinemia may promote lipogenesis, inhibit lipolysis and increase lipid storage in adipocytes. In addition, calorie excess and hyperinsulinemia can induce insulin resistance and contribute to progressive and excessive ectopic fat accumulation in the liver and pancreas by the conversion of excess calories into fat. The personal fat threshold hypothesis proposes that in susceptible individuals, excessive ectopic fat accumulation may eventually lead to hepatic insulin receptor resistance, the loss of pancreatic insulin secretion, hyperglycemia and the development of frank type 2 diabetes. Thus, type 2 diabetes seems (partly) to be caused by hyperinsulinemia-induced excess ectopic fat accumulation in the liver and pancreas. Increasing evidence further shows that interventions (hypocaloric diet and/or bariatric surgery), which remove ectopic fat in the liver and pancreas by introducing a negative energy balance, can normalize insulin secretion and glucose tolerance and induce the sustained biochemical remission of type 2 diabetes. This pathophysiological insight may have major implications and may cause a paradigm shift in the management of type 2 diabetes: avoiding/reducing ectopic fat accumulation in the liver and pancreas may both be essential to prevent and cure type 2 diabetes.

Dietary determinants of overnutrition among hypertensive patients in southwest Ethiopia: an ordinal regression model.

Overnutrition is a recognized risk factor for hypertension, but evidence is lacking among hypertensive patients for tailored dietary interventions. This study assessed dietary factors in 331 hypertensive patients in southwest Ethiopia. The data was collected through a questionnaire and analyzed using factor analysis. Body mass index (BMI) was calculated, and a BMI above 25 kg m-2 was considered overnutrition. An ordinal logistic regression model was used to model the data and control confounders. Adjusted odds ratio and p-values were reported. Among the 331 respondents, consumption of cereals and grains (57.0%); roots and tubers (58.5); and legumes (50.0%), while 28.6% drink alcohol, was common. About 29.0% (24.1-34.2) had overnutrition (22%, 17.6-26.6%, overweight and 7.0%, 4.5-10.3%, obesity). While the predicted odds of overnutrition were higher among males (AOR = 2.85; 1.35-6.02), married (AOR = 1.47; 0.69-3.12), illiterates (AOR = 2.09; 1.18-3.72), advanced age (AOR = 1.65; 0.61-4.61), government employees (AOR = 6.83; 1.19-39.2), and urban dwellers (AOR = 4.06; 1.76-9.36), infrequent vegetable consumption (AOR = 1.47; 0.72-2.96) and lower and higher terciles of cereals and animal-source food consumption (AOR = 1.56; 0.72-3.34). Overnutrition among hypertensive patients was significantly high and associated with unhealthy dietary consumption, educational status, residence, and occupation, emphasizing the need for targeted dietary counseling.

Prevalence, determinants, intervention strategies and current gaps in addressing childhood malnutrition in Vietnam: a systematic review.

BACKGROUND: Childhood malnutrition in all forms is a major public health issue worldwide. This review systematically examined the prevalence and determinants and identify the potential interventions and current gap in addressing malnutrition including undernutrition, overnutrition and micronutrient deficiencies (MNDs) in Vietnamese children aged 0-18 years old. METHODS: Embase, Scopus, PubMed, and Web of Science were systematically searched through June 2022 to identify relevant articles published within the past 25 years. Study selection and data extraction were performed by one reviewer and checked for accuracy by the other two reviewers in accordance with PRISMA guideline. Risk of publication bias was assessed using American Dietetic Association Quality Criteria Checklist. RESULTS: Seventy-two studies that met the inclusion criteria were included. Undernutrition has decreased over time but still 22.4%, 5.2% and 12.2% of children under 5 were stunted, wasted and underweight, respectively. Anaemia, iron, zinc, and vitamin D deficiencies were the more common forms of MNDs, the prevalence varied by age, region, and socioeconomic group. Population-based surveys reported that 11% and 48% of children aged 0-11 years old were iron and vitamin D deficient, respectively. Zinc deficiency affected almost one-quarter of the children and adolescents. Retinol deficiency was of less concern (< 20%). However, more evidence on MNDs prevalence is needed. Overweight and obesity is now on the rise, affecting one-third of school-aged children. The key determinants of undernutrition included living in rural areas, children with low birth weight, and poor socio-economic status, whereas living in urban and affluent areas, having an inactive lifestyle and being a boy were associated with increased risk of overweight and obesity. Nutrition specific intervention studies including supplementation and food fortification consistently showed improvements in anthropometric indices and micronutrient biomarkers. National nutrition-sensitive programmes also provided nutritional benefits for children's growth and eating behaviours, but there is a lack of data on childhood obesity. CONCLUSION: This finding highlights the need for effective double duty actions to simultaneously address different forms of childhood malnutrition in Vietnam. However, evidence on the potential intervention strategies, especially on MNDs and overnutrition are still limited to inform policy decision, thus future research is warranted.

Overnutrition is a risk factor for iron, but not for zinc or vitamin A deficiency in children and young people: a systematic review and meta-analysis.

INTRODUCTION: Traditionally associated with undernutrition, increasing evidence suggests micronutrient deficiencies can coexist with overnutrition. Therefore, this work aimed to systematically review the associations between iron, zinc and vitamin A (VA) status and weight status (both underweight and overweight) in children and young people. METHODS: Ovid Medline, Ovid Embase, Scopus and Cochrane databases were systematically searched for observational studies assessing micronutrient status (blood, serum or plasma levels of iron, zinc or VA biomarkers) and weight status (body mass index or other anthropometric measurement) in humans under 25 years of any ethnicity and gender. Risk of bias assessment was conducted using the American Dietetic Association Quality Criteria Checklist. Where possible, random effects restricted maximum likelihood meta-analyses were performed. RESULTS: After screening, 83 observational studies involving 190 443 participants from 44 countries were identified, with many studies having reported on more than one micronutrient and/or weight status indicator. Iron was the most investigated micronutrient, with 46, 28 and 27 studies reporting data for iron, zinc and VA status, respectively. Synthesising 16 records of OR from seven eligible studies, overnutrition (overweight and obesity) increased odds of iron deficiency (ID) (OR (95% CI): 1.51 (1.20 to 1.82), p<0.0001, I2=40.7%). Odds appeared to be higher for children living with obesity (1.88 (1.33 to 2.43), p<0.0001, I2=20.6%) in comparison to those with overweight (1.31 (0.98 to 1.64), p<0.0001, I2=40.5%), although between group differences were not significant (p=0.08). CONCLUSIONS: Overnutrition is associated with increased risk of ID, but not zinc or VA deficiencies, with an inverted U-shaped relationship observed between iron status and bodyweight. Our results highlight significant heterogeneity in the reporting of micronutrient biomarkers and how deficiencies were defined. Inflammation status was rarely adequately accounted for, and the burden of ID may well be under-recognised, particularly in children and young people living with overnutrition. PROSPERO REGISTRATION NUMBER: CRD42020221523.

Sexual dimorphism in thermogenic regulators and metrnl expression in adipose tissue of offspring mice exposed to maternal and postnatal overnutrition.

Current study investigated the impact of maternal and postnatal overnutrition on phenotype of adipose, in relation to offspring thermogenesis and sex. Female C57BL/6 J mice were fed with CHOW or high fat diet (HFD) for 2 weeks before mating, throughout gestation and lactation. At weaning, pups were fed to 9 weeks old with CHOW or HFD, which resulted in four groups for each gender--male or female: CHOW-CHOW (CC), CHOW-HFD (CH), HFD-CHOW (HC), HFD-HFD (HH). Maternal and post-weaning HFD enhanced thermogenic factors such as Acox1, Dio2 and Cox8b in iBAT of male and female offspring, but increased SIRT1, PGC-1α and UCP1 only in female. However, Acox1, Dio2 and Cox8b mRNA expression and SIRT1, PGC-1α and UCP1 protein expression were only enhanced upon maternal and post-weaning HFD in sWAT and pWAT of female offspring. Increased metrnl expression in adipose were observed in sex- and depot-specific manner, while enhanced circulating metrnl level was only observed in male offspring undergoing maternal HFD. Palmitic acid changed metrnl expression during preadipocytes differentiation and siRNA-mediated knockdown of metrnl inhibited preadipocyte differentiation. Female offspring were more prone to resist adverse outcomes induced by maternal and post-weaning overnutrition, which probably related to metrnl expression and thermogenesis.

Con - The Harms of Overfeeding Early in Critical Illness.

Historically, several studies showed an association between malnutrition in critically ill patients and poor outcomes. As a result, the standard practice had been to provide patients with full nutrition as soon as possible to eliminate malnutrition, improve outcomes, and reduce mortality. However, several studies recently suggested that providing more calories and protein is not better in critical illness and may be harmful in certain disease states. This literature review and editorial describe the harms of maximal feeding early in critical illness.

Prepuberty is a window period for curcumin to prevent obesity in postnatal overfed rats.

BACKGROUND: Overnutrition in early life increases the risk of obesity and metabolic diseases. We investigated the effects and the window period of a curcumin (CUR) diet on postnatal overfed rats. METHODS: Male rats aged 3 days were randomly divided into normal litters (NL, 10 pups/litter) and small litters (SL, 3 pups/litter). After weaning (Week 3, W3), NL rats were fed a normal diet (NL) and SL rats were fed a normal diet (SL) or 2% CUR diet from weaning (W3) (SL-CURW13), beginning of puberty (W6) (SL-CURW16), or end of puberty (W8) (SL-CURW18) for 10 weeks. RESULTS: Body weight, glucose intolerance and hyperlipidemia in the SL rats were higher than in the NL rats, especially after puberty. After the CUR intervention, SL-CURW13 and SL-CURW16 rats showed lower body weight gain, adipose tissue weight and mRNA level of C/EBPα in SAT, along with higher mRNA levels of ß-catenin. There was no difference between SL and SL-CURW18 rats. Glucose tolerance, serum lipids and hepatic lipids recovered to normal in the SL-CURW13 rats, but only partially in the SL-CURW16 and SL-CURW18 rats. CONCLUSION: Prepuberty is a window period for CUR intervention to improve programmed outcomes in postnatal overfed rats. IMPACT: Overnutrition during the first 1000 days of life has persistent negative effects on metabolism. Strategies should be taken to prevent overnutrition in early life to reduce the risk of obesity and metabolic disease in later life. A small-litter rat model was utilized to simulate early-life overnutrition in humans. We investigated the different effects and critical period for curcumin intervention on postnatal overfed rats. Dietary curcumin intervention before puberty could effectively transform nutritional programming to reduce obesity and metabolic disorders caused by early-life overnutrition, and an earlier intervention might predict a better outcome.

The effect of nutrition-specific and nutrition-sensitive interventions on the double burden of malnutrition in low-income and middle-income countries: a systematic review.

BACKGROUND: Low-income and middle-income countries (LMICs) experiencing nutrition transition face an increasing double burden of malnutrition (DBM). WHO has urged the identification of risks and opportunities in nutrition interventions to mitigate the DBM, but robust evidence is missing. This review summarises the effect of nutrition-specific and nutrition-sensitive interventions on undernutrition and overnutrition in LMICs. METHODS: We searched four major databases and grey literature for publications in English, French, Portuguese, and Spanish from Jan 1, 2000, to Aug 14, 2023. Eligible studies evaluated nutrition-specific or nutrition-sensitive interventions on both undernutrition and overnutrition, employing robust study designs (individually randomised, cluster randomised, and non-randomised trials; interrupted time series; controlled before-after; and prospective cohort studies). Studies were synthesised narratively, and classified as DBM-beneficial, potentially DBM-beneficial, DBM-neutral, potentially DBM-harmful, and DBM-harmful, using vote counting. This review is registered with PROSPERO (CRD42022320131). FINDINGS: We identified 26 studies evaluating 20 nutrition-specific (maternal and child health [MCH] and school-based programmes) and six nutrition-sensitive (conditional cash transfers and other social policies) interventions. Seven of eight MCH interventions providing food-based or nutritional supplements indicated possible DBM-harmful effects, associated with increased maternal or child overweight. Most school-based programmes and MCH interventions that target behavioural change were considered potentially DBM-beneficial. Two studies of conditional cash transfers suggested DBM-beneficial effects in children, whereas one indicated potentially harmful effects on maternal overweight. A study on a family planning service and one on an education reform revealed possible long-term harmful effects on obesity. INTERPRETATION: There is considerable scope to repurpose existing nutrition interventions to reduce the growing burden of the DBM in LMICs. In settings undergoing rapid nutrition transition, specific policy attention is required to ensure that food-based or supplement-based MCH programmes do not unintentionally increase maternal or child overweight. Consistent reporting of undernutrition and overnutrition outcomes in all nutrition interventions is essential to expand the evidence base to identify and promote interventions maximising benefits and minimising harms on the DBM. FUNDING: President's Scholarship (Imperial College London) and National Institute for Health and Care Research. TRANSLATIONS: For the Portuguese, Spanish and French translations of the abstract see Supplementary Materials section.

DRAK2 suppresses autophagy by phosphorylating ULK1 at Ser56 to diminish pancreatic ß cell function upon overnutrition.

Impeded autophagy can impair pancreatic ß cell function by causing apoptosis, of which DAP-related apoptosis-inducing kinase-2 (DRAK2) is a critical regulator. Here, we identified a marked up-regulation of DRAK2 in pancreatic tissue across humans, macaques, and mice with type 2 diabetes (T2D). Further studies in mice showed that conditional knockout (cKO) of DRAK2 in pancreatic ß cells protected ß cell function against high-fat diet feeding along with sustained autophagy and mitochondrial function. Phosphoproteome analysis in isolated mouse primary islets revealed that DRAK2 directly phosphorylated unc-51-like autophagy activating kinase 1 (ULK1) at Ser56, which was subsequently found to induce ULK1 ubiquitylation and suppress autophagy. ULK1-S56A mutation or pharmacological inhibition of DRAK2 preserved mitochondrial function and insulin secretion against lipotoxicity in mouse primary islets, Min6 cells, or INS-1E cells. In conclusion, these findings together indicate an indispensable role of the DRAK2-ULK1 axis in pancreatic ß cells upon metabolic challenge, which offers a potential target to protect ß cell function in T2D.

Overnutrition in the early postnatal period influences lifetime metabolic risk: Evidence for impact on pancreatic ß-cell mass and function.

Overconsumption of energy-rich foods that disrupt caloric balance is a fundamental cause of overweight, obesity and diabetes. Dysglycemia and the resulting cardiovascular disease cause substantial morbidity and mortality worldwide, as well as high societal cost. The prevalence of obesity in childhood and adolescence is increasing, leading to younger diabetes diagnosis, and higher severity of microvascular and macrovascular complications. An important goal is to identify early life conditions that increase future metabolic risk, toward the goal of preventing diabetes and cardiovascular disease. An ample body of evidence implicates prenatal and postnatal childhood growth trajectories in the programming of adult metabolic disease. Human epidemiological data show that accelerated childhood growth increases risk of type 2 diabetes in adulthood. Type 2 diabetes results from the combination of insulin resistance and pancreatic ß-cell failure, but specific mechanisms by which accelerated postnatal growth impact one or both of these processes remain uncertain. This review explores the metabolic impact of overnutrition during postnatal life in humans and in rodent models, with specific attention to the connection between accelerated childhood growth and future adiposity, insulin resistance, ß-cell mass and ß-cell dysfunction. With improved knowledge in this area, we might one day be able to modulate nutrition and growth in the critical postnatal window to maximize lifelong metabolic health.