Saturday, July 3, 2010

Ghrelin Builds Bone Length?

Ghrelin has long been though of as a negative chemical responsible for hunger(and thereby fat gain).  However, Ghrelin could be a key chemical in regards to building bone length.

Ghrelin, another factor affecting bone metabolism. 

"Ghrelin is a 28 amino acid peptide, identified in the stomach of rats and humans, in 1999. It is an endogenous ligand of the growth hormone secretagogue receptor (GHS-R) that strongly stimulates release of growth hormone at the hypothalamus-pituitary axis. In humans, ghrelin exerts a variety of different endocrine and paracrine actions; from increasing food intake (orexigenic effect) to modulating energy homeostasis. It has been proved that ghrelin affects bone metabolism acting by an autocrine/paracrine mode, independent of GH/IGF-1 axis. Recently, ghrelin was identified in osteoblasts, stimulating proliferation and inhibiting apoptosis. Its expression also was confirmed in rat and human cartilage, being prevalently localized in the proliferative and maturative zone of the epiphyseal growth plate (which further supports the hypothesis of ghrelin's action as a growth factor for chondrocytes). Ghrelin also inhibits prostaglandin and/or leukotriene synthesis. Ghrelin promotes osteogenesis of intramembranous bone and improves the repair of calvarial bone defect in rats in vivo.." 

Ghrelin is actually a chemical that can be modulated.  Any activity that makes you hungry increases Ghrelin levels and any activity that makes you satiated decreases Ghrelin levels. Ghrelin being located in the proliferative zone of the epiphyseal growth plate means it very likely has height increasing effects.  Other Ghrelin effects related to chondrocytes are promotin cAMP accumulation(along with sulfated proteoglycan & hyaluronate synthesis), regulating chondrocyte metabolism(increases proteoglycan synthesis and programmed cell death), upregulates chondroitin sulfate type IV(LSJL also upregulates chondroitin sulfate type IV), and decreases fatty acid uptake by chondrocytes.

The study mentions that the stomach and duodenum are the most significant Ghrelin producers.  GH increases calcium balance by influencing calcium absorption by the gut maybe this plays a role in GH height increase effects.

Factors that Increase Serum Ca2+:
*Vitamin D
* GH

Factors that Decrease Serum Ca2+:
* Calcitonin
* Corticosteroids

According to Role of various cytokines and growth factors in pubertal development, Ghrelin and Leptin play a role in pubertal onset and progression.

The effect of exercise intensity on plasma and tissue acyl ghrelin concentrations in fasted rats. 

"This study was conducted to investigate the effect of exercise training and feeding status on plasma and tissue acyl ghrelin concentrations. 
Thirty-two, eight-week-old male Wistar rats (185+/-5g) were randomly assigned to one of four groups: high intensity (HI: 34m/min approximately 80-85% VO(2)max), moderate intensity (MI: 28m/min approximately 70-75% VO(2)max), low intensity (LI: 20m/min approximately 50-55% VO(2)max), and sedentary control (SED) groups. All experimental groups performed a 12week exercise program consisting of treadmill running on a 0 degrees slope for 1h/day, 5days/week at their respective training intensity. Twenty four hours following the last training session the animals completed a 12h fast. Rats were then killed, blood was collected and plasma separated; the fundus and soleus muscle were excised and frozen in liquid nitrogen for later analysis. Fasting levels of circulating acyl ghrelin and acyl ghrelin content in the soleus muscle and fundus, as well as glycogen in the soleus muscle were measured. Data were analyzed using one-way ANOVA. 
Results demonstrated that 12weeks of exercise training combined with a 12h fast significantly increased plasma as well as soleus muscle concentrations of acyl ghrelin in the HI and MI groups (p<0.05) and reduced acyl ghrelin concentrations in the fundus (p<0.05). CONCLUSION: The results of the study indicate that chronic treadmill exercise training enhances fasting plasma acyl ghrelin in an intensity-dependent manner which is accompanied by a significant increase in soleus muscle and reduction in fundus acyl ghrelin levels." 

So diet wise does this mean you want to eat at or around maintenance calories?  Low bodyfat percentage equals high insulin sentivity and insulin affects stem cell proliferation through the PI3K pathway.  The fundus is another word for the stomach so Ghrelin can be expressed locally by certain muscles and bones(or growth plates) even if you're not hungry.

"Fasting at different durations (18, 24, 48, 72 h, and 7 days) is also known to be associated with increased plasma ghrelin concentrations and expression of ghrelin in gastrointestinal tract, mainly gastric and particularly in the fundus"

"total plasma ghrelin levels are significantly changed during acute and chronic alteration of nutritional status with low levels in simple obesity but higher levels after weight loss. Moreover, ghrelin is up-regulated by fasting, insulin-induced hypoglycemia, and leptin administration"<-It's unclear whether it's a case of total tissue weight loss or just fat loss.  Fasting and leptin administration are two ways to manually induce increase in Ghrelin levels despite the seeming lack of synergy between Ghrelin and Leptin. In fact: "ghrelin is up-regulated by fasting, insulin-induced hypoglycemia, and leptin administration". Leptin is available for sale: Lepti-Trim - Daytime Capsules (180 Ct).  This supplement claims to increase Ghrelin: Xero Limits Engorge -- 224 Capsules.

According to this study Ghrelin plasma levels in patients with idiopathic short stature., Ghrelin signaling is normal in the short stature patients they studied but that does not mean that Ghrelin has no effect on height.  In fact the Ghrelin levels of the short stature patients were 50% greater.

Polymorphisms of the ghrelin/obestatin gene and ghrelin levels in Chinese children with short stature., found that Ghrelin levels was a side effect of Growth Hormone deficiency and not a cause of short stature itself.

The Endogenous Growth Hormone Secretagogue (Ghrelin) Is Synthesized and Secreted by Chondrocytes

"Ghrelin, the endogenous ligand for the GH secretagogue receptor (GHS-R), is a recently isolated hormone, prevalently expressed in stomach but also in other tissues such as hypothalamus and placenta. This novel acylated peptide acts at a central level to stimulate GH secretion and, notably, to regulate food intake. However, the existence of further, as yet unknown, effects or presence of ghrelin in peripheral tissues cannot be ruled out. In this report, we provide clear evidence for the expression of ghrelin peptide and mRNA in human, mouse, and rat chondrocytes. Immunoreactive ghrelin was identified by immunohistochemistry in rat cartilage, being localized prevalently in proliferative and maturative zone of the epiphyseal growth plate, and in mouse and human chondrocytic cell lines. Moreover, ghrelin mRNA was detected by RT-PCR and confirmed by Southern analysis in rat cartilage as well as in mouse and human chondrocytes cell lines. Ghrelin mRNA expression has been studied in rat along early life development showing a stable profile of expression throughout. Although ghrelin expression in chondrocytes suggests the presence of an unexpected autocrine/paracrine pathway, we failed to identify the functional GH secretagogue receptor type 1A by RT-PCR. On the other hand, binding analysis with 125I ghrelin suggests the presence of specific receptors different from the 1A isotype. Scatchard analysis revealed the presence of two receptors with respectively high and low affinity. Finally, ghrelin, in vitro, was able to significantly stimulate cAMP production and inhibits chondrocytes metabolic activity both in human and murine chondrocytes. In addition, ghrelin is able to actively decrease both spontaneous or insulin-induced long chain fatty acid uptake in human and mouse chondrocytes. This study is the first to provide evidence for the presence of this novel peptide in chondrocytes and suggests novel potential roles for this newly recognized component of the GH axis in cartilage metabolism."

"[Ghrelin] is a gastric orexigenic peptide and a ligand for the GHS-R [GH secretagogue (GHS) receptor] that potently stimulates GH release both in vivo and in vitro"

"immunoreactive ghrelin was localized in rat epiphyseal growth plate, where it was expressed in the majority of the chondrocytes in the proliferation and maturation zones and only occasionally in the hypertrophic and provisional calcification area. A similar pattern was observed for IGF-I immunostaining. Ghrelin was found in the cytoplasm, whereas the nuclei were negative. IGF-I-positive staining was more intense around the nuclei."

"ghrelin is able to increase cAMP production in both human and murine chondrocytes in a dose-responsive manner."

"ghrelin may have a significant role in regulating chondrocyte metabolism in the growth plate because it is localized in the proliferative and maturation zones, inhibits cell metabolic rate, promotes cAMP accumulation and inhibits basal and induced fatty acid uptake in chondrocyte cultures"<-perhaps inhibiting fatty acid uptake reduces apoptosis?  According to High fat-diet and saturated fatty acid palmitate inhibits IGF-1 function in chondrocytes, fat reduces IGF-1 expression.

Lack of sleep increase ghrelin levels too but obviously lack of sleep is bad so that's not really a good option.  And you fast during sleep which gives sleep another benefit.  High Intensity Exercise had the most impact on increasing Ghrelin levels(so sprinting...).  Sprinting may not increase levels directly in the growth plate but there may be a spillover effects from the muscles and periosteum.

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