Bovine growth hormone transgenic mice are resistant to diet-induced obesity but develop hyperphagia, dyslipidemia, and diabetes on a high-fat diet

It is known that bovine GH (bGH) transgenic mice have increased body mass, insulin resistance, and altered lipoprotein metabolism when fed a normal diet (ND). In this study, the effects of 8 wk of high-fat diet (HFD) were investigated in 6-month-old male bGH mice. Although littermate controls had unchanged energy intake, energy intake was higher in the bGH mice on a HFD than on a low-fat diet. Nevertheless, the bGH mice were resistant to diet-induced weight gain, and only in the bGH mice did the HFD result in increased energy expenditure. Glucose oxidation was higher in the bGH mice compared with littermate controls on both a HFD and ND. In addition, the bGH mice had 0.5 C higher body temperature throughout the day and increased hepatic uncoupling protein 2 expression; changes that were unaffected by the HFD. On a HFD, the effect of bGH overexpression on serum triglycerides and apolipoprotein B was opposite to that on a ND, resulting in higher serum concentrations of triglycerides and apolipoprotein B compared with littermate controls. Increased serum triglycerides were explained by decreased triglyceride clearance. The HFD led to diabetes only in the bGH mice. In conclusion, bGH transgenic mice were resistant to diet-induced obesity despite hyperphagia, possibly due to increased energy expenditure. On a HFD, bGH mice became dyslipidemic and diabetic and thereby more accurately reflect the metabolic situation in acromegalic patients.     

Effect of growth hormone on susceptibility to diet-induced obesity

Mice with a deficiency in GH function due to disruption of the GH receptor/binding protein gene (GHR(-/-)) are long lived, insulin sensitive, and obese, whereas mice with excess GH function due to expression of a bovine GH transgene (bGH) are short lived, glucose intolerant, and lean. When challenged with a high-fat (HF) diet, we hypothesized that these mice would be differentially susceptible to diet-induced obesity. To test this hypothesis, GHR(-/-), bGH, and littermate control (WT) mice were fed a HF diet (40% kcal) or a nutrient-matched low-fat diet (9% kcal) for 12 wk. On the HF diet, all mice, regardless of genotype, showed a similar percent weight gain and exhibited a significant increase in percent body fat and the mass of epididymal, retroperitoneal, and sc fat pads. For bGH mice, the increase in adipose tissue was relatively small, compared with the WT or GHR(-/-) mice, suggesting some resiliency, although not immunity, to diet-induced obesity. GHR(-/-) mice, which are relatively obese on a low-fat diet, responded to the dietary challenge in a manner similar to WT controls. With HF feeding, all genotypes experienced an increase in insulin levels and depot-dependent effect of adipose tissue. Together, these results further support a role for GH in energy balance regulation and nutrient partitioning. More importantly, because there were genotype-specific effects of diet, these data stress the importance of diet selection and sampling multiple adipose depots in studies with these mouse models.     

Increased atherosclerotic lesion area in apoE deficient mice overexpressing bovine growth hormone

Human growth hormone (GH) excess is linked to increased cardiovascular morbidity and mortality. However, little is known about the effect of GH excess on atherosclerosis. We developed a new mouse model to assess the hypothesis that GH overexpression accelerates atherosclerotic lesion formation. apoE(-/-) mice were crossed with bovine GH (bGH) transgenic mice to yield apoE(-/-) mice overexpressing bGH (apoE(-/-)/bGH). The mice were fed either standard or Western diet. At 22 weeks, atherosclerotic lesion area of thoracic aorta was larger in apoE(-/-)/bGH mice compared with littermate apoE(-/-) mice fed either diet (standard: +161+/-50%, Western: +430+/-134%). Aortic sinus lesions were more severe in apoE(-/-)/bGH mice fed standard diet compared with littermate apoE(-/-) mice. apoE(-/-)/bGH mice had lower (VLDL+LDL)/HDL ratios compared with littermate apoE(-/-) mice, while systolic blood pressure was higher in apoE(-/-)/bGH mice, irrespective of diet. The levels of serum amyloid A and hepatic CRP mRNA were higher in apoE(-/-)/bGH mice than in littermate apoE(-/-) mice. In conclusion, this study shows that excess GH augments the development of atherosclerosis in apoE(-/-) mice. The mechanisms could be direct effects of GH on cellular processes in the vessel wall or the result of concomitant processes such as hypertension or a general inflammatory state.     

Comparing adiposity profiles in three mouse models with altered GH signaling.

Three mouse lines with altered growth hormone (GH) signaling were used to study GH's role in adiposity. Dwarf GH receptor knockout mice (GHR -/-) and bovine GH antagonist expressing mice (GHA) had an increased percent body fat with most of the excess fat mass accumulating in the subcutaneous region. Giant bovine GH expressing mice (bGH) had a reduced percent body fat. Only GHA mice consumed significantly more food per body weight. Serum leptin levels were significantly increased in GHA mice and decreased in bGH mice but unchanged in the GHR -/- mice. Interestingly, serum adiponectin levels were significantly increased in the GHR -/- and GHA lines but decreased in bGH mice. These data suggest that suppression or absence of GH action and enhanced GH action indeed have opposite metabolic effects in terms of adiposity. Interestingly, adiponectin levels were positively correlated with previously reported insulin sensitivity of these mice, but also positively correlated with adiposity, which is contrary to findings in other mouse models. Thus, adiponectin levels were negatively correlated with GH function suggesting a role for adiponectin in GH-induced insulin resistance.     

Hormonal determinants of regional body composition in adolescent girls with anorexia nervosa and controls

We have previously demonstrated that girls with anorexia nervosa (AN) have higher levels of GH and cortisol and lower levels of estradiol than healthy adolescents. The effects of endocrine alterations on regional body composition in AN, however, have not been reported. We, therefore, enrolled 23 adolescent girls with AN and 20 healthy girls of comparable maturity in a study examining regional body composition. Levels of estradiol and IGF-I, as well as measures of GH and cortisol concentration (using cluster analysis of data obtained from frequent sampling q30' for 12 h overnight) were examined to determine hormonal determinants of regional body composition in adolescent girls with AN and controls. Girls with AN were followed for 1 yr and examined again at weight recovery (10% increase in body mass index) (n = 11). Percent trunk fat and trunk to extremity fat ratio (T/E fat) were significantly reduced in girls with AN compared with healthy adolescents (P = 0.001 and 0.01, respectively). Percent trunk lean mass and trunk to extremity lean mass ratio (T/E lean) were higher in AN than in controls (P = 0.01 and 0.009); percent extremity lean mass was lower in AN (P = 0.009). In healthy controls, total area under the curve (AUC) for GH correlated inversely with percent trunk fat and T/E fat (r = -0.66, P = 0.002 and r = -0.62, P = 0.003). Similar correlations were observed between other measures of GH concentration (mean and nadir) and percent trunk fat and T/E fat. No relationship was observed between GH concentration and regional lean mass or between cortisol concentration and regional body composition. In contrast, GH concentration did not predict regional body composition in adolescents with AN on regression analysis. However, nadir cortisol concentration correlated inversely with percent extremity lean mass (r = -0.49; P = 0.02) and positively with percent trunk lean mass and T/E lean (r = 0.48, P = 0.03; and r = 0.49, P = 0.02) in girls with AN. A similar trend was observed between other measures of cortisol concentration (mean cortisol and AUC) and percent trunk lean mass and T/E lean in AN. Trunk fat was lowest in girls with AN who had high GH but low cortisol levels (based on median values), whereas some preservation of trunk fat was observed in girls with low GH and high cortisol levels. Weight recovery occurred in seven of 11 girls with low GH and high cortisol values; however, only two of the nine girls with high GH and low cortisol recovered weight. High GH with lower cortisol levels may thus be a marker of greater severity of AN. Our results suggest that in healthy controls, GH concentration predicts regional body composition and favors a redistribution of body fat such that T/E fat ratio decreases. In AN, however, high levels of GH and cortisol have contrasting associations with fat mass. High cortisol levels in AN predict a redistribution of lean body mass such that extremity lean mass decreases. Further studies are necessary to better understand the implications of these data.     

Longitudinal changes in insulin sensitivity and body composition of small-for-gestational-age adolescents after cessation of growth hormone treatment

Context: GH treatment reduces insulin sensitivity (Si). For small-for-gestational-age (SGA) subjects, who might have an increased risk to develop cardiovascular disease and type 2 diabetes, it is still uncertain how Si, beta-cell function, and body composition change over time after stopping GH treatment. Objective: Our objective was to investigate longitudinal changes in Si, beta-cell function, and body composition after cessation of long-term GH treatment. Design and Patients: We conducted a longitudinal study that included 48 SGA adolescents studied at adult height, while still on GH, and 6 months after GH stop and compared them with 38 appropriate-for-gestational-age (AGA) controls at both time points. Outcome Measure: We took paired measurements of Si and beta-cell function, assessed by frequently sampled iv glucose tolerance tests with tolbutamide, and body composition, measured by dual-energy x-ray absorptiometry. Results: After stopping GH, Si (P = 0.006), glucose effectiveness (Sg; P = 0.009) and beta-cell function (disposition index; P = 0.024) increased, whereas insulin secretion (acute insulin response; not significant) decreased. Fat percentage increased (P < 0.0005), and lean body mass decreased (P < 0.0005), but fat distribution remained unaltered, and body composition remained within the normal range. Compared with AGA controls, Si was lower during GH and became similar after GH stop, acute insulin response was higher at both time points, and glucose effectiveness and disposition index became higher. Conclusions: The GH-induced lower Si in SGA adolescents increases after stopping long-term GH treatment and becomes similar to that of AGA controls. Discontinuation of GH treatment is, however, also associated with an increase in percent body fat and with a decrease in lean body mass, without changes in fat distribution.     

Body composition of prolactin-, growth hormone,and thyrotropin-deficient Ames dwarf mice

Ames dwarf mice have primary deficiency of prolactin (PRL), growth hormone (GH), and thyroid-stimulating hormone (TSH), and live considerably longer than normal animals from the same line. In view of the documented effects of GH, PRL, and thyroid hormones on lean and fat body mass and skeletal growth, and the suspected relationship of body size and composition to life expectancy, it was of interest to examine agerelated changes in body composition of Ames dwarf mice. Lean mass, fat mass, bone area, and bone mineral content (BMC) were determined in dwarf and normal mice at the ages of 2, 4.5–6, and 18 mo using dual X-ray absorptiometry. In addition to the expected significant declines in lean mass, bone area, and BMC, dwarf mice exhibited attenuation of the age-related increase in bone mineral density and delayed or attenuated increase in percentage of body fat. Percentage of body fat was lower in adult dwarfs than in the corresponding normal controls. Patterns of age-related changes in body composition in Ames dwarf mice are consistent with the recent report of age-related changes in body composition in PRL receptor knockout mice. We suspect that reduction in relative adiposity may contribute to the previously reported increase in insulin sensitivity of Ames dwarf mice and thus may be a factor in delayed aging and increased longevity of these animals.     

Alterations in body composition and fat distribution in growth hormone-deficient prepubertal children during growth hormone therapy

Growth hormone (GH) deficiency in children results in increased body fat, reduced fat-free mass (FFM) including muscle (protein) and bone, and abdominal obesity. Thus, proper GH secretion likely has major developmental influences on later health risks including cardiovascular diseases and osteoporosis. However, the in vivo control of the development of the body composition and fat distribution by GH has not yet been accurately investigated using children with GH deficiency as a model. We determined the effect of GH therapy (GH replacement, n = 3; GH + physiologic cortisol and thyroxine replacement, n = 3) on body composition, the proportional composition of the FFM, and body fat distribution in GH-deficient prepubertal children compared with healthy control children (n = 6) not treated with GH. The GH-deficient and control children were initially matched for gender, bone age, and weight. As assessed by a 4-compartment model, GH therapy reduced percent body fat during the first 3 months of therapy but not thereafter. This change was primarily due to FFM, which increased 3-fold more in the GH-deficient group and accounted for 91.5% of the increase in body weight. Fat mass increased in the controls but was unchanged in the GH-deficient group. Therapy temporarily increased the proportional contribution of water to the FFM, decreased the proportion of mineral, and slightly increased the proportion of protein. Using magnetic resonance imaging (MRI), abdominal visceral fat was reduced in the GH-deficient group and unchanged in the controls. Abdominal subcutaneous fat measured in the same image was not changed. The abdominal and suprailiac skinfold thicknesses also were not decreased in the GH-deficient group. In conclusion, within 1 to 3 months, GH therapy accelerates lean tissue accrual, especially the water and protein components, but has a smaller effect on reducing fat mass. GH therapy has site-specific effects on reducing abdominal adiposity.     

Hyperleptinaemia in young adults following cranial irradiation in childhood: growth hormone deficiency or leptin insensitivity?

OBJECTIVE: In order to explore the mechanism of obesity in long-term survivors of childhood leukaemia, fat mass, lean body mass and serum leptin were assessed in a cohort of 32 (17 males) adults who had received cranial irradiation (XRT) in childhood as part of their treatment for acute lymphobiastic leukaemia (ALL), and compared with 35 age and body mass index (BMI) matched young adults (18 male). DESIGN: Thirty-one patients and 18 controls had fat mass and lean body mass assessed by dual x-ray absorptiometry (DEXA), using a lunar DPX-L scanner. Serum leptin concentrations were also measured in 27 patients and all controls. Growth hormone status had previously been determined using an insulin tolerance test and arginine stimulation test. Nine patients were classified as severe growth hormone (GH) deficient (group 1), 12 patients as GH insufficient (group 2) and 11 patients as normal (group 3). RESULTS: BMI and absolute fat mass were not significantly different between the patients and controls regardless of their gender (P = 0.1 and P = 0.14 respectively). In contrast, absolute lean mass was significantly reduced (P < 0.01) and leptin concentrations were significantly increased (P < 0.001) in patients compared with controls. BMI, fat mass and leptin concentrations but not lean mass were significantly different between the three GH status groups (P < 0.01, P < 0.01, P = 0.004, and P = 0.67 respectively). When leptin concentrations were expressed per unit of fat mass, they were increased in the patients compared with the controls (P = 0.03) with significant differences between the GH status groups (P = 0.004), being significantly higher in the severe GH deficient group. CONCLUSIONS: Young adults who receive cranial irradiation in childhood are prone to GH deficiency and hyperleptinaemia. The pathophysiological significance of the hyperleptinaemia remains to be established but it has occurred either as a consequence of radiation induced hypothalamic damage or GH deficiency.     

Functional antagonism between endogenous mouse growth hormone (GH) and a GH analog results in dwarf transgenic mice

A dwarf transgenic mouse (DTM) line has been established in which mice express relatively high levels of a mutated bovine (b) GH gene. This bGH analog binds to mouse liver membrane preparations with an affinity similar to that of wild-type bGH. The mean growth ratio of these mice is approximately 0.7 relative to that of their nontransgenic littermates. Serum insulin-like growth factor-I (IGF-I) levels of DTM were found to be approximately half those in nontransgenic littermates. Liver GH receptor levels were up-regulated in DTM or wild-type bGH transgenic mice. Pituitary GH levels were negatively correlated with serum IGF-I concentrations. Wild-type bGH transgenic mice contain relatively high serum IGF-I and low pituitary GH levels, whereas DTM possess low serum IGF-I and high pituitary GH levels. The decrease in serum IGF-I resulting from the interaction between the bGH analog, the endogenous mouse GH, and GH receptor(s) apparently leads to a dwarf phenotype. These data suggest that this bGH analog has uncoupled GH ligand-receptor binding from IGF-I production and acts as a functional antagonist to the action of endogenous mGH.     

Growth response and androgen receptor expression in seminal vesicles from aging transgenic mice expressing human or bovine growth hormone genes.

Previous work has shown that expression of human (h) GH in transgenic mice is associated with significant age-related enlargement of seminal vesicles. To further explore this aberrant growth activity, we have characterized seminal vesicles from various GH transgenic lines and examined their androgen receptor (AR) content and distribution. Six groups of animals were initially studied: young adult (3-5 months) control mice, old (greater than 12 months) control mice, young adult hGH transgenic mice, old hGH transgenics, young adult bovine (b) GH transgenics, and old bGH transgenic mice. Young transgenic mice (hGH and bGH) possessed seminal vesicles with similar relative weights, DNA and protein contents, and AR levels as nontransgenic littermates. Histologically, the glands appeared similar. With aging, the hGH transgenic seminal vesicles exhibited massive stromal hyperplasia, whereas the glands from controls and bGH transgenic mice did not show this response. Seminal vesicles from old hGH mice presented with a marked increase in cell number (DNA content) and a marked decrease in cell size and/or glandular secretions (protein/DNA ratio) compared to those from old controls and young hGH transgenic mice. Tissue AR content was markedly reduced in old hyperplastic hGH seminal vesicles compared to that in seminal vesicles from young hGH transgenics, old controls, and old bGH transgenic mice. Immunohistochemistry indicated the absence of AR in the proliferating stromal cells, whereas acinar epithelial cells showed similar or moderately reduced AR staining intensity compared to control seminal vesicles. To examine whether the above results may be due to insertional mutagenesis rather than hGH itself, two additional GH transgenic lines were examined. Aged transgenic mice expressing bGH with an alternate promoter possessed seminal vesicle weights that were not different from those of old controls, whereas aged transgenic mice expressing an hGH. V gene (variant gene, placental origin) possessed significantly larger vesicles than the controls, which further suggests that vesicular hyperplasia is specifically related to hGH. To assess androgen responsiveness, aged control and hGH transgenic mice were castrated and examined after 15 days. While control seminal vesicles significantly decreased in size, glands from transgenic mice did not. Regressive changes were observed in the remaining epithelium of hGH transgenic mice; however, stromal tissue exhibited no response to androgen withdrawal. The present results suggest that the aging-associated seminal vesicle hyperplasia in hGH transgenic mice is a result of a massive increase in stromal tissue that is low or devoid of AR, suggesting a loss of direct androgen regulation.(ABSTRACT TRUNCATED AT 400 WORDS)     

Relationship between growth hormone-IGF-I-IGFBP-3 axis and serum leptin levels with bone mass and body composition in patients with rheumatoid arthritis

OBJECTIVES: Hormonal factors playing a role in bone mass and body composition have been rarely assessed in rheumatoid arthritis (RA). In this study, we aimed to evaluate the growth hormone (GH)-insulin-like growth factor-I (IGF-I)-insulin-like growth factor binding protein-3 (IGFPB-3) axis and serum leptin levels in patients with RA and to determine whether these hormonal/growth factors may influence bone mass and body composition in RA. METHODS: Serum GH, IGF-I, IGFPB-3 and leptin were evaluated in 38 corticosteroid-treated RA patients, 14 non-RA patients under corticosteroids (corticosteroid controls, CC) and 32 healthy controls (HC). Bone density was evaluated using dual X-ray absorptiometry (DEXA), and expressed as bone mineral density (BMD), and quantitative ultrasound (QUS). Body composition was assessed by DEXA. RESULTS: The three groups differed regarding femoral neck, total body BMD, lean mass and QUS parameters with lower values in the RA group (all P < or = 0.05). Growth hormone was higher in RA patients (P=0.0001) while IGF-I and IGFBP-3 did not differ between the three groups. In RA patients there was a tendency to high serum leptin levels and leptin strongly correlated with fat mass (r=0.83, P<0.0001), but not with bone mass measurements or inflammatory parameters. There were no differences for lean mass, GH and leptin between CC and HC. CONCLUSION: Our results suggest that these GH and leptin modifications could have an influence on both bone mass and body composition in RA.     

Impairment of cardiac function and bioenergetics in adult transgenic mice overexpressing the bovine growth hormone gene

Cardiovascular abnormalities represent the major cause of death in patients with acromegaly. We evaluated cardiac structure, function, and energy status in adult transgenic mice overexpressing bovine GH (bGH) gene. Female transgenic mice expressing bGH gene (n = 11) 8 months old and aged matched controls (n = 11) were used. They were studied with two-dimensional guided M-mode and Doppler echocardiography. The animals (n = 6) for each group were examined with 31P magnetic resonance spectroscopy to determine the cardiac energy status. Transgenic mice had a significantly higher body weight (BW), 53.2+/-2.4 vs. 34.6+/-3.7 g (P < 0.0001) and hypertrophy of left ventricle (LV) compared with normal controls: LV mass/BW 5.6+/-1.6 vs. 2.7+/-0.2 mg/g, P < 0.01. Several indexes of systolic function were depressed in transgenic animals compared with controls mice such as shortening fraction 25+/-3.0% vs. 39.9+/-3.1%; ejection fraction, 57+/-9 vs. 77+/-5; mean velocity of circumferential shortening, 4.5+/-0.8 vs. 7.0+/-1.1 circ/sec, p < 0.01. Creatine phosphate-to-ATP ratio was significantly lower in bGH overexpressing mice (1.3+/-0.08 vs. 2.1+/-0.23 in controls, P < 0.05). Ultrastructural examination of the hearts from transgenic mice revealed substantial changes of mitochondria. This study provides new insight into possible mechanisms behind the deteriorating effects of long exposure to high level of GH on heart function.     

Body Composition in Detoxified Alcoholics

Body composition was evaluated in healthy detoxified alcoholics (aged 20-39) and lifestyle controls, with the expectation that prolonged, excessive consumption of alcohol may bring about nutritional or toxicologic alterations in the relationship between body fat and lean body mass. Body fat was assessed by measurements of skin-fold thickness and by means of bioelectric impedance methodology. No noteworthy differences were observed between alcoholics and controls with regard to the relationship between lean body mass and body fat or in the relationship between extracellular and intracellular water. It would appear that 15-20 years of heavy alcohol consumption does not necessarily alter body composition in healthy, young alcoholics.     

Growth allometry of the organs in giant transgenic mice

We have analyzed the absolute and relative (allometric) growth of a series of internal organs in giant transgenic (MTrGH) and littermate control mice to determine the general and organ-specific effects of the altered hormonal environment on growth in these rodents. Comparison of cross-sectional growth allometries of organ weights and external body dimensions between the two samples was based on analyses of covariance. We report significantly increased growth in all of the organs and measurements examined except for the brain. Coefficients of growth allometry differ significantly from isometric values in a number of cases, and thus, the adult transgenic mice exhibit body proportions different from those of the adult controls. Most of these shape differences reflect general allometric size increase, but the liver and spleen of the transgenics undergo special enlargement or growth. These results indicate that the primary effect of elevated GH and IGF-I levels is increased overall growth, but in the relative proportions set by the intrinsic controls of individual organs and body regions.     

Bovine growth hormone transgenic mice display alterations in locomotor activity and brain monoamine neurochemistry

Recent clinical and experimental data indicate a role for GH in mechanisms related to anhedonia/hedonia, psychic energy, and reward. In the present study we have investigated whether bovine GH (bGH) transgenic mice and nontransgenic controls differ in spontaneous locomotor activity, a behavioral response related to brain dopamine (DA) and reward mechanisms, as well as in locomotor activity response to drugs of abuse known to interfere with brain DA systems. The animals were tested for locomotor activity once a week for 4 weeks. When first exposed to the test apparatus, bGH transgenic animals displayed significantly more locomotor activity than controls during the entire registration period (1 h). One week later, after acute pretreatment with saline, the two groups did not differ in locomotor activity, whereas at the third test occasion, bGH mice were significantly more stimulated by d-amphetamine (1 mg/kg, ip) than controls. At the fourth test, a tendency for a larger locomotor stimulatory effect of ethanol (2.5 g/kg, ip) was observed in bGH transgenic mice. bGH mice displayed increased tissue levels of serotonin and 5-hydroxyindoleacetic acid in several brain regions, decreased DA levels in the brain stem, and decreased levels of the DA metabolite 3,4-dihydroxyphenylacetic acid in the mesencephalon and diencephalon, compared with controls. In conclusion, bGH mice display more spontaneous locomotor activity than nontransgenic controls in a novel environment and possibly also a disturbed habituation process. The finding that bGH mice were also more sensitive to d-amphetamine-induced locomotor activity may suggest that the behavioral differences observed are related to differences in brain DA systems, indicating a hyperresponsiveness of these systems in bGH transgenic mice. These findings may constitute a neurochemical basis for the reported psychic effects of GH in humans.     

Physiological studies of transgenic mice overexpressing growth hormone (GH) secretagogue receptor 1A in GH-releasing hormone neurons

The type 1A GH secretagogue (GHS) receptor (GHSR) has been proposed to mediate the effects of ghrelin on GH release, food intake, and body composition. We have overexpressed GHSR in GH-producing GC cells and GHRH neurons in an attempt to enhance signaling via this pathway selectively, in the GH axis. Constitutive overexpression of human GHSR in rat GC cell lines resulted in increased basal phosphoinositol turnover and rendered them responsive to GHS ligands. We then generated transgenic mice overexpressing human GHSR in GHRH neurons using a 38-kb rat GHRH cosmid promoter. GHRH-GHSR transgenic mice showed increased hypothalamic GHRH expression, pituitary GH contents, and postweaning growth rates. Body weights of the transgenic mice became similar in adulthood, whereas adipose mass was reduced, particularly so in female GHRH-GHSR mice. Organ and muscle weights of transgenic mice were increased despite chronic exposure to a high fat diet. These results suggest that constitutive overexpression of GHSR in GHRH neurons up-regulates basal activity in the GHRH-GH axis. However, GHRH-GHSR mice showed no evidence of increased sensitivity to acute or chronic treatment with exogenous GHS ligands. Food intake and adipose tissue responses to chronic high fat feeding and treatment with GHS ligands were unaffected, as were locomotor and anxiety behaviors, although GHRH-GHSR mice remained significantly leaner than wild-type littermates. Thus, constitutive overexpression of GHSR can up-regulate basal signaling activity in the GHRH/GH axis and reduce adiposity without affecting other GHSR-mediated signals.     

Effects of exogenous growth hormone on growth and body composition in genetically selected mice.

The effects of exogenous GH on growth and body composition were investigated in lines of mice selected for high or low body weight (P-lines) or high or low body fat (F-lines). Mice from all lines were given daily injections of recombinant bovine GH or a placebo for 21 days from 4 weeks old. They were killed and various organ weights measured. There was no consistent effect of GH on organ weights. In all lines of mice the rate of weight gain and final weight increased in response to GH. In both lines selected for body fat, GH treatment decreased fat content. The low body weight mice also became less fat, but in the high body weight mice GH treatment increased fat percentage. The results indicate that the differences in growth rate and body composition observed in these lines are not due to differences in responsiveness to GH.     

Effects of recombinant mouse growth hormone treatment on growth and body composition in GHRH knock out mice.

OBJECTIVE: GH deficiency (GHD) causes growth failure and alterations in body composition both in humans and mice. Mouse models of GHD are used to study the effect of GH replacement therapy on these parameters. As the administration of human GH to mice causes development of antibodies and progressive reduction of its effectiveness, the use of species-specific GH is recommended. To determine the optimal GH replacement schedule in GHD mice, and to study its effect on body composition, we treated mice with targeted ablation of the GHRH gene (GHRH knock out-GHRHKO) with recombinant mouse GH (rmGH). DESIGN: One week-old GHRHKO male animals received either placebo or one of two different regimens of escalating doses of rmGH: R1: 30 microg/daily (1st week), 50 microg/daily (2nd week), 70 microg/daily (3rd-4th week); R2: 15 microg/twice a day (1st week), 25 microg/twice a day (2nd week), 35 microg/twice a day (3rd-4th week). Sex- and age-matched wild-type (WT) animals served as controls. At the end of the study we measured body length and weight, tibia and femur length, and body composition. RESULTS: While R1 normalized all growth parameters (TBW, N-A, femur, tibia length), R2 mice achieved significantly higher TBW, N-A and femur length when compared to WT. Body composition abnormalities (increased subcutaneous fat and reduced lean mass) were completely reverted by both treatment schedules. None of the GH-induced parameter modification described above was reflected in parallel changes in circulating serum IGF-1 and liver IGF-1 mRNA. CONCLUSIONS: Our findings indicate that in GHD mice body composition changes are reverted by rmGH and that twice/daily is more effective than daily administration.     

HCV synergizes with body weight in the promotion of insulin resistance

Summary. Hepatitis C virus (HCV) infection appears to contribute to the development of insulin resistance (IR). Among the multiple determinants of IR, body mass index (BMI) is the most important. We investigated the contribution of HCV to BMI‐associated IR using a transgenic mouse model expressing HCV core protein. Eight transgenic and five nontransgenic littermate controls were evaluated. Glucose and insulin tolerance tests (ITT) were performed on two separate occasions. Multivariate linear mixed modelling was used to evaluate and compare the effect of weight on IR between HCV core transgenic and nontransgenic controls. There were no statistically significant differences in glucose or ITT (P = 0.58 and P = 0.59, respectively) between the two groups, and no difference in median weights between transgenic and control mice (P = 0.11). However, there was greater variance in the distributions of Tg when compared to nontransgenic mice for both glucose and insulin tolerance. When evaluating this closely, a differential contribution of weight to IR curves between these groups was noted (P = 0.05). Among nontransgenic mice, IR curves for mice of different weights were comparable, however, for transgenic mice, higher weights resulted in larger levels of IR curves with slower decay. In all animals, steatosis was absent or minimal. We conclude that weight has a greater effect on IR in HCV core expressing transgenic mice than littermate controls. HCV therefore synergizes with weight in the promotion of IR. Steatosis was not a prerequisite for the development of IR, implying that HCV’s effects on IR may be independent of steatosis.