Increased capacity to maintain glucose homeostasis in a transgenic mouse expressing human but not mouse growth hormone with developing high-fat diet-related insulin resistance, hepatic steatosis and adipose dysfunction.

The objective was to assess the potential differential effects of human versus mouse growth hormone in vivo, given that human unlike mouse growth hormone can bind prolactin as well as the growth hormone receptor. To this end, a transgenic CD-1 mouse expressing human but not mouse growth hormone was generated, and the phenotypes of male mice fed with a regular chow or high-fat diet were assessed. Pancreas and epididymal white adipose tissue gene expression and/or related function were targeted as the pancreas responds to both prolactin and growth hormone receptor signaling, and catabolic effects like lipolytic activity are more directly attributable to growth hormone and growth hormone receptor signaling.

Effect of high fat diet on maternal behavior, brain-derived neurotrophic factor and neural stem cell proliferation in mice expressing human placental lactogen during pregnancy.

Maternal obesity is a serious health concern because it increases risks of neurological disorders, including anxiety and peripartum depression. In mice, a high fat diet (HFD) in pregnancy can negatively affect placental structure and function as well as maternal behavior reflected by impaired nest building and pup-retrieval. In humans, maternal obesity in pregnancy is associated with reduced placental lactogen (PL) gene expression, which has been linked to a higher risk of depression.

Neurogenesis in the Maternal Rodent Brain: Impacts of Gestation-Related Hormonal Regulation, Stress, and Obesity.

In order to maintain maternal behavior, it is important that the maternal rodent brain promotes neurogenesis. Maternal neurogenesis is altered by the dynamic shifts in reproductive hormone levels during pregnancy. Thus, lifestyle events such as gestational stress and obesity that can affect hormone production will affect neuroendocrine control of maternal neurogenesis.

Elimination of endogenous high molecular weight FGF2 prevents pressure-overload-induced systolic dysfunction, linked to increased FGFR1 activity and NR1D1 expression.

Fibroblast growth factor 2 (FGF2), produced as high (Hi-) and low (Lo-) molecular weight isoforms, is implicated in cardiac response to injury. The role of endogenous FGF2 isoforms during chronic stress is not well defined. We investigated the effects of endogenous Hi-FGF2 in a mouse model of simulated pressure-overload stress achieved by transverse aortic constriction (TAC) surgery.

Dexamethasone Rescues an Acute High-Fat Diet-Induced Decrease in Human Growth Hormone Gene Expression in Male Partially Humanized CD-1 Mice.

Obesity in puberty, already a time of insulin resistance, increases the risk of developing type 2 diabetes. Human (h) growth hormone (GH) levels also peak during puberty, where it contributes to growth and energy homeostasis through positive effects on maintaining pancreatic β cell mass. Thus, it is important to understand the effects of overeating and obesity on hGH production in puberty.

Effects of high fat diet-induced obesity and pregnancy on prepartum and postpartum maternal mouse behavior.

Obesity before and during pregnancy negatively affects the mental and physical health of the mother. A diet high in fat also increases the risk for anxiety, depression and cognitive dysfunction. We examined the effects of high fat diet (HFD) -induced obesity and pregnancy on maternal behavior, cognitive function and anxiety- and depression-like behaviors in mice.

Sleep deprivation and diet affect human GH gene expression in transgenic mice in vivo.

Human (h) growth hormone (GH) production studies are largely limited to effects on secretion. How pituitary hGH gene (hGH-N/GH1) expression is regulated is important in our understanding of the role hGH plays in physiology and disease. Here we assess for the first time the effect of sleep deprivation (SD) and high-fat diet (HFD) on hGH-N expression in vivo using partially humanized 171hGH/CS transgenic (TG) mice, and attempted to elucidate a role for DNA methylation.

Obesity and regulation of human placental lactogen production in pregnancy.

The four genes coding for placental members of the human (h) growth hormone (GH) family include two that code independently for placental lactogen (PL), also known as chorionic somatomammotrophin hormone, one that codes for placental growth hormone (PGH) and a pseudogene for which RNA but no protein product is reported. These genes are expressed preferentially in the villus syncytiotrophoblast of the placenta in pregnancy. In higher primates, the placental members, including hPL and PGH, are the result of multiple duplication events of the GH gene.

Negative Effects of Cyclic Palmitate Treatment on Glucose Responsiveness and Insulin Production in Mouse Insulinoma Min6 Cells Are Reversible.

Pancreatic β-cell failure is characterized by compromised insulin secretion in response to glucose, which ultimately results in hyperglycemia, the clinical hallmark of type 2 diabetes mellitus (T2DM). Acute exposure to plasma free fatty acids (FFAs) potentiates glucose stimulated insulin secretion (GSIS), while chronic exposure impairs GSIS, and the latter has been associated with the mechanism of β cell failure in obesity linked T2DM. By contrast, growth hormone (GH) signaling has been linked positively to GSIS in β cells.

Elimination or neutralization of endogenous high-molecular-weight FGF2 mitigates doxorubicin-induced cardiotoxicity.

Cardiac fibroblast growth factor 2 (FGF2) exerts multiple paracrine activities related to cardiac response to injury. Endogenous FGF2 is composed of a mixture of 70% high- and 30% low-molecular-weight isoforms (Hi-FGF2 and Lo-FGF2, respectivley); although exogenously added Lo-FGF2 is cardioprotective, the roles of endogenous Hi-FGF2 or Lo-FGF2 have not been well defined. Therefore, we investigated the effect of elimination of Hi-FGF2 expression on susceptibility to acute cardiac damage in vivo caused by an injection of the genotoxic drug doxorubicin (Dox).

Cardiac Fgf-16 Expression Supports Cardiomyocyte Survival and Increases Resistance to Doxorubicin Cytotoxicity.

The fibroblast growth factor (FGF) 16 gene is preferentially expressed by cardiomyocytes after birth with levels increasing into adulthood. Null mice and isolated heart studies suggest a role for FGF-16 in cardiac maintenance and survival, including increased resistance to doxorubicin (DOX)-induced injury. A single treatment with DOX was also shown to rapidly deplete endogenous rat FGF-16 mRNA at 6 h in both adult heart and neonatal cardiomyocytes.

A useful model to compare human and mouse growth hormone gene chromosomal structure, expression and regulation, and immune tolerance of human growth hormone analogues.

Human (h) pituitary growth hormone (GH) is both physiologically and clinically important. GH reaches its highest circulatory levels in puberty, where it contributes to energy homeostasis and somatogenic growth. GH also helps to maintain tissues and organs and, thus, health and homeostasis.

Chromosomal architecture and placental expression of the human growth hormone gene family are targeted by pre-pregnancy maternal obesity.

The human (h) placental lactogenic hormone chorionic somatomammotropin (CS) is highly produced during pregnancy and acts as a metabolic adaptor in response to maternal insulin resistance. Maternal obesity can exacerbate this "resistance", and a >75% decrease in CS RNA levels was observed in term placentas from obese vs. lean women.

Fibroblast growth factor-2-mediated protection of cardiomyocytes from the toxic effects of doxorubicin requires the mTOR/Nrf-2/HO-1 pathway.

Background: Cardiotoxic side effects impose limits to the use of anti-tumour chemotherapeutic drugs such as doxorubicin (Dox). There is a need for cardioprotective strategies to prevent the multiple deleterious effects of Dox. Here, we examined the ability of administered fibroblast growth factor-2 (FGF-2), a cardioprotective protein that is synthesized as high and low molecular weight (Hi-, Lo-FGF-2) isoforms, to prevent Dox-induced: oxidative stress; cell death; lysosome dysregulation; and inactivation of potent endogenous protective pathways, such as the anti-oxidant/detoxification nuclear factor erythroid-2-related factor (Nrf-2), heme oxygenase-1 (HO-1) axis.

Expression of the Cardiac Maintenance and Survival Factor FGF-16 Gene Is Regulated by Csx/Nkx2.5 and Is an Early Target of Doxorubicin Cardiotoxicity.

The fibroblast growth factor (FGF) 16 gene (Fgf-16) is preferentially expressed by neonatal cardiomyocytes after birth, with levels increasing into adulthood. Null mice and isolated heart studies suggest a role for FGF-16 in cardiac maintenance and survival, including increased resistance to doxorubicin (DOX)-induced injury. However, the effect of DOX on endogenous FGF-16 synthesis and specifically regulation of cardiac Fgf-16 expression has not been reported.

Evidence for a Circadian Effect on the Reduction of Human Growth Hormone Gene Expression in Response to Excess Caloric Intake.

Rhythmicity of biological functions is fundamental for optimal adaptations to environmental cues. Growth hormone (GH) is a major metabolic homeostatic factor that is secreted with a circadian pattern, but whether it is synthesized rhythmically is unknown. We used transgenic mice containing the human (h) GH gene (hGH1) locus to investigate the rhythmicity of hGH synthesis and secretion and to show that RNA and secreted protein levels oscillate over a 24-h cycle.

Expression of Placental Members of the Human Growth Hormone Gene Family Is Increased in Response to Sequential Inhibition of DNA Methylation and Histone Deacetylation.

The genes coding for human (h) chorionic somatomammotropin (CS), hCS-A and hCS-B, and placental growth hormone (GH-V), hGH-V, are located at a single locus on chromosome 17. Efficient expression of these placental genes has been linked to local regulatory (5' P and 3' enhancer) sequences and a remote locus control region (LCR), in part, through gene transfer in placental and nonplacental tumor cells. However, low levels of endogenous hCS/GH-V transcripts are reported in the same cells compared with term placenta, suggesting that chromatin structure, or regulatory region accessibility, versus transcription factor availability contributes to the relatively low levels.

Identification of three novel FGF16 mutations in X-linked recessive fusion of the fourth and fifth metacarpals and possible correlation with heart disease.

Nonsense mutations in FGF16 have recently been linked to X-linked recessive hand malformations with fusion between the fourth and the fifth metacarpals and hypoplasia of the fifth digit (MF4; MIM#309630). The purpose of this study was to perform careful clinical phenotyping and to define molecular mechanisms behind X-linked recessive MF4 in three unrelated families. We performed whole-exome sequencing, and identified three novel mutations in FGF16.

Energy homeostasis targets chromosomal reconfiguration of the human GH1 locus.

Levels of pituitary growth hormone (GH), a metabolic homeostatic factor with strong lipolytic activity, are decreased in obese individuals. GH declines prior to the onset of weight gain in response to excess caloric intake and hyperinsulinemia; however, the mechanism by which GH is reduced is not clear. We used transgenic mice expressing the human GH (hGH) gene, GH1, to assess the effect of high caloric intake on expression as well as the local chromosome structure of the intact GH1 locus.

Heart-specific expression of FGF-16 and a potential role in postnatal cardioprotection.

Fibroblast growth factor 16 (FGF-16) was originally cloned from rat heart. Subsequent investigation of mouse FGF-16, including generation of null mice, revealed a specific pattern of expression in the endocardium and epicardium, and role for FGF-16 during embryonic heart development. FGF-16 is expressed mainly in brown adipose tissue during rat embryonic development, but is expressed mainly in the murine heart after birth.

CCAAT-enhancer-binding protein β (C/EBPβ) and downstream human placental growth hormone genes are targets for dysregulation in pregnancies complicated by maternal obesity.

Human chorionic somatomammotropin (CS) and placental growth hormone variant (GH-V) act as metabolic adaptors in response to maternal insulin resistance, which occurs in "normal" pregnancy. Maternal obesity can exacerbate this "resistance," suggesting that CS, GH-V, or transcription factors that regulate their production might be targets. The human CS genes, hCS-A and hCS-B, flank the GH-V gene.

FGF-2 and FGF-16 protect isolated perfused mouse hearts from acute doxorubicin-induced contractile dysfunction.

The anti-cancer drug doxorubicin is associated with an increased risk of cardiac damage and dysfunction, which can be acute as well as chronic. Fibroblast growth factor 2 (FGF-2) provides cardioprotection from ischemia-reperfusion injury but its effects on doxorubicin-induced damage are not known. We investigated the acute effects of doxorubicin administered in the absence and presence of FGF-2 pre-treatment, on isolated mouse perfused heart function over a period of 120 min.

FGF-2 protects cardiomyocytes from doxorubicin damage via protein kinase C-dependent effects on efflux transporters.

Aims: The anti-cancer anthracycline doxorubicin (DOX) increases the risk of cardiac damage, indicating a need to protect the heart and still allow the benefits of drug treatment. Fibroblast growth factor-2 (FGF-2) is cardioprotective against ischaemia-reperfusion injury. Our aim is to investigate: (i) the ability of FGF-2 to protect against DOX-induced cardiomyocyte damage and (ii) the contribution of efflux drug transport to any increase in injury-resistance.

The hidden but positive role for glucocorticoids in the regulation of growth hormone-producing cells.

Growth hormone (GH) is a prominent metabolic factor that is targeted by glucocorticoids; however, their role in GH production remains controversial. This is explained in part by discrepancies between in vitro and in vivo, short-term versus long-term exposure and even species-specific effects. The prevailing view, however, is that glucocorticoids are negative modulators of growth and GH production.