"Intrauterine growth restriction (IUGR) is closely linked with metabolic diseases, appetite disorders and obesity at adulthood. Leptin, a major adipokine secreted by adipose tissue, circulates in direct proportion to body fat stores, enters the brain and regulates food intake and energy expenditure. Deficient leptin neuronal signalling favours weight gain by affecting central homeostatic circuitry. The aim of this study was to determine if leptin resistance was programmed by perinatal nutritional environment and to decipher potential cellular mechanisms underneath.We clearly demonstrated that 5 months old IUGR rats develop a decrease of leptin sentivity, characterized by no significant reduction of food intake following an intraperitoneal injection of leptin. Apart from the resistance to leptin injection, results obtained from IUGR rats submitted to rapid catch-up growth differed from those of IUGR rats with no catch-up since we observed, for the first group only, fat accumulation, increased appetite for food rich in fat and increased leptin synthesis. Centrally, the leptin resistant state of both groups was associated with a complex and not always similar changes in leptin receptor signalling steps. Leptin resistance in IUGR rats submitted to rapid catch-up was associated with alteration in AKT and mTOR pathways. Alternatively, in IUGR rats with no catch-up, leptin resistance was associated with low hypothalamic expression of LepRa and LepRb."
"a reduction of leptin activated STAT3 pathway at PND1 after nursing IUGR pups by ad libitum fed dams in order to induce a rapid catch-up growth"
"Adipocytes size is an important determinant of leptin synthesis, since larger adipocytes contain more leptin than smaller"
"Activation of the LepRb results in the phosphorylation of tyrosine residues on JAK2 and three tyrosines on LepRb (Tyr985, Tyr1077, and Tyr1138). Phosphorylation of LepRb Tyr1138 leads to the phosphorylation, dimerization and nuclear translocation of the signal transducer and activator of transcription (STAT3) which activates the transcription of the suppressor of cytokine signaling-3 (SOCS-3){up in LSJL}. SOCS-3 then binds to Tyr985 of LepRb and inhibits its activity. The tyrosine phosphatase, SHP2, also binds LepRb on Tyr985 and activates the MAPK cascade via the extracellular signal-regulated kinase (ERK). Leptin also activates phosphatidylinositol3-kinase (PI3-k) pathway and mammalian target of rapamycin (mTOR) via AKT{LSJL activates Akt}"
"increased mRNA levels of several GH target genes (i.e., IGF-I, SOCS-2, CIS, CYP2C11{downregulated in LSJL as Stat5b}, CYP2C13) [suggests] that the increased hepatic GH activity observed in these [rats] was possibly associated with catch-up growth."
"catch-up growth was associated with the overexpression of SOCS-2 and CIS in adult CH rats."
Nutrition and Catch-up Growth
"The length of the tibia increased significantly in the leptin-treated animals compared with the untreated controls. Although it was previously described that leptin affects growth centrally by stimulating GH secretion through its effect on GH-releasing hormone, we have shown that the effect of leptin was independent of insulin-like growth factor 1 and that leptin has a local, direct, GH-independent stimulatory effect on the EGP[Growth Plate] through its receptor "
"leptin's effect on the growth-plate chondrocytes is specifically mediated through ERK1/2 and STAT3"
"In the growth plate, histone deacetylase (HDAC) 4 [is] essential for the hypertrophy process. Furthermore, the cartilage-specific miR-140 regulates HDAC4 in growth plate, thus suggesting a complex mode of epigenetic regulation. Another class of HDACs, the sirtuins{Sirts 2 and 5 are downregulated by LSJL}, are highly conserved enzymes that use nicotinamide adenine dinucleotide (NAD+) to deacetylate a number of histone and nonhistone substrates. Recently, it was shown that both SIRT1 and SIRT6 are increased in response to long-term energy restriction in several organs, suggesting that similar effect can occur in the EGP"
Nutrition-induced catch-up growth increases hypoxia inducible factor 1alpha RNA levels in the growth plate.
"we subjected prepubertal rats to 10 days of 40% food restriction, followed by a renewal of the regular food supply to induce catch-up growth"
"Male Sprague–Dawley rats, 24 days old"
3 Groups:
Normal Diet(AL)
40% caloric restriction for 17 days(RES)
Restriction for 10 days followed by normal diet for 7 days(CU)
Genes downregulated by caloric restriction(and upregulated in catch growth) also down(or -up) regulated by LSJL:
Eno1
Agc1(up)
Col2a1(up)
Col5a2(up)
Col11a1(up)
Rtcd1
Cox6a1
Downstream targets of HIF1a also up(or -down regulated) by LSJL:
Eno1(down)
Sox9
Vim
The changes in HIF1a were exclusive to the growth plate and not the liver.
MicroRNAs in the growth plate are responsive to nutritional cues: association between miR-140 and SIRT1
"[Male Sprague–Dawley rats, 24 days old] were fed ad libitum or were subjected to 40% food restriction for 10 days followed by a renewal of the regular food supply. At sacrifice, tibial EGPs were excised, and the total RNA was extracted and loaded on miRNA microarrays. The miRNA microarray yielded more than 400 miRNAs that are expressed in the EGP of mature animals. Results were confirmed by quantitative polymerase chain reaction. Chondrocyte-specific miR-140-3p showed the highest expression in the mature EGP, and it was one of the few miRNAs that were significantly reduced following nutrition restriction. Changes in predicted miRNA targets were then followed with Western immunoblotting. Direct binding was demonstrated using exogenous miRNA, the 3′UTR of the target mRNA and a luciferase reporter assay. Nutrition restriction induced an increase in the level of the miR-140-3p target, NAD+-dependent SIRT1."
" the 3′UTR of SIRT1, containing the putative binding site for miR-140-3p, is expressed by EGP chondrocytes "
"The mRNA levels of IGFBP7 were significantly reduced by calorie restriction, but the level of the protein was significantly increased (P<.05). However, in contrast to the results for miR-140-3p and SIRT1, after 1 day of refeeding (CU group), the IGFBP7 protein expression returned to baseline, and the IGFBP7 mRNA level remained low."
"SIRT1 knockout rodents are small"
"While calorie restriction reduces the level of miR-140-3p, it relieves the inhibition on the translation of SIRT1, and the level of SIRT1 protein is increased."
Possible miR's affecting height growth:
mir-23-a which can cause hypertrophic growth
mir-199a-3p BMP-2 responsive and regulates Smad1. Smad1 is downregulated by LSJL and BMP is upregulated by LSJL so this miR is likely involved in LSJL.
miR-93 regulates E2F1(downregulated by LSJL) and reduces cell response to TGF-Beta.
Catch-up growth after hypothyroidism is caused by delayed growth plate senescence.
Catch-up growth after hypothyroidism is caused by delayed growth plate senescence.
"Catch-up growth occurs because growth-inhibiting conditions conserve the limited proliferative capacity of growth plate chondrocytes, thus slowing the normal process of growth plate senescence. When the growth-inhibiting condition resolves, the growth plates are less senescent and therefore grow more rapidly than normal for age. To test this hypothesis, we administered propylthiouracil to newborn rats for 8 wk to induce hypothyroidism and then stopped the propylthiouracil to allow catch-up growth. In untreated controls, the growth plates underwent progressive, senescent changes in multiple functional and structural characteristics. We also identified genes that showed large changes in mRNA expression in growth plate and used these changes as molecular markers of senescence. In treated animals, after stopping propylthiouracil, these functional, structural, and molecular senescent changes were delayed, compared with controls. This delayed senescence included a delayed decline in longitudinal growth rate, resulting in catch-up growth. The findings demonstrate that growth inhibition due to hypothyroidism slows the developmental program of growth plate senescence, including the normal decline in the rate of longitudinal bone growth, thus accounting for catch-up growth."
"the limited proliferative capacity of growth plate chondrocytes that appears to underlie growth plate senescence may not be cell autonomous but instead appears to be dependent on cell-cell and/or cell-matrix interactions within the growth plate"<-Thus it can be altered.
"We identified genes whose mRNA expression in growth plate chondrocytes changes markedly during growth plate senescence [which includes] chondroadherin[binds type II collagen and chondrocytes through a2b1 integrin], osteoprotegerin[decoy receptor for receptor activator of nuclear factor-κB ligand, expressed by growth plate chondrocytes and may negatively regulate cartilage resorption by an inhibitory effect on osteoclast recruitment to the growth plate, inactivating mutations cause short stature], secreted frizzled-related protein 4, reelin, and nuclear protein 1."<-all these are reduced in mice after mice experiencing catch growth after 3 weeks. However at 8 weeks, levels of SFRP were increased in hypothyroid mice with no other differences.
"levels of chondroadherin, osteoprotegerin, secreted frizzled-related protein 4, reelin, and nuclear protein 1 increased with age in growth plates from control animals"
Look at B which is the hypothyroid GP for eight weeks it's almost like nothing is happening.
"at 11 wk of age, the serum IGF-I levels were actually lower in the rats undergoing catch-up growth than in controls."
"the rate of growth is dependent on the proliferation rate of the nonstem cells in the proliferative zone. If hypothyroidism slows proliferation in the proliferative zone more than it slows proliferation in the resting zone, it might have a greater inhibitory effect on the rate of growth than on the rate of senescence. In this situation, each cell division of the stem-like cells would produce a smaller clone of proliferative zone chondrocytes, resulting in less efficient growth. In this situation, catch-up growth would be expected to be incomplete."
"Another possible explanation is that the number of stem-cell divisions tends to be similar in various hormonal and nutritional states but is not completely invariant."
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