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.

Postnatal Overfeeding during Lactation Induces Endothelial Dysfunction and Cardiac Insulin Resistance in Adult Rats.

Early overnutrition is associated with cardiometabolic alterations in adulthood, likely attributed to reduced insulin sensitivity due to its crucial role in the cardiovascular system. This study aimed to assess the long-term effects of early overnutrition on the development of cardiovascular insulin resistance. An experimental childhood obesity model was established using male Sprague Dawley rats. Rats were organized into litters of 12 pups/mother (L12-Controls) or 3 pups/mother (L3-Overfed) at birth. After weaning, animals from L12 and L3 were housed three per cage and provided ad libitum access to food for 6 months. L3 rats exhibited elevated body weight, along with increased visceral, subcutaneous, and perivascular fat accumulation. However, heart weight at sacrifice was reduced in L3 rats. Furthermore, L3 rats displayed elevated serum levels of glucose, leptin, adiponectin, total lipids, and triglycerides compared to control rats. In the myocardium, overfed rats showed decreased IL-10 mRNA levels and alterations in contractility and heart rate in response to insulin. Similarly, aortic tissue exhibited modified gene expression of TNFα, iNOS, and IL-6. Additionally, L3 aortas exhibited endothelial dysfunction in response to acetylcholine, although insulin-induced relaxation remained unchanged compared to controls. At the molecular level, L3 rats displayed reduced Akt phosphorylation in response to insulin, both in myocardial and aortic tissues, whereas MAPK phosphorylation was elevated solely in the myocardium. Overfeeding during lactation in rats induces endothelial dysfunction and cardiac insulin resistance in adulthood, potentially contributing to the cardiovascular alterations observed in this experimental model.

Long-term changes in the diurnal temporal regulation and set points of metabolic parameters associated with chronic maternal overnutrition in rabbits.

Metabolic syndrome (MS) and obesity have become a worldwide epidemic with an alarming prevalence in women of reproductive age. Maternal metabolic condition is considered a risk factor for adverse birth outcomes and long-term MS. In this study, we developed a rabbit model of maternal overnutrition via the chronic intake of a high-fat and carbohydrate diet (HFCD), and we determined the effects of this diet on maternal metabolism and offspring metabolic set points and temporal metabolic regulation in adult life. Before and during pregnancy, the female rabbits that consumed the HFCD exhibited significant changes in body weight, serum levels of analytes associated with carbohydrate and lipid metabolism, levels of liver and kidney damage markers, and liver histology. Our data suggest that rabbits are a valuable model for studying the development of MS associated with the chronic intake of unbalanced diets and fetal metabolic programming. Furthermore, the offspring of overnourished dams exhibited considerable changes in 24-h serum metabolite profiles in adulthood, with notable sexual dimorphism. These data suggest that maternal nutritional conditions due to the chronic intake of an HFCD adversely impact key elements related to the development of circadian rhythmicity in offspring.NEW & NOTEWORTHY Maternal overnutrition previous and during pregnancy leads to long-term changes in the 24-h regulation and setpoint of metabolic profiles of the offspring.

SIRT6 regulates SREBP1c-induced glucolipid metabolism in liver and pancreas via the AMPKα-mTORC1 pathway.

The aim of this study was to determine the mechanism by which SIRT6 regulates glucolipid metabolism disorders. We detected histological and molecular changes in Sprague-Dawley rats as well as in BRL 3A and INS-1 cell lines subjected to overnutrition and starvation. SIRT6, SREBP1c, and glucolipid metabolism biomarkers were identified by fluorescence co-localization, real-time PCR, and western blotting. Gene silencing studies were performed. Recombinant SIRT6, AMPK agonist (AICAR), mTOR inhibitor (rapamycin), and liver X receptor (LXR) agonist (T0901317) were used to pre-treated in BRL 3A and INS-1 cells. Real-time PCR and western blotting were used to detect related proteins, and cell counting was utilized to detect proliferation. We obtained conflicting results; SIRT6 and SREBP1c appeared in both the liver and pancreas of high-fat and hungry rats. Recombinant SIRT6 alleviated the decrease in AMPKα and increase in mTORC1 (complex of mTOR, Raptor, and Rheb) caused by overnutrition. SIRT6 siRNA reversed the glucolipid metabolic disorders caused by the AMPK agonist and mTOR inhibitor but not by the LXR agonist. Taken together, our results demonstrate that SIRT6 regulates glycolipid metabolism through AMPKα-mTORC1 regulating SREBP1c in the liver and pancreas induced by overnutrition and starvation, independent of LXR.

Metabolic programming in the offspring after gestational overfeeding in the mother: toward neonatal rescuing with metformin in a swine model.

OBJECTIVES: Maternal overfeeding during gestation may lead to adverse metabolic programming in the offspring mediated by epigenetic alterations. Potential reversal, in early life, of these alterations may help in the prevention of future cardio-metabolic conditions. In this context, our aims were: (1) to study the effects of maternal overfeeding on the metabolic and epigenetic programming of offspring's adipose tissue; and (2) to test the potential of postnatal metformin treatment to reverse these changes. METHODS: We used a swine animal model where commercial production sows were either overfed or kept under standard diet during gestation, and piglets at birth were randomly assigned to metformin (n = 16 per group) or vehicle treatment during lactation (n = 16 per group). RESULTS: Piglets born to overfed sows showed a worse metabolic profile (higher weight, weight gain from birth and abdominal circumference; all p < 0.05) together with altered serological markers (increased HOMA-IR, fructosamine, total cholesterol, C-Reactive Protein and lower HMW adiponectin; all p < 0.05). The visceral adipose tissue also showed altered morphology (increased adipocyte area, perimeter and diameter; all p < 0.05), as well as changes in gene expression (higher CCL2 and INSR, lower DLK1; all p < 0.05), and in DNA methylation (96 hypermethylated and 99 hypomethylated CpG sites; FDR < 0.05). Metformin treatment significantly ameliorated the abnormal metabolic profile, decreasing piglets' weight, weight gain from birth, abdominal circumference and fructosamine (all p < 0.05) and reduced adipocyte area, perimeter, and diameter in visceral adipose tissue (all p < 0.05). In addition, metformin treatment potentiated several associations between gene expression in visceral adipose tissue and the altered metabolic markers. CONCLUSIONS: Maternal overfeeding during gestation leads to metabolic abnormalities in the offspring, including adipose tissue alterations. Early metformin treatment mitigates these effects and could help rescue the offspring's metabolic health.

Neonatal leptin antagonism improves metabolic programming of postnatally overnourished mice.

BACKGROUND/OBJECTIVES: Alteration of the perinatal nutritional environment is an important risk factor for the development of metabolic diseases in later life. The hormone leptin plays a critical role in growth and development. Previous studies reported that postnatal overnutrition increases leptin secretion during the pre-weaning period. However, a direct link between leptin, neonatal overnutrition, and lifelong metabolic regulation has not been investigated. METHODS: We used the small litter mouse model combined with neonatal leptin antagonist injections to examine whether attenuating leptin during early life improves lifelong metabolic regulation in postnatally overnourished mice. RESULTS: Postnatally overnourished mice displayed rapid weight gain during lactation and remained overweight as adults. These mice also showed increased adiposity and perturbations in glucose homeostasis in adulthood. Neonatal administration of a leptin antagonist normalized fat mass and insulin sensitivity in postnatally overnourished mice. These metabolic improvements were associated with enhanced sensitivity of hypothalamic neurons to leptin. CONCLUSIONS: Early postnatal overnutrition causes metabolic alterations that can be permanently attenuated with the administration of a leptin antagonist during a restricted developmental window.

CTRP6 rapidly responds to acute nutritional changes, regulating adipose tissue expansion and inflammation in mice.

In chronic obesity, activated adipose tissue proinflammatory cascades are tightly linked to metabolic dysfunction. Yet, close temporal analyses of the responses to obesogenic environment such as high-fat feeding (HFF) in susceptible mouse strains question the causal relationship between inflammation and metabolic dysfunction, and/or raises the possibility that certain inflammatory cascades play adaptive/homeostatic, rather than pathogenic roles. Here, we hypothesized that CTRP6, a C1QTNF family member, may constitute an early responder to acute nutritional changes in adipose tissue, with potential physiological roles. Both 3-days high-fat feeding (3dHFF) and acute obesity reversal [2-wk switch to low-fat diet after 8-wk HFF (8wHFF)] already induced marked changes in whole body fuel utilization. Although adipose tissue expression of classical proinflammatory cytokines (Tnf-α, Ccl2, and Il1b) exhibited no, or only minor, change, C1qtnf6 uniquely increased, and decreased, in response to 3dHFF and acute obesity reversal, respectively. CTRP6 knockout (KO) mouse embryonic fibroblasts (MEFs) exhibited increased adipogenic gene expression (Pparg, Fabp4, and Adipoq) and markedly reduced inflammatory genes (Tnf-α, Ccl2, and Il6) compared with wild-type MEFs, and recombinant CTRP6 induced the opposite gene expression signature, as assessed by RNA sequencing. Consistently, 3dHFF of CTRP6-KO mice induced a greater whole body and adipose tissue weight gain compared with wild-type littermates. Collectively, we propose CTRP6 as a gene that rapidly responds to acute changes in caloric intake, acting in acute overnutrition to induce a "physiological inflammatory response" that limits adipose tissue expansion.NEW & NOTEWORTHY CTRP6 (C1qTNF6), a member of adiponectin gene family, regulates inflammation and metabolism in established obesity. Here, short-term high-fat feeding in mice is shown to increase adipose tissue expression of CTRP6 before changes in the expression of classical inflammatory genes occur. Conversely, CTRP6 expression in adipose tissue decreases early in the course of obesity reversal. Gain- and loss-of-function models suggest CTRP6 as a positive regulator of inflammatory cascades, and a negative regulator of adipogenesis and adipose tissue expansion.

Nutrition and its role in epigenetic inheritance of obesity and diabetes across generations.

Nutritional constraints including not only caloric restriction or protein deficiency, but also energy-dense diets affect metabolic health and frequently lead to obesity and insulin resistance, as well as glucose intolerance and type 2 diabetes. The effects of these environmental factors are often mediated via epigenetic modifiers that target the expression of metabolic genes. More recently, it was discovered that such parentally acquired metabolic changes can alter the metabolic health of the filial and grand-filial generations. In mammals, this epigenetic inheritance can either follow an intergenerational or transgenerational mode of inheritance. In the case of intergenerational inheritance, epimutations established in gametes persist through the first round of epigenetic reprogramming occurring during preimplantation development. For transgenerational inheritance, epimutations persist additionally throughout the reprogramming that occurs during germ cell development later in embryogenesis. Differentially expressed transcripts, genomic cytosine methylations, and several chemical modifications of histones are prime candidates for tangible marks which may serve as epimutations in inter- and transgenerational inheritance and which are currently being investigated experimentally. We review, here, the current literature in support of epigenetic inheritance of metabolic traits caused by nutritional constraints and potential mechanisms in man and in rodent model systems.

Substrate utilization and metabolic profile in response to overfeeding with a high-fat diet in South Asian and white men: a sedentary lifestyle study.

BACKGROUND: For the same BMI, South Asians have a higher body fat percentage, a higher liver fat content and a more adverse metabolic profile than whites. South Asians may have a lower fat oxidation than whites, which could result in an unfavorable metabolic profile when exposed to increased high-fat foods consumption and decreased physical activity as in current modern lifestyle. OBJECTIVE: To determine substrate partitioning, liver fat accumulation and metabolic profile in South Asian and white men in response to overfeeding with high-fat diet under sedentary conditions in a respiration chamber. DESIGN: Ten South Asian men (BMI, 18-29 kg/m2) and 10 white men (BMI, 22-33 kg/m2), matched for body fat percentage, aged 20-40 year were included. A weight maintenance diet (30% fat, 55% carbohydrate, and 15% protein) was given for 3 days. Thereafter, a baseline measurement of liver fat content (1H-MRS) and blood parameters was performed. Subsequently, subjects were overfed (150% energy requirement) with a high-fat diet (60% fat, 25% carbohydrate, and 15% protein) over 3 consecutive days while staying in a respiration chamber mimicking a sedentary lifestyle. Energy expenditure and substrate use were measured for 3 × 24-h. Liver fat and blood parameters were measured again after the subjects left the chamber. RESULTS: The 24-h fat oxidation as a percentage of total energy expenditure did not differ between ethnicities (P = 0.30). Overfeeding increased liver fat content (P = 0.02), but the increase did not differ between ethnicities (P = 0.64). In South Asians, overfeeding tended to increase LDL-cholesterol (P = 0.08), tended to decrease glucose clearance (P = 0.06) and tended to elevate insulin response (P = 0.07) slightly more than whites. CONCLUSIONS: Despite a similar substrate partitioning and similar accretion of liver fat, overfeeding with high-fat under sedentary conditions tended to have more adverse effects on the lipid profile and insulin sensitivity in South Asians.

Early metformin treatment improves pancreatic function and prevents metabolic dysfunction in early overfeeding male rats at adulthood.

NEW FINDINGS: What is the central question of this study? Studies reported the efficacy of metformin as a promising drug for preventing or treating of metabolic diseases. Nutrient stresses during neonatal life increase long-term risk for cardiometabolic diseases. Can early metformin treatment prevent the malprogramming effects of early overfeeding? What is the main finding and its importance? Neonatal metformin treatment prevented early overfeeding-induced metabolic dysfunction in adult rats. Inhibition of early hyperinsulinaemia and adult hyperphagia might be associated with decreased metabolic disease risk in these animals. Therefore, interventions during infant development offer a key area for future research to identify potential strategies to prevent the long-term metabolic diseases. We suggest that metformin is a potential tool for intervention. ABSTRACT: Given the need for studies investigating the possible long-term effects of metformin use at crucial stages of development, and taking into account the concept of metabolic programming, the present work aimed to evaluate whether early metformin treatment might program rats to resist the development of adult metabolic dysfunctions caused by overnutrition during the neonatal suckling phase. Wistar rats raised in small litters (SLs, three pups per dam) and normal litters (NLs, nine pups per dam) were used as models of early overfeeding and normal feeding, respectively. During the first 12 days of suckling, animals from SL and NL groups received metformin, whereas the controls received saline injections. Food intake and body weight were monitored from weaning until 90 days of age, when biometric and biochemical parameters were assessed. The metformin treatment decreased insulin concentrations in pups from SL groups, and as adults, these animals showed improvements in glucose tolerance, insulin sensitivity, body weight gain, white fat pad stores and food intake. Low-glucose insulinotrophic effects were observed in pancreatic islets from both NL and SL groups. These results indicate that early postnatal treatment with metformin inhibits early overfeeding-induced metabolic dysfunctions in adult rats.

The Actions of IGF-1 in the Growth Plate and Its Role in Postnatal Bone Elongation.

PURPOSE OF REVIEW: Bone elongation is a complex process driven by multiple intrinsic (hormones, growth factors) and extrinsic (nutrition, environment) variables. Bones grow in length by endochondral ossification in cartilaginous growth plates at ends of developing long bones. This review provides an updated overview of the important factors that influence this process. RECENT FINDINGS: Insulin-like growth factor-1 (IGF-1) is the major hormone required for growth and a drug for treating pediatric skeletal disorders. Temperature is an underrecognized environmental variable that also impacts linear growth. This paper reviews the current state of knowledge regarding the interaction of IGF-1 and environmental factors on bone elongation. Understanding how internal and external variables regulate bone lengthening is essential for developing and improving treatments for an array of bone elongation disorders. Future studies may benefit from understanding how these unique relationships could offer realistic new approaches for increasing bone length in different growth-limiting conditions.

Programming of Cardiovascular Dysfunction by Postnatal Overfeeding in Rodents.

Nutritional environment in the perinatal period has a great influence on health and diseases in adulthood. In rodents, litter size reduction reproduces the effects of postnatal overnutrition in infants and reveals that postnatal overfeeding (PNOF) not only permanently increases body weight but also affects the cardiovascular function in the short- and long-term. In addition to increased adiposity, the metabolic status of PNOF rodents is altered, with increased plasma insulin and leptin levels, associated with resistance to these hormones, changed profiles and levels of circulating lipids. PNOF animals present elevated arterial blood pressure with altered vascular responsiveness to vasoactive substances. The hearts of overfed rodents exhibit hypertrophy and elevated collagen content. PNOF also induces a disturbance of cardiac mitochondrial respiration and produces an imbalance between oxidants and antioxidants. A modification of the expression of crucial genes and epigenetic alterations is reported in hearts of PNOF animals. In vivo, a decreased ventricular contractile function is observed during adulthood in PNOF hearts. All these alterations ultimately lead to an increased sensitivity to cardiac pathologic challenges such as ischemia-reperfusion injury. Nevertheless, caloric restriction and physical exercise were shown to improve PNOF-induced cardiac dysfunction and metabolic abnormalities, drawing a path to the potential therapeutic correction of early nutritional programming.

Sex-associated preventive effects of low-dose aspirin on obesity and non-alcoholic fatty liver disease in mouse offspring with over-nutrition in utero.

Aspirin has been found to diminish hypertriglyceridemia and hyperglycemia in both obese rodents and patients with type 2 diabetes mellitus. We aimed to test whether low-dose aspirin can prevent obesity and the progression of non-alcoholic fatty liver disease (NAFLD) in high-risk subjects. We used offspring mice with maternal over-nutrition as a high-risk model of obesity and NAFLD. The offspring were given postnatal HF-diet and diethylnitrosamine (DEN) to induce obesity and NAFLD, and were treated with or without a low dose of aspirin for 12 weeks (ASP or CTL groups). Aspirin treatment reduced body weight gain, reversed glucose intolerance, and depressed hepatic lipid accumulation in female, but not in male mice. Female mice displayed re-sensitized insulin/Akt signaling and overactivated AMPK signaling, with enhanced level of hepatic PPAR-γ, Glut4, and Glut2, while male mice only enhanced hepatic PPAR-α and PPAR-γ levels. The female ASP mice had inhibited p44/42 MAPK activity and enhanced Pten expression, while male displayed activated p38 MAPK signaling. Furthermore, the female but not the male ASP mice reduced Wnt-signaling activity via both the epigenetic regulation of Apc expression and the post-transcriptional regulation of ß-catenin degradation. In summary, our study demonstrates a sex-associated effect of low-dose aspirin on obesity and NAFLD prevention in female but not in male mice.

Reuniting overnutrition and undernutrition, macronutrients, and micronutrients.

Over-nutrition and its late consequences are a dominant theme in medicine today. In addition to the health hazards brought on by over-nutrition, the medical community has recently accumulated a roster of health benefits with obesity, grouped under "obesity paradox." Throughout the world and throughout history until the 20th century, under-nutrition was a dominant evolutionary force. Under-nutrition brings with it a mix of benefits and detriments that are opposite to and continuous with those of over-nutrition. This continuum yields J-shaped or U-shaped curves relating body mass index to mortality. The overweight have an elevated risk of dying in middle age of degenerative diseases while the underweight are at increased risk of premature death from infectious conditions. Micronutrient deficiencies, major concerns of nutritional science in the 20th century, are being neglected. This "hidden hunger" is now surprisingly prevalent in all weight groups, even among the overweight. Because micronutrient replacement is safe, inexpensive, and predictably effective, it is now an exceptionally attractive target for therapy across the spectrum of weight and age. Nutrition-related conditions worthy of special attention from caregivers include excess vitamin A, excess vitamin D, and deficiency of magnesium.

Arcuate nucleus kisspeptin response to increased nutrition in rams.

Rams respond to acute nutritional supplementation by increasing the frequency of gonadotrophin-releasing hormone (GnRH) pulses. Kisspeptin neurons may mediate the effect of environmental cues on GnRH secretion, so we tested whether the ram response to nutrition involves activation of kisspeptin neurons in the arcuate nucleus (ARC), namely kisspeptin, neurokin B, dynorphin (KNDy) neurons. Rams were given extra lupin grain with their normal ration. Blood was sampled before feeding, and continued until animals were killed for collection of brain tissue at 2 or 11h after supplementation. In supplemented rams, LH pulse frequency increased after feeding, whereas control animals showed no change. Within the caudal ARC, there were more kisspeptin neurons in supplemented rams than in controls and a higher proportion of kisspeptin cells coexpressed Fos, regardless of the time the rams were killed. There were more Fos cells in the mid-ARC and mid-dorsomedial hypothalamus of the supplemented compared with control rams. No effect of nutrition was found on kisspeptin expression in the rostral or mid-ARC, or on GnRH expression in the preoptic area. Kisspeptin neurons in the caudal ARC appear to mediate the increase in GnRH and LH production due to acute nutritional supplementation, supporting the hypothesised role of the KNDy neurons as the pulse generator for GnRH.

Strengthened Data Systems to Mitigate the Double Burden of Malnutrition: The Role of Stable Isotope Technique-Derived Nutrition Indicators.

Indicators reflecting the double burden of malnutrition are rarely measured in nutrition surveys and are needed to strengthen national data systems. Indicators such as body composition reflect both metabolic response to undernutrition and obesity risk and nutrition-related noncommunicable diseases. Stable isotope techniques (SITs) provide accurate data on body composition, exclusive breastfeeding and vitamin A status that are otherwise problematic with routine methods. Integration of SIT-derived nutrition indicators in data systems could improve the design and evaluation of programmes focused on obesity prevention, food fortification and infant and young child feeding practices. The Working Group at the symposium considered "how SIT-derived nutrition indicators may be integrated into surveillance systems to strengthen data availability and capacity at national and regional levels". Practical considerations for the use of SITs include cost, sample size, rigorous training and logistics. It was concluded that SITs are best suited, at present, for use in sub-samples of population surveys and for validating tools that can be scaled-up more easily in population surveys. In the long term, SITs could be applied to larger surveys following potential innovations in more affordable, hand-held devices for analysis of stable isotope enrichment in the field and simpler specimen collection protocols.

Maternal overnutrition programs epigenetic changes in the regulatory regions of hypothalamic Pomc in the offspring of rats.

BACKGROUND AND OBJECTIVE: Maternal overnutrition has been implicated in affecting the offspring by programming metabolic disorders such as obesity and diabetes, by mechanisms that are not clearly understood. This study aimed to determine the long-term impact of maternal high-fat (HF) diet feeding on epigenetic changes in the offspring's hypothalamic Pomc gene, coding a key factor in the control of energy balance. Further, it aimed to study the additional effects of postnatal overnutrition on epigenetic programming by maternal nutrition. METHODS: Eight-week-old female Sprague-Dawley rats were fed HF diet or low-fat (LF) diet for 6 weeks before mating, and throughout gestation and lactation. At postnatal day 21, samples were collected from a third offspring and the remainder were weaned onto LF diet for 5 weeks, after which they were either fed LF or HF diet for 12 weeks, resulting in four groups of offspring differing by their maternal and postweaning diet. RESULTS: With maternal HF diet, offspring at weaning had rapid early weight gain, increased adiposity, and hyperleptinemia. The programmed adult offspring, subsequently fed LF diet, retained the increased body weight. Maternal HF diet combined with offspring HF diet caused more pronounced hyperphagia, fat mass, and insulin resistance. The ARC Pomc gene from programmed offspring at weaning showed hypermethylation in the enhancer (nPE1 and nPE2) regions and in the promoter sequence mediating leptin effects. Interestingly, hypermethylation at the Pomc promoter but not at the enhancer region persisted long term into adulthood in the programmed offspring. However, there were no additive effects on methylation levels in the regulatory regions of Pomc in programmed offspring fed a HF diet. CONCLUSION: Maternal overnutrition programs long-term epigenetic alterations in the offspring's hypothalamic Pomc promoter. This predisposes the offspring to metabolic disorders later in life.

Treatment with soy isoflavones during early adulthood improves metabolism in early postnatally overfed rats.

PURPOSE: The incidences of obesity and related diseases have reached epidemic proportions, and new therapeutic approaches are needed. Soy isoflavones have been identified as an important dietary factor for preventing and treating metabolic dysfunction. This study examined the effects of high doses of isoflavone on glucose and fat metabolism in a model of programmed obesity and evaluated its effects on the autonomic nervous system. METHODS: Litters of Wistar rats were standardized at nine pups per dam in normal litters (NL) or reduced to three pups per dam at the third day of life (P3) in small litters (SL) to induce postnatal overfeeding. Gavage with a soy bean isoflavone mixture (1 g/day) diluted in water was started at P60 and continued for 30 days. The control animals received vehicle gavage. At P90, biometric and metabolic parameters as well as direct autonomic nerve activity were measured. RESULTS: Increases in glycaemia and insulinaemia observed in SL rats were reduced by isoflavone treatment, which also caused lower glucose-induced insulin secretion by pancreatic islets. Sympathetic activity in the major splanchnic nerve was increased, while vagus nerve activity was reduced by isoflavone treatment. The dyslipidaemia induced by overfeeding in SL rats was restored by isoflavone treatment. CONCLUSION: The present study shows that treatment with isoflavone reduces adiposity and improves glucose and lipid metabolism. Collectively, these effects may depend on autonomic changes.

Transient postnatal over nutrition induces long-term alterations in cardiac NLRP3-inflammasome pathway.

BACKGROUND AND AIMS: The prevalence of obesity is increasing worldwide at an alarming rate. Altered early nutrition, in particular postnatal overfeeding (PNOF), is a risk factor for impaired cardiac function in adulthood. In the understanding of the initiation or progression of heart diseases, NLRP3 inflammasome and non-coding RNAs have been proposed as key players. In this context, the aim of this study was to decipher the role of NLRP3 inflammasome and its post transcriptional control by micro-RNAs in the regulation of cardiac metabolic function induced by PNOF in mice. METHODS AND RESULTS: Based on a model of mice exposed to PNOF through litter size reduction, we observed increased cardiac protein expression levels of NLRP3 and ETS-1 associated with alterations in insulin signaling. Additionally, miR-193b levels were down-regulated in the adult hearts of overfed animals. In a cardiomyocyte cell line, transfection with miR-193b induced down-regulation of ETS-1 and NLRP3 and improved insulin signaling. CONCLUSIONS: These findings suggest that the miR-193b could be involved in cardiac phenotypic changes observed in adulthood induced by PNOF likely through the regulation of ETS-1 and NLRP3 expression, and through this of insulin signaling.

Pathogenesis of NASH: How Metabolic Complications of Overnutrition Favour Lipotoxicity and Pro-Inflammatory Fatty Liver Disease.

Overnutrition, usually with obesity and genetic predisposition, lead to insulin resistance, which is an invariable accompaniment of nonalcoholic fatty liver disease (NAFLD). The associated metabolic abnormalities, pre- or established diabetes, hypertension and atherogenic dyslipidemia (clustered as metabolic syndrome) tend to be worse for nonalcoholic steatohepatitis (NASH), revealing it as part of a continuum of metabolic pathogenesis. The origins of hepatocellular injury and lobular inflammation which distinguish NASH from simple steatosis have intrigued investigators, but it is now widely accepted that NASH results from liver lipotoxicity. The key issue is not the quantity of liver fat but the type(s) of lipid molecules that accumulate, and how they are "packaged" to avoid subcellular injury. Possible lipotoxic mediators include free (unesterified) cholesterol, saturated free fatty acids, diacylglycerols, lysophosphatidyl-choline, sphingolipids and ceramide. Lipid droplets are intracellular storage organelles for non-structural lipid whose regulation is influenced by genetic polymorphisms, such as PNPLA3. Cells unable to sequester chemically reactive lipid molecules undergo mitochondrial injury, endoplasmic reticulum (ER) stress and autophagy, all processes of interest for NASH pathogenesis. Lipotoxicity kills hepatocytes by apoptosis, a highly regulated, non-inflammatory form of cell death, but also by necrosis, necroptosis and pyroptosis; the latter involve mitochondrial injury, oxidative stress, activation of c-Jun N-terminal kinase (JNK) and release of danger-associated molecular patterns (DAMPs). DAMPs stimulate innate immunity by binding pattern recognition receptors, such as Toll-like receptor 4 (TLR4) and the NOD-like receptor protein 3 (NLRP3) inflammasome, which release a cascade of pro-inflammatory chemokines and cytokines. Thus, lipotoxic hepatocellular injury attracts inflammatory cells, particularly activated macrophages which surround ballooned hepatocytes as crown-like structures. In both experimental and human NASH, livers contain cholesterol crystals which are a second signal for NLRP3 activation; this causes interleukin (IL)-1ß and IL18 secretion to attract and activate macrophages and neutrophils. Injured hepatocytes also liberate plasma membrane-derived extracellular vesicles; these have been shown to circulate in NASH and to be pro-inflammatory. The way metabolic dysfunction leads to lipotoxicity, innate immune responses and the resultant pattern of cellular inflammation in the liver are likely also relevant to hepatic fibrogenesis and hepatocarcinogenesis. Pinpointing the key molecules involved pharmacologically should eventually lead to effective pharmacotherapy against NASH.