A specific type of insulin-like peptide regulates the conditional growth of a beetle weapon.

Evolutionarily conserved insulin/insulin-like growth factor (IGF) signaling (IIS) has been identified as a major physiological mechanism underlying the nutrient-dependent regulation of sexually selected weapon growth in animals. However, the molecular mechanisms that couple nutritional state with weapon growth remain largely unknown. Here, we show that one specific subtype of insulin-like peptide (ILP) responds to nutrient status and thereby regulates weapon size in the broad-horned flour beetle Gnatocerus cornutus. By using transcriptome information, we identified five G. cornutus ILP (GcorILP1-5) and two G. cornutus insulin-like receptor (GcorInR1, -2) genes in the G. cornutus genome. RNA interference (RNAi)-mediated gene silencing revealed that a certain subtype of ILP, GcorILP2, specifically regulated weapon size. Importantly, GcorILP2 was highly and specifically expressed in the fat body in a condition-dependent manner. We further found that GcorInR1 and GcorInR2 are functionally redundant but that the latter is partially specialized for regulating weapon growth. These results strongly suggest that GcorILP2 is an important component of the developmental mechanism that couples nutritional state to weapon growth in G. cornutus. We propose that the duplication and subsequent diversification of IIS genes played a pivotal role in the evolution of the complex growth regulation of secondary sexual traits.

The Clinical Application of Growth Hormone and Its Biological and Molecular Mechanisms in Assisted Reproduction.

Growth hormone (GH) has been used as a co-gonadotrophin in assisted reproduction, particularly in poor ovarian responders. The application of GH has been alleged to activate primordial follicles and improve oocyte quality, embryo quality, and steroidogenesis. However, the effects of GH on the live birth rate among women is controversial. Additionally, although the basic biological mechanisms that lead to the above clinical differences have been investigated, they are not yet well understood. The actions of GH are mediated by GH receptors (GHRs) or insulin-like growth factors (IGFs). GH regulates the vital signal transduction pathways that are involved in primordial follicular activation, steroidogenesis, and oocyte maturation. However, the therapeutic windows and duration of GH administration during assisted reproductive technology require further investigation. The review aimed to clarify the role of GH in human fertility from a molecular and biological point of view to provide evidence for proper GH administration.

Causal roles of mitochondrial dynamics in longevity and healthy aging.

Mitochondria are organized in the cell in the form of a dynamic, interconnected network. Mitochondrial dynamics, regulated by mitochondrial fission, fusion, and trafficking, ensure restructuring of this complex reticulum in response to nutrient availability, molecular signals, and cellular stress. Aberrant mitochondrial structures have long been observed in aging and age-related diseases indicating that mitochondrial dynamics are compromised as cells age. However, the specific mechanisms by which aging affects mitochondrial dynamics and whether these changes are causally or casually associated with cellular and organismal aging is not clear. Here, we review recent studies that show specifically how mitochondrial fission, fusion, and trafficking are altered with age. We discuss factors that change with age to directly or indirectly influence mitochondrial dynamics while examining causal roles for altered mitochondrial dynamics in healthy aging and underlying functional outputs that might affect longevity. Lastly, we propose that altered mitochondrial dynamics might not just be a passive consequence of aging but might constitute an adaptive mechanism to mitigate age-dependent cellular impairments and might be targeted to increase longevity and promote healthy aging.

Insulin-Like Peptide Receptor-Mediated Signaling Pathways Orchestrate Regulation of Growth in the Pacific Oyster (Crassostrea gigas), as Revealed by Gene Expression Profiles.

The involvement of insulin/insulin-like growth factor signaling (IIS) pathways in the growth regulation of marine invertebrates remains largely unexplored. In this study, we used a fast-growing Pacific oyster (Crassostrea gigas) variety "Haida No.1" as the material with which to unravel the role of IIS systems in growth regulation in oysters. Systematic bioinformatics analyses allowed us to identify major components of the IIS signaling pathway and insulin-like peptide receptor (ILPR)-mediated signaling pathways, including PI3K-AKT, RAS-MAPK, and TOR, in C. gigas. The expression levels of the major genes in IIS and its downstream signaling pathways were significantly higher in "Haida No.1" than in wild oysters, suggesting their involvement in the growth regulation of C. gigas. The expression profiles of IIS and its downstream signaling pathway genes were significantly altered by nutrient abundance and culture temperature. These results suggest that the IIS signaling pathway coupled with the ILPR-mediated signaling pathways orchestrate the regulation of energy metabolism to control growth in Pacific oysters.

Maternal exercise in rats upregulates the placental insulin-like growth factor system with diet- and sex-specific responses: minimal effects in mothers born growth restricted.

KEY POINTS: The placental insulin-like growth factor (IGF) system is critical for normal fetoplacental growth, which is dysregulated following several pregnancy perturbations including uteroplacental insufficiency and maternal obesity. We report that the IGF system was altered in placentae of mothers born growth restricted compared to normal birth weight mothers, with maternal diet- and fetal sex-specific responses. Additionally, we report increased body weight and plasma IGF1 concentrations in fetuses from chow-fed normal birth weight mothers that exercised prior to and continued during pregnancy compared to sedentary mothers. Exercise initiated during pregnancy, on the other hand, resulted in placental morphological alterations and increased IGF1 and IGF1R protein expression, which may in part be modulated by reduced Let 7f-1 miRNA abundance. Growth restriction of mothers before birth and exercise differentially regulate the placental IGF system with diet- and sex-specific responses, probably as a means to improve fetoplacental growth and development, and hence neonatal survival. This increased neonatal survival may prevent adult disease onset. ABSTRACT: The insulin-like growth factor (IGF) system regulates fetoplacental growth and plays a role in disease programming. Dysregulation of the IGF system is implicated in several pregnancy perturbations associated with altered fetal growth, including intrauterine growth restriction and maternal obesity. Limited human studies have demonstrated that maternal exercise enhances fetoplacental growth and decreases cord IGF ligands, which may restore the placental IGF system in complicated pregnancies. This study investigated the impact maternal exercise has on the placental IGF system in placentae from mothers born growth restricted and if these outcomes are dependent on maternal diet or fetal sex. Uteroplacental insufficiency (Restricted) or sham (Control) surgery was induced on embryonic day (E) 18 in Wistar-Kyoto rats. F1 offspring were fed a chow or high-fat diet from weaning, and at 16 weeks were randomly allocated an exercise protocol: Sedentary, Exercised prior to and during pregnancy (Exercise), or Exercised during pregnancy only (PregEx). Females were mated (20 weeks) with placentae associated with F2 fetuses collected at E20. The placental IGF system mRNA abundance and placental morphology was altered in mothers born growth restricted. Exercise increased fetal weight and Control plasma IGF1 concentrations, and decreased female placental weight. PregEx did not influence fetoplacental growth but increased placental IGF1 and IGF1R (potentially modulated by reduced Let 7f-1 miRNA) and decreased placental IGF2 protein. Importantly, these placental IGF system changes occurred with sex-specific responses. These data highlight that exercise differently influences fetoplacental growth and the placental IGF system depending on maternal exercise initiation, which may prevent the transgenerational transmission of deficits and dysfunction.

Placental phenotype and the insulin-like growth factors: resource allocation to fetal growth.

The placenta is the main determinant of fetal growth and development in utero. It supplies all the nutrients and oxygen required for fetal growth and secretes hormones that facilitate maternal allocation of nutrients to the fetus. Furthermore, the placenta responds to nutritional and metabolic signals in the mother by altering its structural and functional phenotype, which can lead to changes in maternal resource allocation to the fetus. The molecular mechanisms by which the placenta senses and responds to environmental cues are poorly understood. This review discusses the role of the insulin-like growth factors (IGFs) in controlling placental resource allocation to fetal growth, particularly in response to adverse gestational environments. In particular, it assesses the impact of the IGFs and their signalling machinery on placental morphogenesis, substrate transport and hormone secretion, primarily in the laboratory species, although it draws on data from human and other species where relevant. It also considers the role of the IGFs as environmental signals in linking resource availability to fetal growth through changes in the morphological and functional phenotype of the placenta. As altered fetal growth is associated with increased perinatal morbidity and mortality and a greater risk of developing adult-onset diseases in later life, understanding the role of IGFs during pregnancy in regulating placental resource allocation to fetal growth is important for identifying the mechanisms underlying the developmental programming of offspring phenotype by suboptimal intrauterine growth.

Exercise-induced biochemical changes and their potential influence on cancer: a scientific review.

AIM: To review and discuss the available international literature regarding the indirect and direct biochemical mechanisms that occur after exercise, which could positively, or negatively, influence oncogenic pathways. METHODS: The PubMed, MEDLINE, Embase and Cochrane libraries were searched for papers up to July 2016 addressing biochemical changes after exercise with a particular reference to cancer. The three authors independently assessed their appropriateness for inclusion in this review based on their scientific quality and relevance. RESULTS: 168 papers were selected and categorised into indirect and direct biochemical pathways. The indirect effects included changes in vitamin D, weight reduction, sunlight exposure and improved mood. The direct effects included insulin-like growth factor, epigenetic effects on gene expression and DNA repair, vasoactive intestinal peptide, oxidative stress and antioxidant pathways, heat shock proteins, testosterone, irisin, immunity, chronic inflammation and prostaglandins, energy metabolism and insulin resistance. SUMMARY: Exercise is one of several lifestyle factors known to lower the risk of developing cancer and is associated with lower relapse rates and better survival. This review highlights the numerous biochemical processes, which explain these potential anticancer benefits.

Effects of sustained exercise on GH-IGFs axis in gilthead sea bream (Sparus aurata).

The endocrine system regulates growth mainly through the growth hormone (GH)/insulin-like growth factors (IGFs) axis and, although exercise promotes growth, little is known about its modulation of these factors. The aim of this work was to characterize the effects of 5 wk of moderate sustained swimming on the GH-IGFs axis in gilthead sea bream fingerlings. Plasma IGF-I/GH ratio and tissue gene expression of total IGF-I and three splice variants, IGF-II, three IGF binding proteins, two GH receptors, two IGF-I receptors, and the downstream molecules were analyzed. Fish under exercise (EX) grew more than control fish (CT), had a higher plasma IGF-I/GH ratio, and showed increased hepatic IGF-I expression (mainly IGF-Ia). Total IGF-I expression levels were similar in the anterior and caudal muscles; however, IGF-Ic expression increased with exercise, suggesting that this splice variant may be the most sensitive to mechanical action. Moreover, IGFBP-5b and IGF-II increased in the anterior and caudal muscles, respectively, supporting enhanced muscle growth. Furthermore, in EX fish, hepatic IGF-IRb was reduced together with both GHRs; GHR-II was also reduced in anterior muscle, while GHR-I showed higher expression in the two muscle regions, indicating tissue-dependent differences and responses to exercise. Exercise also increased gene and protein expression of target of rapamycin (TOR), suggesting enhanced muscle protein synthesis. Altogether, these data demonstrate that moderate sustained activity may be used to increase the plasma IGF-I/GH ratio and to potentiate growth in farmed gilthead sea bream, modulating the gene expression of different members of the GH-IGFs axis (i.e., IGF-Ic, IGF-II, IGFBP-5b, GHR-I, and TOR).

Releasing prophase arrest in zebrafish oocyte: synergism between maturational steroid and Igf1.

Binding of 17ß-estradiol (E2) to novel G-protein coupled receptor, Gper1, promotes intra-oocyte adenylyl cyclase activity and transactivates epidermal growth factor receptor to ensure prophase-I arrest. Although involvement of either membrane progestin receptor (mPR) or Igf system has been implicated in regulation of meiosis resumption, possibility of concurrent activation and potential synergism between 17α,20ß-dihydroxy-4-pregnen-3-one (DHP)- and Igf-mediated signalling cascades in alleviating E2 inhibition of oocyte maturation (OM) has not been investigated. Here using zebrafish (Danio rerio) defolliculated oocytes, we examined the effect of DHP and Igf1, either alone or in combination, in presence or absence of E2, on OM in vitro. While priming of denuded oocytes with E2 blocked spontaneous maturation, co-treatment with DHP (3 nM) and Igf1 (10 nM), but not alone, reversed E2 inhibition and promoted a robust increase in germinal vesicle breakdown (GVBD). Although stimulation with either Igf1 or DHP promoted Akt phosphorylation, pharmacological inhibition of PI3K/Akt signalling prevented Igf1-induced GVBD but delayed DHP action till 4-5 h of incubation. Moreover, high intra-oocyte cAMP attenuates both DHP and Igf1-mediated OM and co-stimulation with DHP and Igf1 could effectively reverse E2 action on PKA phosphorylation. Interestingly, data from in vivo studies reveal that heightened expression of igf1, igf3 transcripts in intact follicles corresponded well with elevated phosphorylation of Igf1r and Akt, mPRa immunoreactivity, PKA inhibition and accelerated GVBD response just prior to ovulation. This indicates potential synergism between maturational steroid and Igf1 which might have physiological relevance in overcoming E2 inhibition of meiosis resumption in zebrafish oocytes.

MicroRNA regulation of mitogenic signaling networks in the human placenta.

Placental cell growth depends on an adaptable combination of an endogenous developmental program and the exogenous influence of maternal growth factors, both of which may be influenced by microRNA (miR)-dependent effects on gene expression. We have previously shown that global miR suppression in placenta accelerates proliferation and enhances levels of growth factor signaling mediators in cytotrophoblast. This study aimed to identify miRs involved in regulating placental growth. An initial array revealed 58 miR species whose expression differs between first trimester, when cytotrophoblast proliferation is rapid, and term, by which time proliferation has slowed. In silico analysis defined potential growth-regulatory miRs; among these, hsa-miR-145, hsa-miR-377, and hsa-let-7a were predicted to target known placental growth genes and were higher at term than in the first trimester, so they were selected for further analysis. Overexpression of miR-377 and let-7a, but not miR-145, in first trimester placental explants significantly reduced basal cytotrophoblast proliferation and expression of ERK and MYC. PCR arrays, in silico analysis, Western blotting, and 3'-UTR luciferase reporter assays revealed targets of miR-145 within the insulin-like growth factor axis. Analysis of proliferation in placental explants overexpressing miR-145 demonstrated its role as a mediator of insulin-like growth factor-induced trophoblast proliferation. These findings identify miR-377 and let-7a in regulation of endogenous cell growth and miR-145 in the placental response to maternal stimulation and will aid the development of therapeutic strategies for problem pregnancies.

Comparison of the mammalian insulin signalling pathway to invertebrates in the context of FOXO-mediated ageing.

MOTIVATION: A large number of experimental studies on ageing focus on the effects of genetic perturbations of the insulin/insulin-like growth factor signalling pathway (IIS) on lifespan. Short-lived invertebrate laboratory model organisms are extensively used to quickly identify ageing-related genes and pathways. It is important to extrapolate this knowledge to longer lived mammalian organisms, such as mouse and eventually human, where such analyses are difficult or impossible to perform. Computational tools are needed to integrate and manipulate pathway knowledge in different species. RESULTS: We performed a literature review and curation of the IIS and target of rapamycin signalling pathways in Mus Musculus. We compare this pathway model to the equivalent models in Drosophila melanogaster and Caenorhabtitis elegans. Although generally well-conserved, they exhibit important differences. In general, the worm and mouse pathways include a larger number of feedback loops and interactions than the fly. We identify 'functional orthologues' that share similar molecular interactions, but have moderate sequence similarity. Finally, we incorporate the mouse model into the web-service NetEffects and perform in silico gene perturbations of IIS components and analyses of experimental results. We identify sub-paths that, given a mutation in an IIS component, could potentially antagonize the primary effects on ageing via FOXO in mouse and via SKN-1 in worm. Finally, we explore the effects of FOXO knockouts in three different mouse tissues. AVAILABILITY AND IMPLEMENTATION: http://www.ebi.ac.uk/thornton-srv/software/NetEffects.

The role of the insulin­like growth factor (IGF) axis in osteogenic and odontogenic differentiation.

The insulin-like growth factor (IGF) axis is a multicomponent molecular network which has important biological functions in the development and maintenance of differentiated tissue function(s). One of the most important functions of the IGF axis is the control of skeletal tissue metabolism by the finely tuned regulation of the process of osteogenesis. To achieve this, the IGF axis controls the activity of several cell types­osteoprogenitor cells, osteoblasts, osteocytes and osteoclasts to achieve the co-ordinated development of appropriate hard tissue structure and associated matrix deposition. In addition, there is an increasing awareness that the IGF axis also plays a role in the process of odontogenesis (tooth formation). In this review, we highlight some of the key findings in both of these areas. A further understanding of the role of the IGF axis in hard tissue biology may contribute to tissue regeneration strategies in cases of skeletal tissue trauma.

The TORC1/P70S6K and TORC1/4EBP1 signaling pathways have a stronger contribution on skeletal muscle growth than MAPK/ERK in an early vertebrate: Differential involvement of the IGF system and atrogenes.

Knowledge about the underlying mechanisms, particularly the signaling pathways that account for muscle growth in vivo in early vertebrates is still scarce. Fish (Paralichthys adspersus) were fasted for 3weeks to induce a catabolic period of strong muscle atrophy. Subsequently, fish were refed for 2weeks to induce compensatory muscle hypertrophy. During refeeding, the fish were treated daily with either rapamycin (TORC blocker), PD98059 (MEK blocker), or PBS (V; vehicle), or were untreated (C; control). Rapamycin and PD98059 differentially impaired muscle cellularity in vivo, growth performance, and the expression of growth-related genes, and the inhibition of TORC1 had a greater impact on fish muscle growth than the inhibition of MAPK. Blocking TORC1 inhibited the phosphorylation of P70S6K and 4EBP1, two downstream components activated by TORC1, thus affecting protein contents in muscle. Concomitantly, the gene expression in muscle of igf-1, 2 and igfbp-4, 5 was down-regulated while the expression of atrogin-1, murf-1, and igfbp-2, 3 was up-regulated. Muscle hypertrophy was abolished and muscle atrophy was promoted, which finally affected body weight. TORC2 complex was not affected by rapamycin. On the other hand, the PD98059 treatment triggered ERK inactivation, a downstream component activated by MEK. mRNA contents of igf-1 in muscle were down-regulated, and muscle hypertrophy was partially impaired. The present study provides the first direct data on the in vivo contribution of TORC1/P70S6K, TORC1/4EBP1, and MAPK/ERK signaling pathways in the skeletal muscle of an earlier vertebrate, and highlights the transcendental role of TORC1 in growth from the cellular to organism level.

Candidate genes that affect aging through protein homeostasis.

Because aging is a multifactorial, pleiotropic process where many interacting mechanisms contribute to the organismal decline, the candidate gene approach rarely provides a clear message. This chapter discusses some of the inherent complexity, focusing on aspects that impinge upon protein homeostasis and maintain a healthy proteome. We discuss candidate genes that operate in these pathways, and compare their actions in invertebrates, mice and humans. We highlight several themes that emerge from recent research­the interconnections of pathways that regulate aging, the pleiotropic effects of mutations and other manipulations of the candidate proteins and the tissue specificity in these pleiotropic outcomes. This body of knowledge highlights the need for multiple specific readouts of manipulating longevity genes, beyond measuring lifespan, as well as the need to understand the integrated picture, beyond examining the immediate outputs of individual longevity pathways.

Fetal alcohol exposure and mammary tumorigenesis in offspring: role of the estrogen and insulin-like growth factor systems.

Fetal alcohol spectrum disorders affect a significant number of live births each year, indicating that alcohol consumption during pregnancy is an important public health issue. Environmental exposures and lifestyle choices during pregnancy may affect the offspring's risk of disease in adulthood, leading to the idea that a woman's risk of breast cancer may be pre-programmed prior to birth. Exposure of pregnant rats to alcohol increases tumorigenesis in the adult offspring in response to mammary carcinogens. The estrogen and insulin-like growth factor (IGF-I) axes occupy central roles in normal mammary gland development and breast cancer. 17-ß estradiol (E2) and IGF-I synergize to regulate formation of terminal end buds and ductal elongation during pubertal development. The intracellular signaling pathways mediated by the estrogen and IGF-I receptors cross-talk at multiple levels through both genomic and non-genomic mechanisms. Several components of the E2 and IGF-I systems are altered in early development in rat offspring exposed to alcohol in utero, therefore, these changes may play a role in the enhanced susceptibility to mammary carcinogens observed in adulthood. Alcohol exposure in utero induces a number of epigenetic alterations in non-mammary tissues in the offspring and other adverse in utero exposures induce epigenetic modifications in the mammary gland. Future studies will determine if fetal alcohol exposure can induce epigenetic modifications in genes that regulate E2/IGF action at key phases of mammary development, ultimately leading to changes in susceptibility to carcinogens.

Insulin signaling mediates sexual attractiveness in Drosophila.

Sexually attractive characteristics are often thought to reflect an individual's condition or reproductive potential, but the underlying molecular mechanisms through which they do so are generally unknown. Insulin/insulin-like growth factor signaling (IIS) is known to modulate aging, reproduction, and stress resistance in several species and to contribute to variability of these traits in natural populations. Here we show that IIS determines sexual attractiveness in Drosophila through transcriptional regulation of genes involved in the production of cuticular hydrocarbons (CHC), many of which function as pheromones. Using traditional gas chromatography/mass spectrometry (GC/MS) together with newly introduced laser desorption/ionization orthogonal time-of-flight mass spectrometry (LDI-MS) we establish that CHC profiles are significantly affected by genetic manipulations that target IIS. Manipulations that reduce IIS also reduce attractiveness, while females with increased IIS are significantly more attractive than wild-type animals. IIS effects on attractiveness are mediated by changes in CHC profiles. Insulin signaling influences CHC through pathways that are likely independent of dFOXO and that may involve the nutrient-sensing Target of Rapamycin (TOR) pathway. These results suggest that the activity of conserved molecular regulators of longevity and reproductive output may manifest in different species as external characteristics that are perceived as honest indicators of fitness potential.

Insulin-Like Growth Factor Binding Proteins--an Update.

The insulin-like growth factor (IGF) system is essential for normal growth and development, and its perturbation is implicated in a number of diseases. IGF activity is finely regulated by a family of six high-affinity IGF binding proteins (IGFBPs). 1GFBPs usually inhibit IGF actions but may enhance them under certain conditions. Additionally, IGFBPs bind non-IGF ligands in the extracellular space, cell membrane, cytoplasm and nucleus, thereby modulating cell proliferation, survival and migration in an IGF-independent manner. IGFBP activity is regulated by transcriptional mechanisms as well as by post-translational modifications and proteolysis. Understanding the balance between the various actions of IGFBPs in vivo may lead to novel insights into disease processes and possible IGFBP-based therapeutics.

Specific insulin-like peptides encode sensory information to regulate distinct developmental processes.

An insulin-like signaling pathway mediates the environmental influence on the switch between the C. elegans developmental programs of reproductive growth versus dauer arrest. However, the specific role of endogenous insulin-like peptide (ILP) ligands in mediating the switch between these programs remains unknown. C. elegans has 40 putative insulin-like genes, many of which are expressed in sensory neurons and interneurons, raising the intriguing possibility that ILPs encode different environmental information to regulate the entry into, and exit from, dauer arrest. These two developmental switches can have different regulatory requirements: here we show that the relative importance of three different ILPs varies between dauer entry and exit. Not only do we find that one ILP, ins-1, ensures dauer arrest under harsh environments and that two other ILPs, daf-28 and ins-6, ensure reproductive growth under good conditions, we also show that daf-28 and ins-6 have non-redundant functions in regulating these developmental switches. Notably, daf-28 plays a more primary role in inhibiting dauer entry, whereas ins-6 has a more significant role in promoting dauer exit. Moreover, the switch into dauer arrest surprisingly shifts ins-6 transcriptional expression from a set of dauer-inhibiting sensory neurons to a different set of neurons, where it promotes dauer exit. Together, our data suggest that specific ILPs generate precise responses to dauer-inducing cues, such as pheromones and low food levels, to control development through stimulus-regulated expression in different neurons.

Body size regulation and insulin-like growth factor signaling.

How animals achieve their specific body size is a fundamental, but still largely unresolved, biological question. Over the past decades, studies on the insect model system have provided some important insights into the process of body size determination and highlighted the importance of insulin/insulin-like growth factor signaling. Fat body, the Drosophila counterpart of liver and adipose tissue, senses nutrient availability and controls larval growth rate by modulating peripheral insulin signaling. Similarly, insulin-like growth factor I produced from liver and muscle promotes postnatal body growth in mammals. Organismal growth is tightly coupled with the process of sexual maturation wherein the sex steroid hormone attenuates body growth. This review summarizes some important findings from Drosophila and mammalian studies that shed light on the general mechanism of animal size determination.

The influence of growth hormone on bone and adipose programming.

In utero growth hormone exposure is associated with distinct immediate growth responses and long term impacts on adult physiological parameters that include obesity, insulin resistance, and bone function. Growth hormone accelerates cellular proliferation in many tissues but is exemplified by increases in the number of cells within the cartilaginous growth plate of bone. In some cases growth hormone also potentiates differentiation as seen in the differentiation of adipocytes that rapidly fill upon withdrawal of growth hormone. Growth hormone provokes these changes either by direct action or through intermediaries such as insulin-like growth factor-I and other downstream effector molecules. The specific mechanism used by growth hormone in programming tissues is not yet fully characterized and likely represents a multipronged approach involving DNA modification, altered adult hormonal milieu, and the development of an augmented stem cell pool capable of future engagement as is seen in adipose accrual. This review summarizes findings of growth hormone's influence on in utero and neonatal cellular and metabolic profiles related to bone and adipose tissue.