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We evaluated whether early-life protein restriction alters structural parameters that affect β-cell mass on the 15th day and 20th day of gestation in control pregnant (CP), control non-pregnant (CNP), low-protein pregnant (LPP) and low-protein non-pregnant (LPNP) rats from the fetal to the adult life stage as well as in protein-restricted rats that recovered after weaning (recovered pregnant (RP) and recovered non-pregnant). On the 15th day of gestation, the CNP group had a higher proportion of smaller islets, whereas the CP group exhibited a higher proportion of islets larger than the median. The β-cell mass was lower in the low-protein group than that in the recovered and control groups. Gestation increased the β-cell mass, β-cell proliferation frequency and neogenesis frequency independently of the nutritional status. The apoptosis frequency was increased in the recovered groups compared with that in the other groups. On the 20th day of gestation, a higher proportion of islets smaller than the median was observed in the non-pregnant groups, whereas a higher proportion of islets larger than the median was observed in the RP, LPP and CP groups. β-Cell mass was lower in the low-protein group than that in the recovered and control groups, regardless of the physiological status. The β-cell proliferation frequency was lower, whereas the apoptosis rate was higher in recovered rats compared with those in the low-protein and control rats. Thus, protein malnutrition early in life did not alter the mass of β-cells, especially in the first two-thirds of gestation, despite the increase in apoptosis. [ABSTRACT FROM AUTHOR]

Obesity is a global epidemic, and maternal smoking has been shown to be associated with the development of childhood obesity. Overall, approximately 40% of children worldwide are exposed to tobacco smoke at home. It iswell known that environmental changes within a critical window of development, such as gestation or lactation, can initiate permanent alterations in metabolism that lead to diseases in adulthood, a phenomenon called programming. It is known that programming is based on epigenetic alterations (changes in DNA methylation, histone acetylation, or small interfering RNA expression) that change the expression pattern of several genes. However, little is known concerning the mechanisms by which smoke exposure in neonatal life programs the adipose tissue and endocrine function. Here, we review several epidemiological and experimental studies that confirm the association between maternal nicotine or tobacco exposure during gestation or lactation and the development of obesity and endocrine dysfunction. For example, a positive correlation was demonstrated in rodents between increased serum leptin in the neonatal period and exposure of the mothers to nicotine during lactation, and the further development of leptin and insulin resistance, and thyroid and adrenal dysfunction, in adulthood in the same offspring. Thus, a smoke-free environment during the lactation period is essential to improving health outcomes in adulthood and reducing the risk for future diseases. An understanding of the pathophysiological mechanisms underlying the effects of smoking on programming can provide new insights into therapeutic strategies for obesity. [ABSTRACT FROM AUTHOR]

It is known that Ca therapy may have anti-obesity effects. Since early weaning leads to obesity, hyperleptinaemia and insulin resistance, we studied the effect of dietary Ca supplementation in a rat model. Lactating rats were separated into two groups: early weaning (EW) – dams were wrapped with a bandage to interrupt lactation in the last 3 d of lactation and control (C) – dams whose pups had free access to milk during the entire lactation period (21 d). At 120 d, EW and C offspring were subdivided into four groups: (1) C, received standard diet; (2) CCa, received Ca supplementation (10 g of calcium carbonate/kg of rat chow); (3) EW, received standard diet; (4) EWCa, received Ca supplementation similar to CCa. The rats were killed at 180 d. The significance level was at P < 0·05. Adult EW offspring displayed hyperphagia (28 %), higher body weight (9 %) and adiposity (77 %), hyperleptinaemia (twofold increase), hypertriacylglycerolaemia (64 %), hyperglycaemia (16 %), higher insulin resistance index (38 %) and higher serum 25-hydroxyvitamin D3 (fourfold increase), but lower adiponectinaemia:adipose tissue ratio (44 %). In addition, they showed Janus tyrosine kinase 2 and phosphorylated signal transducer and activator of transcription 3 underexpression in hypothalamus (36 and 34 %, respectively), suggesting leptin resistance. Supplementation of Ca for 2 months normalised these disorders. The EW group had no change in serum insulin, thyroxine or triiodothyronine, and Ca treatment did not alter these hormones. In conclusion, we reinforced that early weaning leads to late development of some components of the metabolic syndrome and leptin resistance. Dietary Ca supplementation seems to protect against the development of endocrine and metabolic disorders in EW offspring, maybe through vitamin D inhibition. [ABSTRACT FROM PUBLISHER]

Neonatal malnutrition is associated with several features of the metabolic syndrome, later in life. Although the recovery of malnutrition was studied with different high-fat diets, few studies compare the effects of enriched vegetable oil diets, containing PUFA and MUFA, after weaning. Our aim was to evaluate the recovery with soya oil- or rapeseed oil-enriched diet, after malnutrition in rats whose mothers were food restricted (FR) during lactation. Dams were 50 % FR and compared to standard diet-fed dams (control, C). At 21 d, FR offspring had a lower body mass and length. After weaning C and FR offspring were fed a diet containing 7 % soya oil (7 %sC and 7 %sFR), or supplemented with 19 % soya oil (19 %sC or 19 %sFR) or 19 % rapeseed oil (19 %cC or 19 %cFR). The normal animals fed enriched vegetable oil diets had more visceral fat mass, but lower serum TAG and higher HDL-cholesterol. The 19 %FR groups showed significantly less food intake and body development compared to the 7 %sFR, and the same pattern was observed when this group was compared to the C groups. Absolute and relative mass of vital organs and body were lower in the FR groups. Visceral fat depot was lower in 19 %FR than 7 %FR and C groups. Serum glucose, albumin, TAG, cholesterol, leptin and triiodothyronine did not show significant changes. However, 19 %FR groups showed higher HDL-cholesterol and the 19 %sFR group showed lower serum thyroxine. The data suggest that a higher vegetable oil diet in the recovery of neonatal malnutrition ameliorates some features of the metabolic syndrome later in life. [ABSTRACT FROM PUBLISHER]

Previously we had shown that neonatal leptin treatment programmes for both hyperleptinaemia and hyperinsulinaemia, which lead to leptin resistance and low expression of the hypothalamic leptin receptor (OB-Rb) of rats aged 150 d. Here we investigated in young post-weaned rats (age 30 d) if leptin treatment during lactation induces leptin and insulin resistance and if those changes are accompanied by changes in the suppressor of cytokine signalling-3 (SOCS-3) expression and serum adiponectin concentration. After delivery, the pups were divided into two groups: (1) a leptin group (Lep) that were injected with leptin daily (8 μg/100 g body weight subcutaneously) for the first 10 d of lactation; (2) a control (C) group, receiving saline. After weaning (day 21), body weight was monitored until the animals were age 30 d. They were tested for food intake in response to either leptin (0·5 mg/kg body weight intraperitoneally) (CL, LepL) or saline (CSal, LepSal) when they were aged 30 d. The CL group showed lower food intake, but no response was observed in the LepL group, suggesting leptin resistance. The Lep group had hyperleptinaemia (five-fold), hyperinsulinaemia (+42·5 %) and lower levels of serum adiponectin ( − 43·2 %). The hypothalamic expression of OB-Rb was lower ( − 22 %) and SOCS-3 was higher (+52·8 %) in the Lep group. We conclude that neonatal leptin treatment programmes for leptin resistance as soon as 30 d and suggests that SOCS-3 appears to be of particular importance in this event. In the Lep group, the lower serum adiponectin levels were accompanied by higher serum insulin, indicating a probable insulin resistance. [ABSTRACT FROM PUBLISHER]

Introduction: The role of the fatty acid in the prevention or progression of chronic diseases has generated significant interest on the part of researchers. Thus, our objective was to evaluate the long-term effects of high-fat diet containing soybean or canola oil on body development and bone parameters of male rats. Methods: After weaning, rats were grouped and fed either a control diet (7S) or a high-fat diet containing soybean (19S) or canola oil (19C). Femur and lumbar vertebra (LV4) structure were determined at 180 days by dual-energy X-ray absorptiometry and computed tomography. Results: The groups showed similar food intake, body mass and length development. The bone parameters of the 19C were similar to the control group, while the 19S showed lower bone parameters when compared to the other groups. Conclusions: The high-fat diet containing soybean oil was unfavorable to bone structure, while the canola oil contributed bone health during the adult stage of life. [ABSTRACT FROM AUTHOR]

Childhood and puberty can affect metabolism, leading to tissue injury and malfunction later in life. The consumption of high-processed foods rich in salt and sugar is increasing in middle- and high-income countries, especially among young people. It is necessary to evaluate the effects of high salt and sugar levels in the youth on most injured organs during metabolic challenges. We aimed to investigate whether high salt/sucrose intake affects whole-body development and leads to end-organ injury. Weaned Male Wistar rats were divided into two groups: a control group fed a standard diet (CO) and tap water, and an experimental group (SS) fed a standard diet and a beverage containing 1.8% NaCl and 20% sucrose instead of tap water. The animals were treated for 60 days, starting after weaning at 21 days of age, after which the animals were subjected to glucose and insulin tolerance tests, urine collection, and heart rate monitoring, and euthanized for sample collection at 81 days of age. SS showed reduced body weight gain and increased food intake of sodium/sucrose solution. Interestingly, high salt/sucrose intake led to increased body adiposity, liver lipid inclusion, heart rate, and renal dysfunction. SS exhibits increased levels of peroxisome proliferator-activated receptor alpha to counterbalance the hypertrophy of brown adipose tissue. Our findings reveal that the SS rat model exhibits non-obvious obesity with end-organ damage and preserved brown adipose tissue function. This model closely parallels human conditions with normal BMI but elevated visceral adiposity, providing a relevant tool for studying atypical metabolic disorders.

Introduction and Aims: Obesity is a multifactorial condition with high health risk, associated with important chronic disorders such as diabetes, dyslipidemia, and cardiovascular dysfunction. Citrus aurantium L. ( C. aurantium ) is a medicinal plant, and its active component, synephrine, a β-3 adrenergic agonist, can be used for weight loss. We investigated the effects of C. aurantium and synephrine in obese adolescent mice programmed by early postnatal overfeeding., Methods: Three days after birth, male Swiss mice were divided into a small litter (SL) group (3 pups) and a normal litter (NL) group (9 pups). At 30 days old, SL and NL mice were treated with C. aurantium standardized to 6% synephrine, C. aurantium with 30% synephrine, isolated synephrine, or vehicle for 19 days., Results: The SL group had a higher body weight than the NL group. Heart rate and blood pressure were not elevated. The SL group had hyperleptinemia and central obesity that were normalized by C. aurantium and synephrine. In brown adipose tissue, the SL group showed a higher lipid droplet sectional area, less nuclei, a reduction in thermogenesis markers related to thermogenesis (UCP-1, PRDM16, PGC-1α and PPARg), and mitochondrial disfunction. C. aurantium and synephrine treatment normalized these parameters., Conclusion: Our data indicates that the treatment with C. aurantium and synephrine could be a promising alternative for the control of some obesity dysfunction, such as improvement of brown adipose tissue dysfunction and leptinemia., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Guimarães, de Moura, Silva, Lopes, Bertasso, Pietrobon, Quitete, de Oliveira Malafaia, Souza, Lisboa and de Oliveira.)

Key Points: The World Health Organization recommends exclusive breastfeeding until 6 months of age as an important strategy to reduce child morbidity and mortality. Studies have associated early weaning with the development of obesity and type 2 diabetes in adulthood. In our model, we demonstrated that early weaning leads to increased insulin secretion in adolescent males and reduced insulin secretion in adult offspring. Early weaned males exhibit insulin resistance in skeletal muscle. Early weaning did not change insulin signalling in the muscle of female offspring. Taking into account that insulin resistance is one of the primary factors for the development of type 2 diabetes mellitus, this work demonstrates the importance of breastfeeding in the fight against this disease., Abstract: Early weaning (EW) leads to short- and long-term obesity and diabetes. This phenotype is also observed in experimental models, in which early-weaned males exhibit abnormal insulinaemia in adulthood. However, studies regarding the effect of EW on pancreatic islets are rare. We investigated the mechanisms by which glycaemic homeostasis is altered in EW models through evaluations of insulin secretion and its signalling pathway in offspring. Lactating Wistar rats and their pups were divided into the following groups: non-pharmacological EW (NPEW): mothers were wrapped with an adhesive bandage on the last 3 days of lactation; pharmacological EW (PEW): mothers received bromocriptine to inhibit prolactin (1 mg/kg body mass/day) on the last 3 days of lactation; and control (C): pups underwent standard weaning at PN21. Offspring of both sexes were euthanized at PN45 and PN180. At PN45, EW males showed higher insulin secretion (vs. C). At PN170, PEW males exhibited hyperglycaemia in an oral glucose tolerance test (vs. C and NPEW). At PN180, EW male offspring were heavier; however, both sexes showed higher visceral fat. Insulin secretion was lower in EW offspring of both sexes. Males from both EW groups had lower glucokinase in islets, but unexpectedly, PEW males showed higher GLUT2, than did C. EW males exhibited lower insulin signalling in muscle. EW females exhibited no changes in these parameters compared with C. We demonstrated distinct alterations in the insulin secretion of EW rats at different ages. Despite the sex dimorphism in insulin secretion in adolescence, both sexes showed impaired insulin secretion in adulthood due to EW., (© 2019 Universidade do Estado do Rio de Janeiro. The Journal of Physiology © 2019 The Physiological Society.)

Aim: To investigate the effects of bariatric surgery on metabolic parameters, incretin hormone secretion, and duodenal and ileal mucosal gene expression., Methods: Nine patients with type 2 diabetes mellitus (T2DM), chronic serum hyperglycemia for more than 2 years, and a body mass index (BMI) of 30-35 kg/m(2) underwent metabolic surgery sleeve gastrectomy with transit bipartition between May 2011 and December 2011. Blood samples were collected pre and 3, 6 and 12 mo postsurgery. Duodenal and ileal mucosa samples were collected pre- and 3 mo postsurgery. Pre- and postoperative blood samples were collected in the fasting state before ingestion of a standard meal (520 kcal) and again 30, 60, 90, and 120 min after the meal to determine hemoglobin A1c (HbA1c) levels and the lipid profile, which consisted of triglyceride and total cholesterol levels. Intestinal gene expression of p53 and transforming growth factor (TGF)-β was analyzed using quantitative reverse-transcription PCR. Gastric inhibitory polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) were quantified using the enzyme-linked immunoassay method and analyzed pre- and postoperatively. Student's t test or repeated measurements analysis of variance with Bonferroni corrections were performed as appropriate., Results: BMI values decreased by 15.7% within the initial 3 mo after surgery (31.29 ± 0.73 vs 26.398 ± 0.68, P < 0.05) and then stabilized at 22% at 6 mo postoperative, resulting in similar values 12 mo postoperatively (20-25 kg/m(2)). All of the patients experienced improved T2DM, with 7 patients (78%) achieving complete remission (HbA1c < 6.5%), and 2 patients (22%) achieving improved diabetes (HbA1c < 7.0% with or without the use of oral hypoglycemic agents). At 3 mo postoperatively, fasting plasma glucose had also decreased (59%) (269.55 ± 18.24 mg/dL vs 100.77 ± 3.13 mg/dL, P < 0.05) with no further significant changes at 6 or 12 mo postoperatively. In the first month postoperatively, there was a complete withdrawal of hypoglycemic medications in all patients, who were taking at least 2 hypoglycemic drugs preoperatively. GLP-1 levels significantly increased after surgery (149.96 ± 31.25 vs 220.23 ± 27.55) (P < 0.05), while GIP levels decreased but not significantly. p53 gene expression significantly increased in the duodenal mucosa (P < 0.05, 2.06 fold) whereas the tumor growth factor-β gene expression significantly increased (P < 0.05, 2.52 fold) in the ileal mucosa after surgery., Conclusion: Metabolic surgery ameliorated diabetes in all of the patients, accompanied by increased anti-proliferative intestinal gene expression in non-excluded segments of the intestine.

It is known that Ca therapy may have anti-obesity effects. Since early weaning leads to obesity, hyperleptinaemia and insulin resistance, we studied the effect of dietary Ca supplementation in a rat model. Lactating rats were separated into two groups: early weaning (EW) - dams were wrapped with a bandage to interrupt lactation in the last 3 d of lactation and control (C) - dams whose pups had free access to milk during the entire lactation period (21 d). At 120 d, EW and C offspring were subdivided into four groups: (1) C, received standard diet; (2) CCa, received Ca supplementation (10 g of calcium carbonate/kg of rat chow); (3) EW, received standard diet; (4) EWCa, received Ca supplementation similar to CCa. The rats were killed at 180 d. The significance level was at P < 0·05. Adult EW offspring displayed hyperphagia (28 %), higher body weight (9 %) and adiposity (77 %), hyperleptinaemia (twofold increase), hypertriacylglycerolaemia (64 %), hyperglycaemia (16 %), higher insulin resistance index (38 %) and higher serum 25-hydroxyvitamin D₃ (fourfold increase), but lower adiponectinaemia:adipose tissue ratio (44 %). In addition, they showed Janus tyrosine kinase 2 and phosphorylated signal transducer and activator of transcription 3 underexpression in hypothalamus (36 and 34 %, respectively), suggesting leptin resistance. Supplementation of Ca for 2 months normalised these disorders. The EW group had no change in serum insulin, thyroxine or triiodothyronine, and Ca treatment did not alter these hormones. In conclusion, we reinforced that early weaning leads to late development of some components of the metabolic syndrome and leptin resistance. Dietary Ca supplementation seems to protect against the development of endocrine and metabolic disorders in EW offspring, maybe through vitamin D inhibition.

Maternal malnutrition during lactation programmes for overweight and central leptin resistance in adulthood. The inhibition of lactation by maternal treatment with bromocriptine (a prolactin inhibitor) programmes for obesity, hyperleptinaemia and leptin resistance. Here, we evaluated the short- and long-term effects of early weaning (EW) on body-weight regulation, leptin signalling, and hormone and lipid profiles in rats offspring. Lactating rats were separated into two groups: EW--dams were wrapped with a bandage to interrupt the lactation in the last 3 d of lactation; control--dams whose pups had free access to milk during all lactation (21 d). Data were significant at P < 0·05. At weaning, EW pups presented lower body weight (-10%), length (-4%), visceral fat (-40%), total fat (-30%), serum leptin (-73%), glycaemia (-10%), serum insulin (-20%) and insulin resistance index (IRI; -30 %), but higher total body protein content (+40%). At 180 d, EW offspring showed hyperphagia, higher length (+3%), body weight (+8%), visceral and total fat (+36 and 84%), serum TAG (+96%), glycaemia (+15%), leptinaemia (+185%) and IRI (+29%); however, they showed lower total protein content (-23%), leptin:body fat ratio (41%), prolactinaemia (-38%) and adiponectinaemia (-59%). Despite unchanged leptin receptor (OB-R) and signal transducer and activator of transcription 3 (STAT3), they displayed lower hypothalamic janus tyrosine kinase 2, phosphorylated STAT3 and a higher suppressor of cytokine signalling 3 levels, suggesting a central leptin resistance. Adult rats that were early weaned displayed higher adiposity, insulin resistance and dyslipidaemia, which are related to metabolic syndrome development. Our model reinforces the idea that neonatal malnutrition caused by shortening of the lactation period is important for metabolic programming of future diseases.