Details
Fragment 176-191
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Synonyms: |
Frag-176, GH Frag-176, AOD9604 |
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CAS RN.: |
N/A |
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Sequence: |
Tyr-Leu-Arg-Ile-Val-Gln-Cys-Arg-Ser-Val-Glu-Gly-Ser-Cys-Gly-Phe |
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Molecular Weight: |
1815.1 |
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Molecular Formula: |
C78H123N23O23S2 |
Description
Rat Body Weight Gain Reduced Over 50%
Initial studies done used high oral dosing techniques to induce losRs of adipose tissue in obese rats. In this study, Zucker rats were used. This strain of rat is bred specifically to be obese and hypertensive. The study showed that in the rats on AOD9604 only half the amount of weight was gained as the control set:
"A synthetic analogue (AOD9604) of the lipolytic domain of human growth hormone (hGH) has been studied for its metabolic actions in obese Zucker rats. Daily treatment with an oral dose of AOD9604 of 500 microg/kg body weight for 19 days reduced over 50% (15.8 +/- 0.6 vs. 35.6 +/- 0.8 g) body weight gain of the animals in comparison with the control. The adipose tissues of the AOD9604--treated animals were found to have an increase in lipolytic activity. In contrast to chronic treatment with intact hGH, chronic treatment with AOD9604 showed no adverse effect on insulin sensitivity of the animals, as demonstrated with euglycemic clamp techniques. The results in the present study suggest that the analogue of the hGH lipolytic domain may have the potential to be developed into an orally usable and safe therapeutic agent for obesity. [1]"
GH Fragment 176 Increases Fat Oxidation and Weight Loss
A year after the above studies were done, research moved forward to investigate how the growth hormone fragment (AOD9604) actually affected body weight, energy balance and oxidation rates in both lean and obese mice. Also, how the fragment actually interacts with the hGH receptor was looked into.
In this study, both obese and lean mice were treated with hGH, AOD9604 or saline for 14 days using mini-osmotic pumps. So by this point, the oral dosing was abandoned for an internal pump mechanism simulating daily infusion. Body weight, caloric intake, resting energy expenditure, fat oxidation, glucose oxidation, and plasma glucose, insulin and glycerol were measured before and after treatment.
Both hGH and AOD significantly reduced body weight gain in obese mice. This was associated with increased in vivo fat oxidation and increased plasma glycerol levels (an index of lipolysis). Unlike hGH, however, AOD9604 did not induce hyperglycemia or reduce insulin secretion. AOD9604 does not compete for the hGH receptor and nor does it induce cell proliferation, unlike hGH.
14 Day Chronic AOD9604 Use Enhanced Rat Lypolysis Activity
A similar, but more in depth study was performed by the same group soon after the above. In long term treatment on mice, both human GH (hGH) and a fragment (AOD9604) synthesized from its C-terminus were found to be capable of inducing weight loss and increasing lipolytic sensitivity. This study describes how hGH and AOD9604 were used for 14 days of chronic intraperitoneal injection to reduce weight and body fat in obese mice. It is believed that this result is only partially mediated through the β3-AR RNA (beta-3 adrenergic receptors) as the results seen correlate with increases in the level of expression of β3-AR RNA, the major lipolytic receptor found in fat cells. Both hGH and AOD9604 increase repressed levels of β3-AR RNA in obese mice to levels comparable with those in lean mice. So, obese mice have the same fat loss abilities as lean mice. In conclusion, this study demonstrates that the lipolytic actions of both hGH and AOD9604 are not mediated directly through the β3-AR although both compounds increase β3-AR expression, which may subsequently contribute to enhanced lipolytic sensitivity.
Studies on hGH have shown profound lipolytic/antilipogenic actions resulting in weight loss, decreased fat mass, and increased lean mass. Studies in vitro and in vivo have indicated that this response is mediated in part by an increase in β -adrenoceptor coupling efficiency, a reduction in Gi expression, increased activity of hormone sensitive lipase, and an inhibitory effect on the action of insulin. A synthesized fragment of hGH (AOD9604) contains a lipolytic domain that may be responsible for the lipolytic action of hGH. The nature of the response to both hGH and AOD9604 is not clearly understood at this time. It is believed that both molecules may influence the expression of the β3-adrenergic receptors (β3-ARs), the major lipolytic receptor in fat tissue. Both AOD9604 and hGH can increase β3-AR mRNA expression, as well as protein levels and function, in mouse and human cell lines in vitro. This response was investigated at the level of RNA and protein expression and function. The results for each mode of analysis were consistent in that both hGH and AOD9604 acted in a dose- and time-dependent manner to modulate the β3-AR response:
"Following a 14-d chronic administration with AOD9604 or hGH, adipose tissue weights were measured, and β3-AR mRNA expression was determined. The decrease in weight of adipose tissue depots in the ob/ob mice was associated with increasedβ 3-AR expression. Further studies inβ 3-AR knock-out (β3-KO) mice showed that the presence of the β3-AR is necessary to mediate the chronic effectiveness of hGH and AOD9604 with regards to weight loss and fat mass reduction. However, an acute dose of AOD9604 was capable of increasing energy expenditure inβ 3-KO mice, although the response was less than that seen in the wild-type control mice."
Animals and treatment:
"Lean C57BL/6J and obese (ob/ob) mice aged 12 wk were used in this study. There were 18 mice in each group, and they were divided into three treatment groups [saline (n = 6); AOD (250μ g/kg·d; n = 6); hGH (1 mg/k·d; n = 6)]. The animals were housed in the Departmental Animal Facility at a constant temperature and humidity in a 12-h light, 12-h dark cycle. Animals were injected with a single intraperitoneal dose of saline, AOD9604, or hGH at 0800 h each day for 14 d using a 1-ml syringe and 23-gauge needle. The body weights of the animals were recorded every second day along with food intake."
Acute effects of AOD9604 and BRL37344 in WT and β 3-KO mice:
"WT (n = 9) and β3-KO (n = 9) mice were used in this study. Animals were fasted 2 h before being individually placed in an indirect calorimeter. Calorimetry was performed as in previous studies (8). After baseline readings were taken, mice were injected with one of the following compounds: saline (control; n = 3); AOD9604 (2 mg/kg body weight; n = 3); or BRL37344 (250 μg/kg body weight; n = 3). Rates of energy expenditure, fat oxidation, and glucose oxidation were measured for an additional 30 min. The concentrations of AOD9604 and BRL37344 were determined as lowest concentration needed to give a maximal response in these mice. Rates of energy expenditure and fat and glucose oxidation were plotted as a change from the average baseline values."
Results:
"Figure 1A⇓ shows the chronic effect of saline, AOD9604, and hGH in lean C57BL/6J mice on body weight and food intake. The hGH potently increased the body weight gain of these mice, reaching significance by d 8. There was an increase in body weight after AOD9604 only on the last day of treatment. In contrast, ob/ob mice (Fig. 1B⇓) showed a profound decrease in body weight after both AOD9604 and hGH. Importantly, these effects were not attributed to changes in food intake in either the lean or the ob/ob mice (Fig. 1⇓, C and D, respectively)."
"The effect of a single daily ip dose of saline, AOD9604, or hGH on body weight changes in lean male C57BL/6J (A) or obese (ob/ob) mice (B) for 14 d. Caloric intake was recorded every second day and presented as an average for each day in lean (C) and obese (D) mice. Results are expressed as the mean ± se of six animals in each group."
"Figure 2A⇓ shows that neither hGH nor AOD9604 had any significant effect on the weight of epididymal adipose tissue in the lean mice. However, in the ob/ob mice, AOD9604 induced a 28% decrease in epididymal adipose tissue mass, and hGH induced a 40% reduction in epididymal adipose tissue mass (P < 0.05). Brown adipose tissue weights were also measured (Fig. 2B⇓). In this tissue, both AOD9604 and hGH induced a reduction in the weight of brown adipose tissue in both the lean and ob/ob mice."
"The effect of chronic 14-d administration of saline, AOD9604, or hGH on the weight of white (epididymal) adipose tissue (A) or interscapular brown adipose tissue (B) in both lean C57BL/6J and obese (ob/ob) mice."
"The final study involved an assessment of the acute effect of AOD9604 and a β3-AR agonist (BRL37344) on energy expenditure, fat oxidation, and glucose oxidation in WT andβ 3-KO mice. When AOD9604 or BRL37344 were administered to WT mice, an acute increase in fat oxidation and energy expenditure occurred, with an associated reduction in glucose oxidation (Fig. 6A⇓). The effect plateaued 18 min following injection and remained stable for the duration of the experiment. AOD9604 clearly increases fat oxidation and energy expenditure in β 3-KO mice. The KO mice neither decrease their glucose oxidation in response to AOD9604 nor show a prolonged increase in fat oxidation and energy expenditure in response to AOD9604."
"The effect of an acute single ip injection of saline, AOD9604, or BRL37344 (β3-AR agonist) on changes in the rates of fat oxidation, glucose oxidation, and energy expenditure in WT (A) and β3-KO (B) mice."
Both AOD9604 and, to a greater extent, hGH showed an increase body weight in lean mice, compared with the saline-treated animals. Note that there was not an increase in fat mass, suggesting the increase was lean body mass occurring with these compounds. Both compounds have also been shown in previous studies to reduce both body weight, and adipose tissue in obese mice. These effects elicited by both hGH and AOD9604 occur without significant changes to caloric intake.
In lean animals, neither AOD9604 nor hGH had effects on epididymal white adipose tissue mass, indicating that in lean animals, this fat tissue is not a major target for these drugs in this study. In contrast, the mass of BAT in lean animals was reduced by both hGH and AOD9604.
In obese mice, both AOD9604 and hGH reduced both white and brown adipose tissue mass and increased β3-AR RNA expression. This suggested that an elevation in β 3-AR RNA expression is associated with increased fat metabolism and a reduction in the fat tissue mass in the obese mice. Obese mice have lower levels of β 3-AR expression in their adipose tissues than lean mice. One of the most exciting findings of this study is the ability of AOD9604 and hGH to increase the level of β 3-AR RNA expression in obese mice to a level that is comparable to those in lean mice. However, it must also be considered that both hGH and AOD9604 may influence the expression of other members of the adrenergic pathway, such as the β1-ARs, hormonesensitive lipase, and signaling proteins, which are all expressed in adipose tissue and associated with lipolysis.
This all suggest that the acute effects of AOD9604 are quite different from the chronic effects. Enhanced β 3-AR expression appears to play a major role in the chronic effectiveness of the compound in terms of fat metabolism and weight loss. The acute effects observed in this study confirm that the β3-AR is not the sole mediator of this action. The increase in β3-AR expression in response to hGH and AOD9604 would permit enhanced lipolytic sensitivity. The results also suggest that the effectiveness of AOD9604 and hGH may somewhat rely on their ability to increase levels of β3-AR RNA expression in models of obesity in which the numbers of the lipolytic receptor are low. These unique properties may give AOD9604 an advantage over other lipolytic agonists such as adrenergic agents and hGH, which exhibit undesirable side effects when administered chronically. [3]All products available for purchase are for research purposes only. These laboratory peptides are not intended for use in food products or as any type of drug. Fragment 176-191 peptides are not intended to treat, prevent, mitigate or cure any disease or medical condition.
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References
[1] Ng FM, Sun J, Sharma L, Libinaka R, Jiang WJ, Gianello R. (2000). “Metabolic studies of a synthetic lipolytic domain (AOD9604) of human growth hormone.” Hormone Research. 53(6):274-8.
[2] Heffernan MA, Thorburn AW, Fam B, Summers R, Conway-Campbell B, Waters MJ, Ng FM. (2001). “Increase of fat oxidation and weight loss in obese mice caused by chronic treatment with human growth hormone or a modified C-terminal fragment.” International Journal of Obesity Related Metabolic Disorders. 25(10):1442-9.
[3] Heffernan M, Summers RJ, Thorburn A, Ogru E, Gianello R, Jiang WJ, Ng FM. (2001). “The effects of human GH and its lipolytic fragment (AOD9604) on lipid metabolism following chronic treatment in obese mice and beta(3)-AR knock-out mice.” Endocrinology. 142(12):5182-9.
