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1.  The effects of weight cycling on lifespan in male C57BL/6J mice 
Objective
With the increasing rates of obesity, many people diet in attempts to lose weight. Since weight loss is seldom maintained in a single effort, weight cycling is a common occurrence. Unfortunately, reports from clinical studies that have attempted to determine the effect of weight cycling on mortality are in disagreement, and to date, no controlled animal study has been performed to assess the impact of weight cycling on longevity. Therefore, our objective was to determine whether weight cycling altered lifespan in mice that experienced repeated weight gain and weight loss throughout their lives.
Methods
Male C57BL/6J mice were placed on one of three lifelong diets: a low fat (LF) diet, a high fat (HF) diet, or a cycled diet in which the mice alternated between 4 weeks on the LF diet and 4 weeks on the HF diet. Body weight, body composition, several blood parameters and lifespan were assessed.
Results
Cycling between the HF and LF diet resulted in large fluctuations in body weight and fat mass. These gains and losses corresponded to significant increases and decreases, respectively, in leptin, resistin, GIP, IGF-1, glucose, insulin, and glucose tolerance. Surprisingly, weight cycled mice had no significant difference in lifespan (801±45 days) as compared to LF fed controls (828±74 days), despite being overweight and eating a HF diet for half of their lives. In contrast, the HF fed group experienced a significant decrease in lifespan (544±73days) compared to LF fed controls and cycled mice.
Conclusions
This is the first controlled mouse study to demonstrate the effect of lifelong weight cycling on longevity. The act of repeatedly gaining and losing weight, in itself, did not decrease lifespan and was more beneficial than remaining obese.
doi:10.1038/ijo.2012.203
PMCID: PMC3609933  PMID: 23229739
weight cycling; weight fluctuation; yo-yo dieting; weight loss; mortality; longevity
2.  Age-Related and Depot-Specific Changes in White Adipose Tissue of Growth Hormone Receptor-Null Mice 
Growth hormone receptor-null (GHR−/−) mice are dwarf, insulin sensitive, and long-lived in spite of increased adiposity. However, their adiposity is not uniform, with select white adipose tissue (WAT) depots enlarged. To study WAT depot–specific effects on insulin sensitivity and life span, we analyzed individual WAT depots of 12- and 24-month-old GHR− /− and wild-type (WT) mice, as well as their plasma levels of selected hormones. Adipocyte sizes and plasma insulin, leptin, and adiponectin levels decreased with age in both GHR− /− and WT mice. Two-dimensional gel electrophoresis proteomes of WAT depots were similar among groups, but several proteins involved in endocytosis and/or cytoskeletal organization (Ehd2, S100A10, actin), anticoagulation (S100A10, annexin A5), and age-related conditions (alpha2-macroglobulin, apolipoprotein A-I, transthyretin) showed significant differences between genotypes. Because Ehd2 may regulate endocytosis of Glut4, we measured Glut4 levels in the WAT depots of GHR− /− and WT mice. Inguinal WAT of 12-month-old GHR− /− mice displayed lower levels of Glut4 than WT. Overall, the protein changes detected in this study offer new insights into possible mechanisms contributing to enhanced insulin sensitivity and extended life span in GHR− /− mice.
doi:10.1093/gerona/glt110
PMCID: PMC3859361  PMID: 23873966
Aging; Growth hormone receptor; Adipose tissue depots; Endocytosis; Glut4.
3.  Selective inner retinal dysfunction in growth hormone transgenic mice 
Objective
The discovery of locally produced growth hormone (GH) and its receptor in the retina of rodents raises the possibility that GH might modulate retinal function. To test this hypothesis, we determined the retinal electroretinogram (ERG) of bovine GH (bGH) transgenic mice.
Design
ERGs were recorded from 11 wild type (WT) and 9 bGH mice, at 2 months of age in response to a series of light flashes at increasing intensity. Three ERG components were assessed for their amplitude and timing: a-wave, b-wave and oscillatory potentials (OPs). OPs were isolated with a 75–300 Hz digital filter. Retina layer sizes, nuclei number and vascularisation were assessed by respectively staining cross sections with DAPI and Bandeiraea simplicifolia.
Results
OPs were selectively affected in the bGH mouse compared to WT. When OP amplitude values were normalized to the a-wave amplitude (to account for inter-animal variability in WT and bGH groups), OP2, OP3, and OP4 showed amplitude reductions (of 65%, 72%, and 68%, respectively) in the bGH mouse compared to the WT. This was accompanied by a prolongation of the implicit time for the peak of OP3 (28.1 vs 31.1 ms, WT vs bGH) and OP4 (37.8 vs 41.6 ms), while the implicit time of a- and b-waves were unaffected. Fast Fourier transform analysis revealed that the OPs’ dominant frequency was significantly reduced (P < 0.05) in the bGH mice (100 Hz) compared to WT (108 Hz). There was no significant change in retinal histology except for a significant increase in the axial length of the eye in bGH mice.
Conclusions
Mice expressing bGH display a selective inner retinal defect as demonstrated using ERG recordings. The specific OP defect observed in these mice is similar to the ERG results obtained in patients with diabetic retinopathy and in related animal models.
doi:10.1016/j.ghir.2011.05.008
PMCID: PMC4151295  PMID: 21705251
growth hormone; retina; electroretinography; growth factors; diabetic retinopathy; retinopathy of prematurity
4.  Growth hormone action predicts age-related white adipose tissue dysfunction and senescent cell burden in mice 
Aging (Albany NY)  2014;6(7):575-586.
The aging process is associated with the development of several chronic diseases. White adipose tissue (WAT) may play a central role in age-related disease onset and progression due to declines in adipogenesis with advancing age. Recent reports indicate that the accumulation of senescent progenitor cells may be involved in age-related WAT dysfunction. Growth hormone (GH) action has profound effects on adiposity and metabolism and is known to influence lifespan. In the present study we tested the hypothesis that GH activity would predict age-related WAT dysfunction and accumulation of senescent cells. We found that long-lived GH-deficient and -resistant mice have reduced age-related lipid redistribution. Primary preadipocytes from GH-resistant mice also were found to have greater differentiation capacity at 20 months of age when compared to controls. GH activity was also found to be positively associated with senescent cell accumulation in WAT. Our results demonstrate an association between GH activity, age-related WAT dysfunction, and WAT senescent cell accumulation in mice. Further studies are needed to determine if GH is directly inducing cellular senescence in WAT or if GH actions on other target organs or alternative downstream alterations in insulin-like growth factor-1, insulin or glucose levels are responsible.
PMCID: PMC4153624  PMID: 25063774
adipose tissue; aging; cellular senescence; growth hormone
5.  The GH/IGF-1 axis in ageing and longevity 
Nature reviews. Endocrinology  2013;9(6):366-376.
Secretion of growth hormone (GH), and consequently that of insulin-like growth factor 1 (IGF-1), declines over time until only low levels can be detected in individuals aged ≥60 years. This phenomenon, which is known as the ‘somatopause’, has led to recombinant human GH being widely promoted and abused as an antiageing drug, despite lack of evidence of efficacy. By contrast, several mutations that decrease the tone of the GH/IGF-1 axis are associated with extended longevity in mice. In humans, corresponding or similar mutations have been identified, but whether these mutations alter longevity has yet to be established. The powerful effect of reduced GH activity on lifespan extension in mice has generated the hypothesis that pharmaceutically inhibiting, rather than increasing, GH action might delay ageing. Moreover, mice as well as humans with reduced activity of the GH/IGF-1 axis are protected from cancer and diabetes mellitus, two major ageing-related morbidities. Here, we review data on mouse strains with alterations in the GH/IGF-1 axis and their effects on lifespan. The outcome of corresponding or similar mutations in humans is described, as well as the potential mechanisms underlying increased longevity and the therapeutic benefits and risks of medical disruption of the GH/IGF-1 axis in humans.
doi:10.1038/nrendo.2013.67
PMCID: PMC4074016  PMID: 23591370
6.  Decreased insulin sensitivity and increased oxidative damage in wasting adipose tissue depots of wild-type mice 
Age  2011;34(5):1225-1237.
Unintentional weight loss (wasting) in the elderly is a major health concern as it leads to increased mortality. Several studies have focused on muscle loss, but little is known about the mechanisms giving rise to loss of fat mass at old ages. To investigate potential mechanisms, white adipose tissue (WAT) characteristics and proteomic profiles were compared between adult (10–12-month-old) and aged (22–24-month-old) wild-type mice. Four individual WAT depots were analyzed to account for possible depot-specific differences. Proteomic profiles of WAT depots, along with body weights and compositions, plasma levels of insulin, leptin and adiponectin, insulin tolerance, adipocyte sizes, and products of oxidative damage in each WAT depot were determined. We found that lean mass remained constant while fat mass and insulin tolerance were decreased in old age, as were adipocyte sizes in the WAT depots. Proteomic results showed increased levels of enolase, pyruvate dehydrogenase E1β, NAD+−dependent isocitrate dehydrogenase α, and ATP synthase subunit β, and decreased levels of carbonic anhydrase 3 in WAT of aged mice. These data suggest increased aerobic glucose oxidation in wasting WAT, consistent with decreased insulin signaling. Also, Cu/Zn superoxide dismutase and two chaperones were increased in aged WAT depots, indicating higher stress resistance. In agreement, lipid peroxidation (HNE-His adducts) increased in old age, although protein oxidation (carbonyl groups) showed no increase. In conclusion, features of wasting WAT were similar in the four depots, including decreased adipocyte sizes and alterations in protein expression profiles that indicated decreased insulin sensitivity and increased lipid peroxidation.
Electronic supplementary material
The online version of this article (doi:10.1007/s11357-011-9304-7) contains supplementary material, which is available to authorized users.
doi:10.1007/s11357-011-9304-7
PMCID: PMC3448990  PMID: 21953241
Wasting; Aging; White adipose tissue depots; Proteomics; Oxidative damage; Stress resistance; Insulin resistance
8.  Adiponectin in mice with altered growth hormone action: links to insulin sensitivity and longevity? 
The Journal of endocrinology  2013;216(3):363-374.
Adiponectin is positively correlated with longevity and negatively correlated with many obesity-related diseases. While there are several circulating forms of adiponectin, the high molecular weight (HMW) version has been suggested to have the predominant bioactivity. Adiponectin gene expression and cognate serum protein levels are of particular interest in mice with altered growth hormone (GH) signaling as these mice exhibit extremes in obesity that are positively associated with insulin sensitivity and lifespan as opposed to the typical negative association of these factors. While a few studies have reported total adiponectin levels in young adult mice with altered GH signaling, much remains unresolved, including changes in adiponectin levels with advancing age, proportion of total adiponectin in the HMW form, adipose depot of origin, and differential effects of GH versus IGF1. Therefore, the purpose of this study was to address these issues using assorted mouse lines with altered GH signaling. Our results show that adiponectin is generally negatively associated with GH activity, regardless of age. Further, the amount of HMW adiponectin is consistently linked with the level of total adiponectin and not necessarily with previously reported lifespan or insulin sensitivity of these mice. Interestingly, circulating adiponectin levels correlated strongly with inguinal fat mass, implying the effects of GH on adiponectin are depot-specific. Interestingly rbGH, but not IGF1, decreased circulating total and HMW adiponectin levels. Taken together, these results fill important gaps in the literature related to GH and adiponectin and question the frequently reported associations of total and HMW adiponectin with insulin sensitivity and longevity.
doi:10.1530/JOE-12-0505
PMCID: PMC3756886  PMID: 23261955
adiponectin; high molecular weight adiponectin; growth hormone receptor; growth hormone; growth hormone deficiency; growth hormone antagonist
9.  Growth hormone and adipose tissue: beyond the adipocyte 
The last two decades have seen resurgence in the interest in, and research on, adipose tissue. In part, the increased interest stems from an alarming increase in obesity rates worldwide. However, an understanding that this once simple tissue is significantly more intricate and interactive than previously realized has fostered additional attention. While few would argue that growth hormone (GH) radically alters adipose tissue, a better appreciation of the newer complexities requires that GH's influence on this tissue be reexamined. Therefore, the objective of this review is to describe the more recent understanding of adipose tissue and how GH may influence and contribute to these newer complexities with special focus on the available data from mice with altered GH action.
doi:10.1016/j.ghir.2011.03.002
PMCID: PMC3112270  PMID: 21470887
growth hormone; body composition; obesity; aging; adipose tissue; gender and age differences
10.  Proteomic Changes in the Heart of Diet-Induced Pre-Diabetic Mice 
Journal of proteomics  2011;74(5):716-727.
The development of type 2 diabetes (T2D) is strongly associated with obesity. In humans, T2D increases the risk for end organ complications. Among these, heart disease has been ranked as the leading cause of death. We used a proteomic methodology to test the hypothesis that a pre-diabetic state generated by high-fat diet leads to changes in proteins related to heart function and structure. Over 300 proteins spots were resolved by 2-DE. Fifteen protein spots were found to be altered (7 decreased and 8 increased) in pre-diabetic hearts. The protein spots were then identified by mass spectrometry and immunoblots. Among the decreased proteins, 3 are involved in heart structure (one isoform of desmin, troponin T2 and α-cardiac actin), 3 are involved in energy metabolism (mitochondrial ATP synthase β subunit, adenylate kinase and creatine kinase) and one is a component of the citric acid cycle (isocitrate dehydrogenase 3). In contrast, proteins involved in fatty acid oxidation (two isoforms of peroxisomal enoyl-CoA hydratase) and the citric acid cycle (three isoforms of malate dehydrogenase) were increased in pre-diabetic hearts. The results suggest that changes in the levels of several heart proteins may have implications in the development of the cardiac phenotype associated to T2D.
doi:10.1016/j.jprot.2011.02.018
PMCID: PMC3081671  PMID: 21354350
Type 2 diabetes; obesity; murine models of obesity-type 2 diabetes; heart proteome; heart dysfunction
11.  Plasma Protein Biomarkers Correlated with the Development of Diet-Induced Type 2 Diabetes in Mice 
Clinical proteomics  2010;6(1-2):6-17.
Introduction
Early detection, assessment of disease progression, and application of an appropriate therapeutic intervention are all important for the care of patients with type 2 diabetes. Currently, however, there is no simple test for early detection of type 2 diabetes. Established diagnostic tests for the disease including oral glucose tolerance, fasting blood glucose, and hemoglobin A1c are relatively late markers where the disease has already progressed. Since blood is in direct contact with many tissues, we hypothesized that pathological tissue changes are likely to be reflected in proteomic profiles of plasma.
Methods
Mice were reared either on regular chow or a high-fat diet at weaning and several physiological responses (i.e., weight, fasting plasma glucose and insulin, and glucose tolerance) were monitored at regular time intervals. Plasma was collected at regular intervals for proteomic analysis by two-dimensional gel electrophoresis and subsequent mass spectrometry.
Results
Onset of hyperinsulinemia with corresponding glucose intolerance was observed in 2 weeks and fasting blood glucose levels rose significantly after 4 weeks on the high-fat diet. Many proteins were found to exist in multiple forms (isoforms). Levels of some isoforms including plasma retinol binding protein, transthyretin, Apolipoprotein A1, and kininogen showed significant changes as early as 4 weeks which coincided with the very early development of glucose intolerance.
Conclusions
These results show that a proteomic approach to study the development of type 2 diabetes may uncover unknown early post-translationally modified diagnostic and/or therapeutic protein targets.
doi:10.1007/s12014-009-9040-5
PMCID: PMC2899708  PMID: 20625478
Diabetes; Biomarkers; Mice; Protein isoforms; Two-dimensional gel electrophoresis; Plasma
12.  Two-Year Body Composition Analyses of Long-Lived GHR Null Mice 
Growth hormone receptor gene–disrupted (GHR−/−) mice exhibit increased life span and adipose tissue mass. Although this obese phenotype has been reported extensively for young adult male GHR−/− mice, data for females and for other ages in either gender are lacking. Thus, the purpose of this study was to evaluate body composition longitudinally in both male and female GHR−/− mice. Results show that GHR−/− mice have a greater percent fat mass with no significant difference in absolute fat mass throughout life. Lean mass shows an opposite trend with percent lean mass not significantly different between genotypes but absolute mass reduced in GHR−/− mice. Differences in body composition are more pronounced in male than in female mice, and both genders of GHR−/− mice show specific enlargement of the subcutaneous adipose depot. Along with previously published data, these results suggest a consistent and intriguing protective effect of excess fat mass in the subcutaneous region.
doi:10.1093/gerona/glp175
PMCID: PMC2796884  PMID: 19901018
Body composition; Growth hormone; Obesity; Adipose depots; Gender differences
13.  Perspective: Proteomic approach to detect biomarkers of human growth hormone 
Several serum biomarkers for recombinant human growth hormone (rhGH) have been established, however, none alone or in combination have generate a specific, sensitive, and reproducible ‘kit’ for the detection of rhGH abuse. Thus, the search for additional GH specific biomarkers continues. In this review, we focus on the use of proteomics in general and 2-dimensional electrophoresis (2-DE) in particular for the discovery of new GH induced serum biomarkers. Also, we review some of the protocols involved in 2DE. Finally, the possibility of tissues other than blood for biomarker discovery is discussed.
doi:10.1016/j.ghir.2009.04.018
PMCID: PMC2760539  PMID: 19501004
proteomics; two-dimensional gel electrophoresis; growth hormone; doping; biomarker; blood; urine; skin
14.  Reduced Incidence and Delayed Occurrence of Fatal Neoplastic Diseases in Growth Hormone Receptor/Binding Protein Knockout Mice 
Although studies of Ames and Snell dwarf mice have suggested possible important roles of the growth hormone (GH)/insulin-like growth factor-1 (IGF-1) axis in aging and age-related diseases, the results cannot rule out the possibility of other hormonal changes playing an important role in the life extension exhibited by these dwarf mice. Therefore, growth hormone receptor/binding protein (GHR/BP) knockout (KO) mice would be valuable animals to directly assess the roles of somatotropic axis in aging and age-related diseases because the primary hormonal change is due to GH/IGF-1 deficiency. Our pathological findings showed GHR/BP KO mice to have a lower incidence and delayed occurrence of fatal neoplastic lesions compared with their wild-type littermates. These changes of fatal neoplasms are similar to the effects observed with calorie restriction and therefore could possibly be a major contributing factor to the extended life span observed in the GHR/BP KO mice.
doi:10.1093/gerona/glp017
PMCID: PMC2667132  PMID: 19228785
Growth hormone receptor/binding protein; Knockout mouse; Neoplastic disease; Aging
15.  CIDE-A is expressed in liver of old mice and in type 2 diabetic mouse liver exhibiting steatosis 
Background
Increased levels of circulating fatty acids caused by insulin resistance and increased adipocyte lipolysis can accumulate within the liver resulting in steatosis. This steatosis sensitizes the liver to inflammation and further injury which can lead to liver dysfunction. We performed microarray analysis on normal mouse liver tissue at different ages and type 2 diabetic liver exhibiting steatosis to identify differentially expressed genes involved in lipid accumulation and liver dysfunction.
Results
Microarray analysis identified CIDE-A as the most differentially expressed gene as a function of age. Mice fed a high fat diet developed hyperinsulinemia, hyperglycemia and liver steatosis, all features of the human metabolic syndrome. Increased CIDE-A expression was observed in type 2 diabetic liver and the elevated CIDE-A expression could be reversed by weight loss and normalization of plasma insulin. Also, CIDE-A expression was found to be correlated with hepatic lipid accumulation.
Conclusion
The corresponding increase in CIDE-A expression with hyperinsulinemia and liver steatosis suggests a novel pathway for lipid accumulation in the liver.
doi:10.1186/1476-5926-6-4
PMCID: PMC1868770  PMID: 17472743

Results 1-15 (15)