scholarly journals Maternal protein restriction in mice causes adverse metabolic and hypothalamic effects in the F1 and F2 generations

2011 ◽  
Vol 106 (9) ◽  
pp. 1364-1373 ◽  
Author(s):  
Nayara Peixoto-Silva ◽  
Eliete Dalla Corte Frantz ◽  
Carlos Alberto Mandarim-de-Lacerda ◽  
Alessandra Pinheiro-Mulder
Keyword(s):  
Leptin Receptor ◽  
Protein Restriction ◽  
Metabolic Programming ◽  
Male Offspring ◽  
Leptin Resistance ◽  
Altered Expression ◽  
Leptin Sensitivity ◽  
Maternal Protein Restriction ◽  
Group 5 ◽  
F2 Generation

Maternal protein restriction causes metabolic alterations associated with hypothalamic dysfunction. Because the consequences of metabolic programming can be passed transgenerationally, the present study aimed to assess whether maternal protein restriction alters the expression of hypothalamic neuropeptides in offspring and to evaluate hormonal and metabolic changes in male offspring from the F1 and F2 generations. Female Swiss mice (F0) were mated and fed either a normal-protein (NP group; 19 % protein) or a low-protein (LP group; 5 % protein) diet throughout gestation of the F1 generation (NP1 and LP1). At 3 months of age, F1 females were mated to produce the F2 generation (NP2 and LP2). Animals from all groups were evaluated at 16 weeks of age. LP1 offspring had significantly lower weights and shorter lengths than NP1 offspring at birth, but they underwent a phase of rapid catch-up growth. Conversely, the LP2 offspring were not significantly different from the NP2 offspring in either weight or length. At 16 weeks, no differences were found in body mass among any of the groups, although LP1 and LP2 offspring showed hypercholesterolaemia, hypertriacylglycerolaemia, hyperglycaemia, glucose intolerance, insulin resistance, increased levels of insulin, leptin and resistin, decreased endogenous leptin sensitivity, increased adiposity with elevated leptin levels and leptin resistance characterised by altered expression of neuropeptide Y and pro-opiomelanocortin without any changes in the leptin receptor Ob-Rb. We conclude that severe maternal protein restriction promotes metabolic programming in F1 and F2 male offspring due to a dysregulation of the adipoinsular axis and a state of hypothalamic leptin resistance.

scholarly journals Long-Term Effects of Maternal Low-Protein Diet and Post-weaning High-Fat Feeding on Glucose Metabolism and Hypothalamic POMC Promoter Methylation in Offspring Mice

2021 ◽  
Vol 8 ◽  
Author(s):  
Jia Zheng ◽  
Ling Zhang ◽  
Jiayi Liu ◽  
Yanli Li ◽  
Junqing Zhang
Keyword(s):  
Glucose Metabolism ◽  
Critical Role ◽  
Protein Restriction ◽  
Male Offspring ◽  
Melanocortin Receptor ◽  
High Fat ◽  
Altered Expression ◽  
Low Protein ◽  
Maternal Protein Restriction ◽  
Fat Feeding

Substantial evidence indicated that maternal malnutrition could increase the susceptibility to obesity, insulin resistance, and type 2 diabetes in adulthood. It is increasingly apparent that the brain, especially the hypothalamus, plays a critical role in glucose homeostasis. However, little information is known about the mechanisms linking maternal protein restriction combined with post-weaning high-fat (HF) feeding with altered expression of brain neurotransmitters, and investigations into the epigenetic modifications of hypothalamus in offspring have not been fully elucidated. Our objective was to explore the effects of maternal protein restriction combined with post-weaning HF feeding on glucose metabolism and hypothalamic POMC methylation in male offspring mice. C57/BL6 mice were fed on either low-protein (LP) or normal chow (NC) diet throughout gestation and lactation. Then, the male offspring were randomly weaned to either NC or high-fat (HF) diet until 32 weeks of age. Gene expressions and DNA methylation of hypothalamic proopiomelanocortin (POMC) and melanocortin receptor 4 (MC4R) were determined in male offspring. The results showed that birth weights and body weights at weaning were both significantly lower in male offspring mice of the dams fed with a LP diet. Maternal protein restriction combined with post-weaning high-fat feeding, predisposes higher body weight, persistent glucose intolerance (from weaning to 32 weeks of age), hyperinsulinemia, and hyperleptinemia in male offspring mice. POMC and MC4R expressions were significantly increased in offspring mice fed with maternal LP and postnatal high-fat diet (P < 0.05). Furthermore, maternal protein restriction combined with post-weaning high-fat feeding induced hypomethylation of POMC promoter in the hypothalamus (P < 0.05) and POMC-specific methylation (%) was negatively correlated with the glucose response to a glucose load in male offspring mice (r = −0.42, P = 0.039). In conclusion, maternal LP diet combined with post-weaning high-fat feeding predisposed the male offspring to impaired glucose metabolism and hypothalamic POMC hypomethylation. These findings can advance our thinking about hypothalamic POMC gene methylation between maternal LP diet combined with post-weaning high-fat feeding and metabolic health in offspring.

Maternal protein restriction in pregnancy and/or lactation affects seminiferous tubule organization in male rat offspring

2012 ◽  
Vol 3 (5) ◽  
pp. 321-326 ◽  
Author(s):  
G. L. Rodríguez-González ◽  
R. M. Vigueras-Villaseñor ◽  
S. Millán ◽  
N. Moran ◽  
R. Trejo ◽  
...  
Keyword(s):  
Body Weight ◽  
Germ Cell ◽  
Control Diet ◽  
Protein Restriction ◽  
Male Offspring ◽  
Male Rat ◽  
Testis Weight ◽  
Germ Cell Differentiation ◽  
Maternal Protein Restriction ◽  
Cell Proliferation And Differentiation

Maternal protein restriction (MPR) during pregnancy impaired the reproduction of male offspring. We investigated, during the first wave of spermatogenesis, whether MPR exerts deleterious effects on germ cell proliferation and differentiation, as well as androgen receptor (AR) protein expression, which was used as a marker for Sertoli cell (SC) maturation. At the beginning of pregnancy (day 0), dams were fed a control diet (C: 20% casein) or a restricted isocaloric diet (R: 10% casein). After birth, four groups were established: CC, RR, CR and RC (first letter diet during pregnancy and second during lactation). Male offspring were studied at postnatal days 14, 21 and 36. At birth, pup body weight was unchanged. Body weight and testis weight were reduced in RR and CR groups at all ages evaluated. MPR delayed the germinal epithelium development at all ages evaluated. On performing Western blot and immunohistochemistry, AR expression was found to be lower in the three restricted groups. The results suggest that MPR during pregnancy and/or lactation delays SC maturation and germ cell differentiation, and affects intratubular organization. These changes might be responsible for the lower fertility rate at older ages.

scholarly journals Protection Against High-Fat Diet-Induced Obesity in Helz2-Deficient Male Mice Due to Enhanced Expression of Hepatic Leptin Receptor

Endocrinology ◽  
2014 ◽  
Vol 155 (9) ◽  
pp. 3459-3472 ◽  
Author(s):  
Satoshi Yoshino ◽  
Tetsurou Satoh ◽  
Masanobu Yamada ◽  
Koshi Hashimoto ◽  
Takuya Tomaru ◽  
...  
Keyword(s):  
Gene Expression ◽  
Protein Kinase ◽  
High Fat Diet ◽  
Leptin Receptor ◽  
Leptin Resistance ◽  
High Fat ◽  
Leptin Sensitivity ◽  
Amp Activated Protein Kinase ◽  
Central Leptin Resistance ◽  
Deficient Mice

Abstract Obesity arises from impaired energy balance, which is centrally coordinated by leptin through activation of the long form of leptin receptor (Leprb). Obesity causes central leptin resistance. However, whether enhanced peripheral leptin sensitivity could overcome central leptin resistance remains obscure. A peripheral metabolic organ targeted by leptin is the liver, with low Leprb expression. We here show that mice fed a high-fat diet (HFD) and obese patients with hepatosteatosis exhibit increased expression of hepatic helicase with zinc finger 2, a transcriptional coactivator (Helz2), which functions as a transcriptional coregulator of several nuclear receptors, including peroxisome proliferator-activated receptor γ in vitro. To explore the physiological importance of Helz2, we generated Helz2-deficient mice and analyzed their metabolic phenotypes. Helz2-deficient mice showing hyperleptinemia associated with central leptin resistance were protected against HFD-induced obesity and had significantly up-regulated hepatic Leprb expression. Helz2 deficiency and adenovirus-mediated liver-specific exogenous Leprb overexpression in wild-type mice significantly stimulated hepatic AMP-activated protein kinase on HFD, whereas Helz2-deficient db/db mice lacking functional Leprb did not. Fatty acid-β oxidation was increased in Helz2-deficeint hepatocytes, and Helz2-deficient mice revealed increased oxygen consumption and decreased respiratory quotient in calorimetry analyses. The enhanced hepatic AMP-activated protein kinase energy-sensing pathway in Helz2-deficient mice ameliorated hyperlipidemia, hepatosteatosis, and insulin resistance by reducing lipogenic gene expression and stimulating lipid-burning gene expression in the liver. These findings together demonstrate that Helz2 deficiency ameliorates HFD-induced metabolic abnormalities by stimulating endogenous hepatic Leprb expression, despite central leptin resistance. Hepatic HELZ2 might be a novel target molecule for the treatment of obesity with hepatosteatosis.

An early fish oil-enriched diet reverses biochemical, liver and adipose tissue alterations in male offspring from maternal protein restriction in mice

2011 ◽  
Vol 22 (11) ◽  
pp. 1009-1014 ◽  
Author(s):  
Isabele Bringhenti ◽  
Alini Schultz ◽  
Tamiris Rachid ◽  
Marco A. Bomfim ◽  
Carlos A. Mandarim-de-Lacerda ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Fish Oil ◽  
Protein Restriction ◽  
Male Offspring ◽  
Maternal Protein Restriction ◽  
Tissue Alterations

scholarly journals HF diets increase hypothalamic PTP1B and induce leptin resistance through both leptin-dependent and -independent mechanisms

2009 ◽  
Vol 296 (2) ◽  
pp. E291-E299 ◽  
Author(s):  
Christy L. White ◽  
Amy Whittington ◽  
Maria J. Barnes ◽  
Zhong Wang ◽  
George A. Bray ◽  
...  
Keyword(s):  
Leptin Receptor ◽  
Tyrosine Phosphatase ◽  
Leptin Resistance ◽  
Whole Body ◽  
Mrna Levels ◽  
Protein Levels ◽  
Diet Induced Obesity ◽  
Leptin Sensitivity ◽  
Concomitant Reduction ◽  
Specific Deletion

Protein tyrosine phosphatase 1B (PTP1B) contributes to leptin resistance by inhibiting intracellular leptin receptor signaling. Mice with whole body or neuron-specific deletion of PTP1B are hypersensitive to leptin and resistant to diet-induced obesity. Here we report a significant increase in PTP1B protein levels in the mediobasal hypothalamus ( P = 0.003) and a concomitant reduction in leptin sensitivity following 28 days of high-fat (HF) feeding in rats. A significant increase in PTP1B mRNA levels was also observed in rats chronically infused with leptin (3 μg/day icv) for 14 days ( P = 0.01) and in leptin-deficient ob/ ob mice infused with leptin (5 μg/day sc for 14 days; P = 0.003). When saline-infused ob/ ob mice were placed on a HF diet for 14 days, an increase in hypothalamic PTP1B mRNA expression was detected ( P = 0.001) despite the absence of circulating leptin. In addition, although ob/ ob mice were much more sensitive to leptin on a low-fat (LF) diet, a reduction in this sensitivity was still observed following exposure to a HF diet. Taken together, these data indicate that hypothalamic PTP1B is specifically increased during HF diet-induced leptin resistance. This increase in PTP1B is due in part to chronic hyperleptinemia, suggesting that hyperleptinemia is one mechanism contributing to the development of leptin resistance. However, these data also indicate that leptin is not required for the increase in hypothalamic PTP1B or the development of leptin resistance. Therefore, additional, leptin-independent mechanisms must exist that increase hypothalamic PTP1B and contribute to leptin resistance.

scholarly journals Large Litter Rearing Enhances Leptin Sensitivity and Protects Selectively Bred Diet-induced Obese Rats from Becoming Obese

2010 ◽  
Vol 31 (4) ◽  
pp. 600-601 ◽  
Author(s):  
Christa M. Patterson ◽  
Sebastien G. Bouret ◽  
Sunny Park ◽  
Boman G. Irani ◽  
Ambrose A. Dunn-Meynell ◽  
...  
Keyword(s):  
Body Weight ◽  
Weight Gain ◽  
Paraventricular Nucleus ◽  
Receptor Binding ◽  
Leptin Receptor ◽  
Body Weight Gain ◽  
High Energy ◽  
Leptin Resistance ◽  
Leptin Sensitivity ◽  
Plasma Leptin

Abstract Because rearing rats in large litters (LLs) protects them from becoming obese, we postulated that LL rearing would protect rats selectively bred to develop diet-induced obesity (DIO) from becoming obese by overcoming their inborn central leptin resistance. Male and female DIO rats were raised in normal litters (10 pups/dam) or LLs (16 pups/dam) and assessed for anatomical, biochemical, and functional aspects of leptin sensitivity at various ages when fed low-fat chow or a 31% fat high-energy (HE) diet. LL rearing reduced plasma leptin levels by postnatal d 2 (P) 2 and body weight gain by P8. At P16, LL DIO neonates had increased arcuate nucleus (ARC) binding of leptin to its extracellular receptors and at P28 an associated increase of their agouti-related peptide and α-MSH axonal projections to the paraventricular nucleus. Reduced body weight persisted and was associated with increased ARC leptin receptor binding and sensitivity to the anorectic effects of leptin, reduced adiposity, and enhanced insulin sensitivity in LL DIO rats fed chow until 10 wk of age. The enhanced ARC leptin receptor binding and reduced adiposity of LL DIO rats persisted after an additional 5 wk on the HE diet. Female LL DIO rats had similar reductions in weight gain on both chow and HE diet vs. normal litter DIO rats. We postulate that LL rearing enhances DIO leptin sensitivity by lowering plasma leptin levels and thereby increasing leptin receptor availability and that this both enhances the ARC-paraventricular nucleus pathway development and protects them from becoming obese.

scholarly journals CB1R regulates soluble leptin receptor levels via CHOP, contributing to hepatic leptin resistance

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Adi Drori ◽  
Asaad Gammal ◽  
Shahar Azar ◽  
Liad Hinden ◽  
Rivka Hadar ◽  
...  
Keyword(s):  
Leptin Receptor ◽  
Leptin Resistance ◽  
Dependent Manner ◽  
Molecular Aspect ◽  
Wild Type ◽  
Homologous Protein ◽  
Diet Induced Obesity ◽  
Leptin Sensitivity ◽  
Soluble Leptin Receptor ◽  
Direct Regulation

The soluble isoform of leptin receptor (sOb-R), secreted by the liver, regulates leptin bioavailability and bioactivity. Its reduced levels in diet-induced obesity (DIO) contribute to hyperleptinemia and leptin resistance, effects that are regulated by the endocannabinoid (eCB)/CB1R system. Here we show that pharmacological activation/blockade and genetic overexpression/deletion of hepatic CB1R modulates sOb-R levels and hepatic leptin resistance. Interestingly, peripheral CB1R blockade failed to reverse DIO-induced reduction of sOb-R levels, increased fat mass and dyslipidemia, and hepatic steatosis in mice lacking C/EBP homologous protein (CHOP), whereas direct activation of CB1R in wild-type hepatocytes reduced sOb-R levels in a CHOP-dependent manner. Moreover, CHOP stimulation increased sOb-R expression and release via a direct regulation of its promoter, while CHOP deletion reduced leptin sensitivity. Our findings highlight a novel molecular aspect by which the hepatic eCB/CB1R system is involved in the development of hepatic leptin resistance and in the regulation of sOb-R levels via CHOP.

scholarly journals CB1R Regulates Soluble Leptin Receptor Levels via CHOP, Contributing to Hepatic Leptin Resistance

2020 ◽  
Author(s):  
Adi Drori ◽  
Asaad Gammal ◽  
Shahar Azar ◽  
Liad Hinden ◽  
Rivka Hadar ◽  
...  
Keyword(s):  
Hepatic Steatosis ◽  
Leptin Receptor ◽  
Leptin Resistance ◽  
Dependent Manner ◽  
Molecular Aspect ◽  
Homologous Protein ◽  
Diet Induced Obesity ◽  
Leptin Sensitivity ◽  
Soluble Leptin Receptor ◽  
Direct Regulation

AbstractThe soluble isoform of leptin receptor (sOb-R), secreted by the liver, regulates leptin bioavailability and bioactivity. Its reduced levels in diet-induced obesity (DIO) contributes to hyperleptinemia and leptin resistance, effects that are known to be regulated by the endocannabinoid (eCB)/CB1R system. Here we show that pharmacological activation/blockade as well as genetic overexpression/deletion of hepatic CB1R modulates sOb-R levels and consequently hepatic leptin resistance. Interestingly, peripheral CB1R blockade failed to reverse DIO-induced reduction of sOb-R levels, fat mass, dyslipidemia, and hepatic steatosis in mice lacking C/EBP homologous protein (CHOP), whereas direct activation of CB1R in hepatocytes reduced sOb-R levels in a CHOP-dependent manner. Moreover, CHOP stimulation increased sOb-R expression and release via a direct regulation of its promoter, while CHOP deletion reduced leptin sensitivity. Our findings highlight a novel molecular aspect by which the hepatic eCB/CB1R system involves in the development of hepatic leptin resistance by regulating sOb-R levels via CHOP.SummaryHere we describe a novel molecular aspect by which the hepatic endocannabinoid/CB1R system contributes to hepatic leptin resistance by regulating soluble leptin receptor levels via CHOP.

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