IGF‐I regulates the age‐dependent signaling peptide humanin

Aging is influenced by endocrine pathways including the growth hormone/insulin‐like growth factor‐1 (GH/IGF) axis. Mitochondrial function has also been linked to the aging process, but the relevant mitochondrial signals mediating the effects of mitochondria are poorly understood. Humanin is a novel signaling peptide that acts as a potent regulator of cellular stress responses and protects from a variety of in vitro and in vivo toxic and metabolic insults. The circulating levels of humanin decline with age in mice and humans. Here, we demonstrate a negative correlation between the activity of the GH‐IGF axis and the levels of humanin, as well as a positive correlation between humanin and lifespan in mouse models with altered GH/IGF‐I axis. Long‐lived, GH‐deficient Ames mice displayed elevated humanin levels, while short‐lived GH‐transgenic mice have reduced humanin levels. Furthermore, treatment with GH or IGF‐I reduced circulating humanin levels in both mice and human subjects. Our results indicate that GH and IGF are potent regulators of humanin levels and that humanin levels correlate with lifespan in mice. This suggests that humanin represents a circulating mitochondrial signal that participates in modulating the aging process, adding a coordinated mitochondrial element to the endocrine regulation of aging.     

Reductions in serum IGF‐1 during aging impair health span

In lower or simple species, such as worms and flies, disruption of the insulin‐like growth factor (IGF)‐1 and the insulin signaling pathways has been shown to increase lifespan. In rodents, however, growth hormone (GH) regulates IGF‐1 levels in serum and tissues and can modulate lifespan via/or independent of IGF‐1. Rodent models, where the GH/IGF‐1 axis was ablated congenitally, show increased lifespan. However, in contrast to rodents where serum IGF‐1 levels are high throughout life, in humans, serum IGF‐1 peaks during puberty and declines thereafter during aging. Thus, animal models with congenital disruption of the GH/IGF‐1 axis are unable to clearly distinguish between developmental and age‐related effects of GH/IGF‐1 on health. To overcome this caveat, we developed an inducible liver IGF‐1‐deficient (iLID) mouse that allows temporal control of serum IGF‐1. Deletion of liver Igf ‐1 gene at one year of age reduced serum IGF‐1 by 70% and dramatically impaired health span of the iLID mice. Reductions in serum IGF‐1 were coupled with increased GH levels and increased basal STAT5B phosphorylation in livers of iLID mice. These changes were associated with increased liver weight, increased liver inflammation, increased oxidative stress in liver and muscle, and increased incidence of hepatic tumors. Lastly, despite elevations in serum GH, low levels of serum IGF‐1 from 1 year of age compromised skeletal integrity and accelerated bone loss. We conclude that an intact GH/IGF‐1 axis is essential to maintain health span and that elevated GH, even late in life, associates with increased pathology.     

Growth factors and glucose homeostasis in diabetic rats: effects of exercise training

To investigate the alterations of glucose homeostasis and variables of the insulin‐like growth factor‐1 (IGF‐1) growth system in sedentary and trained diabetic (TD) rats, Wistar rats were divided into sedentary control (SC), trained control (TC), sedentary diabetic (SD), and TD groups. Diabetes was induced by Alloxan (35 mg kg^?1 b.w.). Training program consisted of swimming 5 days week^?1, 1 h day^?1, during 8 weeks. Rats were sacrificed and blood was collected for determinations of serum glucose, insulin, growth hormone (GH), IGF‐1, and IGF binding protein‐3 (IGFBP‐3). Muscle and liver were removed to evaluate glycogen content. Cerebellum was extracted to determinate IGF‐1 content. Diabetes decreased serum GH, IGF‐1, IGFBP‐3, liver glycogen, and cerebellum IGF‐1 peptide content in baseline condition. Physical training recovered liver glycogen and increased serum and cerebellum IGF‐1 peptide in diabetic rats. Physical training induces important metabolic and hormonal alterations that are associated with an improvement in glucose homeostasis and serum and cerebellum IGF‐1 concentrations. Copyright © 2009 John Wiley & Sons, Ltd.     

Vertebral Bone Marrow Fat Is Positively Associated With Visceral Fat and Inversely Associated With IGF‐1 in Obese Women

Recent studies have demonstrated an important physiologic link between bone and fat. Bone and fat cells arise from the same mesenchymal precursor cell within bone marrow, capable of differentiation into adipocytes or osteoblasts. Increased BMI appears to protect against osteoporosis. However, recent studies have suggested detrimental effects of visceral fat on bone health. Increased visceral fat may also be associated with decreased growth hormone (GH) and insulin‐like growth factor 1 (IGF‐1) levels which are important for maintenance of bone homeostasis. The purpose of our study was to assess the relationship between vertebral bone marrow fat and trabecular bone mineral density (BMD), abdominal fat depots, GH and IGF‐1 in premenopausal women with obesity. We studied 47 premenopausal women of various BMI (range: 18–41 kg/m², mean 30 ± 7 kg/m²) who underwent vertebral bone marrow fat measurement with proton magnetic resonance spectroscopy (1H‐MRS), body composition, and trabecular BMD measurement with computed tomography (CT), and GH and IGF‐1 levels. Women with high visceral fat had higher bone marrow fat than women with low visceral fat. There was a positive correlation between bone marrow fat and visceral fat, independent of BMD. There was an inverse association between vertebral bone marrow fat and trabecular BMD. Vertebral bone marrow fat was also inversely associated with IGF‐1, independent of visceral fat. Our study showed that vertebral bone marrow fat is positively associated with visceral fat and inversely associated with IGF‐1 and BMD. This suggests that the detrimental effect of visceral fat on bone health may be mediated in part by IGF‐1 as an important regulator of the fat and bone lineage.     

Alterations in the growth hormone-insulin-like growth factor axis in insulin dependent diabetes mellitus.

The growth hormone (GH)-insulin-like growth factor (IGF) axis and insulin are major anabolic effectors in promoting weight gain and linear growth. These two anabolic systems are interlinked at many levels, thus abnormalities in one of these systems effect the other causing disordered metabolic homeostasis. Insufficient portal insulinization in insulin dependent diabetes mellitus (IDDM) results in hepatic GH resistance and increased production of IGF-binding proteins-1 (IGFBP-1) and IGFBP-2. GH resistance is reflected by decreased hepatic IGF-I production. In addition, changes in other GH-dependent proteins are also observed in IDDM. Increased proteolysis of IGFBP-3 results in reduction of intact IGFBP-3. Serum ALS levels are also slightly diminished in untreated diabetic patients. Hepatic resistance to GH is, at least in part, caused by diminished GH receptors as reflected by diminished circulating GHBP levels. In addition, there is also evidence from experimental and human studies suggesting post-receptor defect(s) in GH action. As a result of these changes, circulating total and free IGF-I levels are decreased during insulinopenia. Lack of negative feed-back effect of IGF-I on GH secretion causes GH hypersecretion which increases hyperglycemia by decreasing sensitivity to insulin. GH hypersecretion in poorly controlled diabetic patients may play a role in the pathogenesis of diabetic vascular complications. Most of these abnormalities in the GH-IGF axis in diabetes are reversed by effective insulinization of the patient. Addition of IGF-I treatment to insulin in adolescents with IDDM allows correction of GH hypersecretion, improves insulin sensitivity and glycemic control, and decreases insulin requirements. The effect of IGF-I treatment on diabetic complications has yet to be seen.     

Long‐lived hypopituitary Ames dwarf mice are resistant to the detrimental effects of high‐fat diet on metabolic function and energy expenditure

Growth hormone (GH) signaling stimulates the production of IGF‐1; however, increased GH signaling may induce insulin resistance and can reduce life expectancy in both mice and humans. Interestingly, disruption of GH signaling by reducing plasma GH levels significantly improves health span and extends lifespan in mice, as observed in Ames dwarf mice. In addition, these mice have increased adiposity, yet are more insulin sensitive compared to control mice. Metabolic stressors such as high‐fat diet (HFD) promote obesity and may alter longevity through the GH signaling pathway. Therefore, our objective was to investigate the effects of a HFD (metabolic stressor) on genetic mechanisms that regulate metabolism during aging. We show that Ames dwarf mice fed HFD for 12 weeks had an increase in subcutaneous and visceral adiposity as a result of diet‐induced obesity, yet are more insulin sensitive and have higher levels of adiponectin compared to control mice fed HFD. Furthermore, energy expenditure was higher in Ames dwarf mice fed HFD than in control mice fed HFD. Additionally, we show that transplant of epididymal white adipose tissue (eWAT) from Ames dwarf mice fed HFD into control mice fed HFD improves their insulin sensitivity. We conclude that Ames dwarf mice are resistant to the detrimental metabolic effects of HFD and that visceral adipose tissue of Ames dwarf mice improves insulin sensitivity in control mice fed HFD.     

No Decrease in Free IGF‐I with Increasing Insulin in Obesity‐Related Insulin Resistance

Objective: Different facts suggest that the insulin growth factor (IGF)/ insulin growth factor‐binding protein (IGFBP) system may be regulated by factors other than growth hormone. It has been proposed that, in healthy subjects, free IGF‐I plays a role in glucose metabolism. The role of free IGF‐I in glucose homeostasis in insulin resistance is poorly understood. This study was undertaken to evaluate the effects of acute changes in plasma glucose and insulin levels on free IGF‐I and IGFBP‐1 in obese and non‐obese subjects. Research Methods and Procedures: Nineteen lean and 24 obese subjects were investigated. A frequently sampled intravenous glucose tolerance test was performed. Free IGF‐I and IGFBP‐1 were determined at 0, 19, 22, 50, 100, and 180 minutes. Results: Basal free IGF‐I levels tended to be higher and IGFBP‐1 lower in obese than in lean subjects. IGFBP‐1 levels inversely correlated with basal insulin concentration. To determine the effects of insulin on the availability of free IGF‐I and IGFBP‐1, changes in their plasma concentrations were measured during a frequently sampled intravenous glucose tolerance test. After insulin administration, a significant suppression of free IGF‐I at 22% was observed in lean subjects. In contrast, plasma‐free IGF‐I levels remained essentially unchanged in the obese group. The differences between both groups were statistically significant at 100 minutes (p < 0.01) and 180 minutes (p < 0.05). Serum IGFBP‐1 was suppressed to a similar extent in both groups. Discussion: These data suggest that the concentrations of free IGF‐I and IGFBP‐1 are differentially regulated by obesity. Obesity‐related insulin resistance leads to unsuppressed free IGF‐I levels.     

Growth hormone and gene expression of in vitro‐matured rhesus macaque oocytes

Growth hormone (GH) in rhesus macaque in vitro oocyte maturation (IVM) has been shown to increase cumulus expansion and development of embryos to the 9–16 cell stage in response to 100 ng/ml recombinant human GH (r‐hGH) supplementation during IVM. Although developmental endpoints for metaphase II (MII) oocytes and embryos are limited in the macaque, gene expression analysis can provide a mechanism to explore GH action on IVM. In addition, gene expression analysis may allow molecular events associated with improved cytoplasmic maturation to be detected. In this study, gene expression of specific mRNAs in MII oocytes and cumulus cells that have or have not been exposed to r‐hGH during IVM was compared. In addition, mRNA expression was compared between in vitro and in vivo‐matured metaphase II (MII) oocytes and germinal vesicle (GV)‐stage oocytes. Only 2 of 17 genes, insulin‐like growth factor 2 (IGF2) and steroidogenic acute regulator (STAR), showed increased mRNA expression in MII oocytes from the 100 ng/ml r‐hGH treatment group compared with other IVM treatment groups, implicating insulin‐like growth factor (IGF) and steroidogenesis pathways in the oocyte response to GH. The importance of IGF2 is notable, as expression of IGF1 was not detected in macaque GV‐stage or MII oocytes or cumulus cells. Mol. Reprod. Dev. 77: 353–362, 2010. © 2009 Wiley‐Liss, Inc.     

Asprosin,a novel pleiotropic adipokine implicated in fasting and obesity-related cardio-metabolic disease: Comprehensive review of preclinical and clinical evidence

White adipose tissue is a dynamic endocrine organ that releases an array of adipokines, which play a key role in regulating metabolic homeostasis and multiple other physiological processes. An altered adipokine secretion profile from adipose tissue depots frequently characterizes obesity and related cardio-metabolic diseases. Asprosin is a recently discovered adipokine that is released in response to fasting. Following secretion, asprosin acts - via an olfactory G-protein coupled receptor and potentially via other unknown receptor(s) - on hepatocytes and agouti-related peptide-expressing neurons in the central nervous system to stimulate glucose secretion and promote appetite, respectively. A growing body of both in vitro and in vivo studies have shown asprosin to exert a number of effects on different metabolic tissues. Indeed, asprosin can attenuate insulin signalling and promote insulin resistance in skeletal muscle by increasing inflammation and endoplasmic reticulum stress. Interestingly, asprosin may also play a protective role in cardiomyocytes that are exposed to hypoxic conditions. Moreover, clinical studies have reported elevated circulating asprosin levels in obesity, type 2 diabetes and other obesity-related cardio-metabolic diseases, with significant associations to clinically relevant parameters. Understanding the spectrum of the effects of this novel adipokine is essential in order to determine its physiologic role and its significance as a potential therapeutic target and/or a biomarker of cardio-metabolic disease. The present review offers a comprehensive overview of the published literature on asprosin, including both clinical and preclinical studies, focusing on its role in metabolism and cardio-metabolic disease.     

Growth hormone secretagogues in critical illness

Alterations within the somatotropic axis occurring during the course of critical illness follow a biphasic pattern. The initial stress response consists of activated growth hormone (GH) release whereas circulating levels of GH-dependent insulin-like growth factor (IGF)-I and IGF binding protein (IGFBP)-3 fall and IGFBP-1 concentrations rise. In contrast, in the chronic intensive care-dependent phase of severe illness, pulsatile GH secretion substantially decreases whereas the non-pulsatile fraction remains relatively elevated, resulting in an abnormally flat GH secretory pattern and low-normal mean nocturnal GH serum concentrations. Specifically the reduced amount of GH released in pulses is found to be related to low circulating levels of IGF-I, IGFBP-3 and acid-labile subunit (ALS), which suggests that a relative hyposomatotropism may participate in the pathogenesis of the wasting syndrome distinctively in the chronic phase of critical illness. The relative hyposomatotropism seems at least in part of hypothalamic origin since the whole somatotropic axis has been found to be very responsive to continuous infusion of GH releasing peptide (GHRP), administered alone or in combination with GH releasing hormone (GHRH), as evidenced by reactivated pulsatile GH secretion followed by substantial increases in circulating levels of IGF-I, IGFBP-3 and ALS. GHRH alone, however, is unable to exert the same effect, which may point to an underlying reduced availability of the endogenous ligand for the GHRP receptor. The presence of considerable responsiveness to restored endogenous pulsatile GH secretion using GHRPs not only further delineates the distinct pathophysiological paradigm of the chronic phase of critical illness, as opposed to the acute phase, which is thought to be primarily a condition of GH resistance, but may also have important therapeutic consequences. Recent data revealed that this novel strategy evokes metabolic improvement related to the balanced endocrine responses. Whether GH secretagogues also enhance clinical recovery of protracted critically ill patients remains to be elucidated.     

Expression profiles of growth-related genes in two Nile tilapia strains and their crossbred provide insights into introgressive breeding effects

The Nile tilapia (Oreochromis niloticus) is a prominent farmed fish in aquaculture worldwide. Crossbreeding has recently been carried out between the Red-Stirling and the wt Chitralada strains of Nile tilapia, producing a heterotic hybrid (7/8 Chitralada and 1/8 Red-Stirling) that combines the superior growth performance of the Chitralada with the reddish coloration of the Red-Stirling strain. While classical selective breeding and crossbreeding strategies are well known, the molecular mechanisms underlying the phenotypic expression of economically advantageous traits in tilapia remain largely unknown. Molecular investigations have shown that variable expression of growth hormone (gh), insulin-like growth factors (igf1 and 2) and somatolactin (smtla) – components of the growth hormone/insulin-like growth factor (GH/IGF) axis – and myostatin (mstn) genes can affect traits of economic relevance in farmed animals. The aim of this study was to assess and compare the gene expression signature among Chitralada, Red-Stirling and their backcross hybrid in order to gain insights into the effects of introgressive breeding in modulation of the GH/IGF axis. Gene expression analyses in distinct tissues showed that most genes of the GH/IGF axis were up-regulated and mstn was down-regulated in backcross animals in comparison with Red-Stirling and Chitralada animals. These gene expression profiles revealed that backcross animals displayed a distinctive expression signature, which attests to the effectiveness of the introgressive breeding technique. Our findings also suggest that the GH/IGF axis and mstn genes might be candidate markers for fish performance and prove useful within genetic improvement programs aimed at the production of superior-quality tilapia strains using introgressive breeding.     

Influences of the environment on the endocrine and paracrine fish growth hormone–insulin‐like growth factor‐I system

Insulin‐like growth factor‐I (IGF‐I) is a key component of the complex system that regulates differentiation, development, growth and reproduction of fishes. The IGF‐I gene is mainly expressed in the liver that represents the principal source of endocrine IGF‐I but also in numerous other organs where the hormone most probably acts in an autocrine–paracrine manner. The primary stimulus for synthesis and release of IGF‐I is growth hormone (GH) from the anterior pituitary. Thus, in analogy to mammals, it is usual to speak of a fish ‘GH–IGF‐I axis'. The GH–IGF‐I system is affected by changes in the environment and probably represents a target of endocrine disrupting compounds (EDC) that impair many physiological processes in fishes. Thus, the review deals with the influences of changes in different environmental factors, such as food availability, temperature, photoperiod, season, salinity and EDCs, on GH gene expression in pituitary, IGF‐I gene expression in liver and extrahepatic sites and the physiological effects resulting from the evoked alterations in endocrine and local IGF‐I. Environmental influences certainly interact with each other but for convenience of the reader they will be dealt with in separate sections. Current trends in GH–IGF‐I research are analysed and future focuses are suggested at the end of the sections.     

Growth hormone secretion is diminished and tightly controlled in humans enriched for familial longevity

Reduced growth hormone (GH) signaling has been consistently associated with increased health and lifespan in various mouse models. Here, we assessed GH secretion and its control in relation with human familial longevity. We frequently sampled blood over 24 h in 19 middle‐aged offspring of long‐living families from the Leiden Longevity Study together with 18 of their partners as controls. Circulating GH concentrations were measured every 10 min and insulin‐like growth factor 1 (IGF‐1) and insulin‐like growth factor binding protein 3 (IGFBP3) every 4 h. Using deconvolution analysis, we found that 24‐h total GH secretion was 28% lower (P = 0.04) in offspring [172 (128–216) mU L^?1] compared with controls [238 (193–284) mU L^?1]. We used approximate entropy (ApEn) to quantify the strength of feedback/feedforward control of GH secretion. ApEn was lower (P = 0.001) in offspring [0.45 (0.39–0.53)] compared with controls [0.66 (0.56–0.77)], indicating tighter control of GH secretion. No significant differences were observed in circulating levels of IGF‐1 and IGFBP3 between offspring and controls. In conclusion, GH secretion in human familial longevity is characterized by diminished secretion rate and more tight control. These data imply that the highly conserved GH signaling pathway, which has been linked to longevity in animal models, is also associated with human longevity.     

In Vitro Metabolic and Mitogenic Signaling of Insulin Glargine and Its Metabolites

Background

Insulin glargine (Lantus®) is a long-acting basal insulin analog that demonstrates effective day-long glycemic control and a lower incidence of hypoglycemia than NPH insulin. After subcutaneous injection insulin glargine is partly converted into the two main metabolites M1 ([Gly^A21]insulin) and M2 ([Gly^A21,des-Thr^B30]insulin). The aim of this study was to characterize the glargine metabolites in vitro with regard to their insulin receptor (IR) and IGF-1 receptor (IGF1R) binding and signaling properties as well as their metabolic and mitogenic activities.

Methods

The affinity of human insulin, insulin glargine and its metabolites to the IR isoforms A and B or IGF1R was analyzed in a competitive binding assay using SPA technology. Receptor autophosphorylation activities were studied via In-Cell Western in CHO and MEF cells overexpressing human IR-A and IR-B or IGF1R, respectively. The metabolic response of the insulins was studied as stimulation of lipid synthesis using primary rat adipocytes. Thymidine incorporation in Saos-2 cells was used to characterize the mitogenic activity.

Conclusions

The binding of insulin glargine and its metabolites M1 and M2 to the IR were similar and correlated well with their corresponding autophosphorylation and metabolic activities in vitro. No differences were found towards the two IR isoforms A or B. Insulin glargine showed a higher affinity for IGF1R than insulin, resulting in a lower EC₅₀ value for autophosphorylation of the receptor and a more potent stimulation of thymidine incorporation in Saos-2 cells. In contrast, the metabolites M1 and M2 were significantly less active in binding to and activation of the IGF1R and their mitogenicity in Saos-2 cells was equal to human insulin. These findings strongly support the idea that insulin glargine metabolites contribute with the same potency as insulin glargine to blood glucose control but lead to significantly reduced growth-promoting activity.     

Central insulin‐like growth factor‐1 (IGF‐1) restores whole‐body insulin action in a model of age‐related insulin resistance and IGF‐1 decline

Low insulin‐like growth factor‐1 (IGF‐1) signaling is associated with improved longevity, but is paradoxically linked with several age‐related diseases in humans. Insulin‐like growth factor‐1 has proven to be particularly beneficial to the brain, where it confers protection against features of neuronal and cognitive decline. While aging is characterized by central insulin resistance in the face of hyperinsulinemia, the somatotropic axis markedly declines in older humans. Thus, we hypothesized that increasing IGF‐1 in the brain may prove to be a novel therapeutic alternative to overcome central insulin resistance and restore whole‐body insulin action in aging. Utilizing hyperinsulinemic‐euglycemic clamps, we show that old insulin‐resistant rats with age‐related declines in IGF‐1 level demonstrate markedly improved whole‐body insulin action, when treated with central IGF‐1, as compared to central vehicle or insulin (P < 0.05). Furthermore, central IGF‐1, but not insulin, suppressed hepatic glucose production and increased glucose disposal rates in aging rats (P < 0.05). Taken together, IGF‐1 action in the brain and periphery provides a ‘balance’ between its beneficial and detrimental actions. Therefore, we propose that strategies aimed at ‘tipping the balance’ of IGF‐1 action centrally are the optimal approach to achieve healthy aging and longevity in humans.     

From white to beige: a new hypothalamic pathway

Understanding how brown and beige adipocytes can be differentially controlled and activated by neuronal circuits is a fundamental prerequisite to fully comprehend the metabolic role that fat tissue plays in energy homeostasis. In this issue of EMBO reports, Wang et al 1 identify a new hypothalamic route that drives the exclusive recruitment of beige fat via the selective control of sympathetic nervous system (SNS) outflow to subcutaneous white adipose tissue. Since the data strongly suggest that the APPL2–AMPK signaling axis is crucial for this activation, this finding sheds a new light on the cross talk between peripheral homeostatic signals and neurons that are part of hypothalamic energy homeostasis regulatory pathways in the ventromedial hypothalamus (VHM) proposing a new defending mechanism to cold and obesity.