Postnatal early overfeeding induces hypothalamic higher SOCS3 expression and lower STAT3 activity in adult rats.

Postnatal early overnutrition (EO) is a risk factor for future obesity and metabolic disorders. Rats raised in small litters (SLs) develop overweight, hyperphagia, hyperleptinemia, hyperinsulinemia and hypertension when adults. As obesity is related to hyperleptinemia, leptin resistance and metabolic syndrome, we aimed to investigate body composition, plasma hormone levels, glucose tolerance and the leptin signaling pathway in hypothalamus from early overfed animals at weaning and adulthood. To induce postnatal EO, we reduced litter size to three pups/litter (SL), and the groups with normal litter size (10 pups/litter) were used as control. Rats had free access to standard diet and water postweaning. Body weight and food intake were monitored daily, and offspring were killed at 21 (weaning) and 180 days old (adulthood). Postnatal EO group had higher body weight and total and visceral fat mass at both periods. Lean mass and serum high-density lipoprotein cholesterol (HDL-C) were higher at 21 days and lower at 180 days. Small litter rats presented higher levels of globulins at both periods, while albumin levels were higher at weaning and lower at adulthood. There was higher leptin, insulin and glucose serum concentrations at 21 days old, while no glucose intolerance was observed in adulthood. Leptin signaling pathway was unaffected at weaning. However, postnatal EO induced lower JAK2 and p-STAT3, and higher SOCS3 expression in adult animals, indicating central leptin resistance in adulthood. In conclusion, postnatal EO induces obesity, higher total and visceral fat mass, lower HDL-C and central leptin resistance in adult life.

Postnatal early overnutrition changes the leptin signalling pathway in the hypothalamic-pituitary-thyroid axis of young and adult rats.

Postnatal early overnutrition (EO) is a risk factor for obesity in adult life. Rats raised in a small litter can develop hyperinsulinaemia, hyperphagia, hyperleptinaemia and hypertension as adults. Since leptin regulates the hypothalamic-pituitary-thyroid axis and the metabolism of thyroid hormones, we studied the leptin signalling pathway in pituitary and thyroid glands of the postnatal EO model. To induce EO, at the third day of lactation the litter size was reduced to three pups per litter (SL group). In control litters (NL group), the litter size was adjusted to 10 pups per litter. Body weight and food intake were monitored. Rat offspring were killed at 21 (weaning) and 180 days old (adulthood). Plasma thyroid hormones, thyroid-stimulating hormone (TSH) and leptin were measured by radioimmunoassay. Proteins of the leptin signalling pathway were analysed by Western blotting. Body weight of offspring in the SL group was higher from the seventh day of lactation (+33%, P < 0.05) until 180 days old (+18%, P < 0.05). Offspring in the SL group showed higher visceral fat mass at 21 and 180 days old (+176 and +52%, respectively, P < 0.05), but plasma leptin was higher only at 21 days (+88%, P < 0.05). The SL offspring showed higher plasma TSH, 3,5,3'-triiodothronine (T(3)) and thyroxine (T(4)) at 21 days (+60, +91 and +68%, respectively, P < 0.05), while the opposite was observed at 180 days regarding thyroid hormones (T(3), -10%; and T(4), -30%, P < 0.05), with no difference in TSH levels. In hypothalamus, no change was observed in the leptin signalling pathway at 21 days. However, lower janus thyrosine kinase 2 (JAK2) and phosphorilated-signal transducer and activator of transcription-3 (p-STAT3) content were detected in adulthood. In pituitary, the SL group presented higher leptin receptors (Ob-R), JAK2 and p-STAT3 content at 21 days and lower JAK2 and STAT3 content at 180 days old. In contrast, in thyroid, the Ob-R expression was lower in young SL rats, while the adult SL group presented higher Ob-R and JAK2 content. We showed that postnatal EO induces short- and long-term effects upon the hypothalamic-pituitary-thyroid axis. These changes may help to explain future development of metabolic and endocrine dysfunctions, such as metabolic syndrome and hypothyroidism.

Maternal protein restriction during early lactation induces GLUT4 translocation and mTOR/Akt activation in adipocytes of adult rats.

Epidemiological and experimental studies have demonstrated that early postnatal nutrition has been associated with long-term effects on glucose homeostasis in adulthood. Recently, our group demonstrated that undernutrition during early lactation affects the expression and activation of key proteins of the insulin signaling cascade in rat skeletal muscle during postnatal development. To elucidate the molecular mechanisms by which undernutrition during early life leads to changes in insulin sensitivity in peripheral tissues, we investigated the insulin signaling in adipose tissue. Adipocytes were isolated from epididymal fat pads of adult male rats that were the offspring of dams fed either a normal or a protein-free diet during the first 10 days of lactation. The cells were incubated with 100 nM insulin before the assays for immunoblotting analysis, 2-deoxyglucose uptake, immunocytochemistry for GLUT4, and/or actin filaments. Following insulin stimulation, adipocytes isolated from undernourished rats presented reduced tyrosine phosphorylation of IR and IRS-1 and increased basal phosphorylation of IRS-2, Akt, and mTOR compared with controls. Basal glucose uptake was increased in adipocytes from the undernourished group, and the treatment with LY294002 induced only a partial inhibition both in basal and in insulin-stimulated glucose uptake, suggesting an involvement of phosphoinositide 3-kinase activity. These alterations were accompanied by higher GLUT4 content in the plasma membrane and alterations in the actin cytoskeleton dynamics. These data suggest that early postnatal undernutrition impairs insulin sensitivity in adulthood by promoting changes in critical steps of insulin signaling in adipose tissue, which may contribute to permanent changes in glucose homeostasis.

Efeito da superalimentação na lactação sobre a regulação da composição corporal, homeostase glicêmica, perfil lipídico, função tireoideana e sinalização da leptina em ratos jovens e adultos / Effect of overfeeding during lactation on the regulation of body composition, glucose homeostasis, lipid profile, thyroid function and leptin signaling in young and adult rats

Ratos criados em ninhadas reduzidas são utilizados como modelo experimental para o estudo dos efeitos imediatos e tardios da superalimentação pós-natal. Nesse trabalho estudamos algumas alterações decorrentes do sobrepeso no início da vida em animais jovens e adultos. Avaliamos a composição corporal e as concentrações séricas de glicose, insulina, leptina, adiponectina, hormônios tireoideanos e TSH, além do perfil lipídico e das proteínas totais séricas e suas frações. Também analisamos a tolerância à glicose, atividades D1 e GPDm em fígado e as proteínas da cascata de sinalização da leptina (Ob-R, JAK2, STAT3, p-STAT3 e SOCS3) no eixo hipotálamo-hipófise-tireóide (HHT). Para induzir a superalimentação, as ninhadas foram ajustadas para 3 filhotes machos/rata lactante a partir do 3º dia de lactação (grupo S). O controle (grupo C) permaneceu com a ninhada completa (dez filhotes/rata lactante) até o desmame (21º dia). O consumo alimentar foi maior no grupo S desde o desmame até os 180 dias, caracterizando uma hiperfagia persistente. A massa corporal, acompanhada durante todo o crescimento, foi maior no grupo S aos 21 dias, mantendo-se assim até os 180 dias de idade. As gorduras visceral e total foram maiores nos animais superalimentados tanto ao desmame como na vida adulta. Em relação à gordura subcutânea, observamos aumento somente nos animais jovens. A massa protéica corporal e o HDL-c sérico foram maiores aos 21 dias, embora menores aos 180 dias de idade. Ao desmame, os animais do grupo S apresentaram aumento nas proteínas totais, albumina e globulina. Já na vida adulta, estes animais apresentaram menor albuminemia e maior globulinemia, sem alterar as proteínas totais. Verificamos maiores concentrações séricas de glicose, insulina, leptina, T3, T4 e TSH, sem alteração na adiponectina no grupo S aos 21 dias. Os animais jovens do grupo S apresentaram maior atividade D1 e menor atividade GPDm no fígado. Aos 180 dias, detectamos somente menor T3 e T4 séricos...

Rats raised in small litters have proven to be an appropriated experimental model to study the consequences of overnutrition during the critical perinatal period. We aimed to study some alterations induced by overweight in early life of young and adult animals. We analyzed the body composition, the serum levels of glucose, insulin, leptin, adiponectin, thyroid hormones and TSH, as well as, the lipid profile and the total proteins and its fractions. We also analyzed the glucose tolerance test in adulthood, liver D1 and mGPD activities and the proteins of leptin signaling pathway (Ob-R, JAK2, STAT3, p-STAT3 e SOCS3) in the HPT axis. To induce early postnatal overnutrition, the litter size was reduced to 3 pups male/litter (small litter-SL group). In control group (normal litter-NL group), the size litter was adjusted to 10 pups/litter until to weaning (21st day). The food intake was higher in the SL group since weaning until adulthood, characterizing the hyperphagia. The body weight of the SL group was higher at 21 days-old and 180 days-old compared to NL group. The visceral and total fat mass were hither in both young and adult SL animals. The protein mass and serum HDL-c were higher at 21 days and lower at 180 days old. The young SL animal presented higher total proteins, albumin and globulin, while the adult SL animals presented lower albumin, higher globulin, with no change in the total proteins. At 21 days-old, we verifies in SL group higher levels of glucose, insulin, leptin, thyroid hormones and TSH, with no change in serum adiponectin. The SL young animals presented higher D1 and lower mGPD activities in liver. At 180 days-old, we only observed lower T3 and T4 levels, and glucose intolerance 2 hours after glucose administration. About leptin signaling pathway in hypothalamus, we observed lower JAK2, lower p-STAT3 and higher SOCS3 expression in the of adult SL animals. In pituitary, the SL group presented higher Ob-R, JAK2 and P-STAT3 content...