GHRP / Ipamorelin _increase_ fat in rats?

[pmxpmx]

It seems that the various GHS increase fat in rats while GH alone does not.
This runs contrary the the current views on peptides.
Does anyone know more about this?
Here are some abstracts that I noticed:

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Growth hormone (GH)-independent stimulation of adiposity by GH secretagogues.
Lall S, Tung LY, Ohlsson C, Jansson JO, Dickson SL.

Department of Physiology, University of Cambridge, Downing Street, Cambridge, CB2 3EG, United Kingdom.

Abstract
Growth hormone secretagogues (GHSs) stimulate growth hormone (GH) secretion, which is lipolytic. Here we compared the effects of twice daily s.c. treatment of GH and the GHS, ipamorelin, on body fat in GH-deficient (lit/lit) and in GH-intact (+/lit and +/+) mice. In +/lit and lit/lit mice ipamorelin induced a small (15%) increase in body weight by 2 weeks, that was not further augmented by 9 weeks. GH treatment markedly enhanced body weight in both groups. Ipamorelin also increased fat pad weights relative to body weight in both lit/lit and +/lit mice. Two weeks GHS treatment (ipamorelin or GHRP-6) also increased relative body fat, quantified by in vivo dual energy X-ray absorpiometry (DEXA) in GH-intact mice. GH decreased relative fat mass in lit/lit mice and had no effect in GH-intact mice. Treatment with GHS, but not GH, increased serum leptin and food intake in GH-intact mice. Thus, GHSs increase body fat by GH-independent mechanisms that may include increased feeding.

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Glucocorticoid-dependent stimulation of adiposity and appetite by a ghrelin mimetic in the rat.
Tung YL, Hewson AK, Dickson SL.

Department of Physiology, University of Cambridge, Downing Street, Cambridge CB2 3EG, Cambridge, UK.

Abstract
OBJECTIVE: Chronic administration of GH secretagogues (GHSs) induces a state of positive energy balance in rodents by a GH-independent mechanism. Here we sought to determine to what extent the GHS effects to increase food intake and increase fat accumulation are glucocorticoid-dependent.

DESIGN: The effects of twice-daily s.c. injections of GH-releasing peptide-6 (GHRP-6) (250 microg/kg) for 2 weeks on body weight, food intake and fat pad weight were determined in both adrenalectomised (ADX) rats (with or without basal corticosterone replacement) and adrenal-intact rats.

RESULTS: All GHS-injected rats had a significantly increased body weight at the end of 2 weeks of treatment compared with saline controls. However, increased fat accumulation was only seen in adrenal-intact rats, with a 15% increase in s.c. inguinal (P<0.05 vs saline controls) and 20% increase in visceral mesenteric (P<0.05) fat pad weights following GHS treatment. The increased body weight observed in ADX rats following GHS treatment was not due to increased fat mass or increased weight of other organs measured. Food intake was increased for up to 7 h following a single injection of GHRP-6 in both the adrenal-intact (P<0.01) and corticosterone-replacement groups (P<0.05). This stimulating effect on food intake was not observed at any time point in the ADX rats without corticosterone replacement.

CONCLUSION: These data suggest that GHS-induced body weight gain is glucocorticoid-independent. However, basal levels of glucocorticoids are permissive for the GHS-induced increase in food intake whilst activation of the hypothalamo-pituitary-adrenal axis appears to contribute to the GHS-induced accumulation of fat mass.

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Eur J Endocrinol. 2004 Jun;150(6):905-11.

Glucocorticoid-dependent stimulation of adiposity and appetite by a ghrelin mimetic in the rat.
Tung YL, Hewson AK, Dickson SL.

Department of Physiology, University of Cambridge, Downing Street, Cambridge CB2 3EG, Cambridge, UK.

Abstract
OBJECTIVE: Chronic administration of GH secretagogues (GHSs) induces a state of positive energy balance in rodents by a GH-independent mechanism. Here we sought to determine to what extent the GHS effects to increase food intake and increase fat accumulation are glucocorticoid-dependent.

DESIGN: The effects of twice-daily s.c. injections of GH-releasing peptide-6 (GHRP-6) (250 microg/kg) for 2 weeks on body weight, food intake and fat pad weight were determined in both adrenalectomised (ADX) rats (with or without basal corticosterone replacement) and adrenal-intact rats.

RESULTS: All GHS-injected rats had a significantly increased body weight at the end of 2 weeks of treatment compared with saline controls. However, increased fat accumulation was only seen in adrenal-intact rats, with a 15% increase in s.c. inguinal (P<0.05 vs saline controls) and 20% increase in visceral mesenteric (P<0.05) fat pad weights following GHS treatment. The increased body weight observed in ADX rats following GHS treatment was not due to increased fat mass or increased weight of other organs measured. Food intake was increased for up to 7 h following a single injection of GHRP-6 in both the adrenal-intact (P<0.01) and corticosterone-replacement groups (P<0.05). This stimulating effect on food intake was not observed at any time point in the ADX rats without corticosterone replacement.

CONCLUSION: These data suggest that GHS-induced body weight gain is glucocorticoid-independent. However, basal levels of glucocorticoids are permissive for the GHS-induced increase in food intake whilst activation of the hypothalamo-pituitary-adrenal axis appears to contribute to the GHS-induced accumulation of fat mass.
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[123cctv]

It seems that the various GHS increase fat in rats while GH alone does not.
This runs contrary the the current views on peptides.
Does anyone know more about this?
Here are some abstracts that I noticed:

First I've seen on this - though I wouldn't doubt the research. One problem with your post though, while all 3 abstracts originated from:
Department of Physiology, University of Cambridge, Downing Street, Cambridge CB2 3EG, Cambridge, UK.

....your last two are identical (duplicates).

 

[pmxpmx]

I appologize, a bad copy-paste on my part.

Here is the third article that I inteded to post, followed by an article mentioning a possible mechanism by which ipamorelin increases insulin.

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The positive effects of growth hormone-releasing peptide-6 on weight gain and fat mass accrual depend on the insulin/glucose status.
Granado M, García-Cáceres C, Frago LM, Argente J, Chowen JA.

Department of Endocrinology, Hospital Infantil Universitario Niño Jesús, Avenida Menéndez Pelayo, Madrid, Spain.

Abstract
Ghrelin and GH secretagogues, including GH-releasing peptide (GHRP)-6, stimulate food intake and adiposity. Because insulin modulates the hypothalamic response to GH secretagogues and acts synergistically with ghrelin on lipogenesis in vitro, we analyzed whether insulin plays a role in the metabolic effects of GHRP-6 in vivo. Streptozotocin-induced diabetic rats received saline, GHRP-6, insulin, or insulin plus GHRP-6 once daily for 8 wk. Rats receiving saline suffered hyperglycemia, hyperphagia, polydipsia, and weight loss. Insulin, but not GHRP-6, improved these parameters (P < 0.001 for all), as well as the diabetes-induced increase in hypothalamic mRNA levels of neuropeptide Y and agouti-related peptide and decrease in proopiomelanocortin. Cocaine amphetamine-related transcript mRNA levels were also reduced in diabetic rats, with GHRP-6 inducing a further decrease (P < 0.03) and insulin an increase. Diabetic rats receiving insulin plus GHRP-6 gained more weight and had increased epididymal fat mass and serum leptin levels compared with all other groups (P < 0.001). In epididymal adipose tissue, diabetic rats injected with saline had smaller adipocytes (P < 0.001), decreased fatty acid synthase (FAS; P < 0.001), and glucose transporter-4 (P < 0.001) and increased hormone sensitive lipase (P < 0.001) and proliferator-activated receptor-gamma mRNA levels (P < 0.01). Insulin normalized these parameters to control values. GHRP-6 treatment increased FAS and glucose transporter-4 gene expression and potentiated insulin's effect on epididymal fat mass, adipocyte size (P < 0.001), FAS (P < 0.001), and glucose transporter-4 (P < 0.05). In conclusion, GHRP-6 and insulin exert an additive effect on weight gain and visceral fat mass accrual in diabetic rats, indicating that some of GHRP-6's metabolic effects depend on the insulin/glucose status.
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Mechanism of ipamorelin-evoked insulin release from the pancreas of normal and diabetic rats.
Adeghate E, Ponery AS.

Department of Anatomy, Faculty of Medicine and Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates. [email protected]

Abstract
OBJECTIVE: To examine the effect of ipamorelin (IPA), a novel pentapeptide with a strong growth hormone releasing potency, on insulin secretion from pancreatic tissue fragments of normal and diabetic rats.

MATERIALS AND METHODS: Diabetes mellitus was induced by streptozotocin (60 mg kg(-1)). Four weeks after the induction of diabetes, pancreatic tissue fragments of normal and diabetic rats were removed and incubated with different concentrations (10(-12) - 10(-6) M) of IPA. Insulin release from the pancreas was measured by radioimmunoassay.

RESULTS: Ipamorelin evoked significant (p<0.04) increases in insulin secretion from the pancreas of normal and diabetic rats. Either diltiazem or yohimbine or propranolol or a combination of atropine, propranolol and yohimbine inhibited IPA-evoked insulin secretion significantly (p<0.03) from the pancreas of normal and diabetic rats. Atropine caused a significant (p<0.007) reduction in the IPA-induced insulin secretion in diabetic but not in normal rats.

CONCLUSION: IPA stimulates insulin release through the calcium channel and the adrenergic receptor pathways. This is the first study to examine the effect of ipamorelin on insulin secretion in the pancreas.

 

[Ehren]

I like the last study, which seems to point to the solution, as Yohimbine is readily available and solves the insulin related problem. I just wonder what dose of Yohimbine is required to get that effect. Thanks for posting those!

 

[Seabiscuit Hogg]

Interesting. Gotta remember they're not timing things the way we do. Anything on GHRP-2?

 

[pmxpmx]

There are definitely differences between rats/mice and people.
I am not sure how these should be interpreted.

Here is an interesting one, referencing the effects of MT-II + GHRP2.
It should be mentioned that mice lacking NPY are usually very lean.


GH-releasing peptide-2 increases fat mass in mice lacking NPY:
indication for a crucial mediating role of hypothalamic agouti-related
protein.


Tschöp M, Statnick MA, Suter TM, Heiman ML.


Endocrine Research, Lilly Research Laboratories, Eli Lilly &
Co., Indianapolis, Indiana 46285, USA. [email protected]



Abstract


Ghrelin, an endogenous GH secretagogue, is capable of stimulating adiposity
in rodents. Because such adiposity was thought to be mediated by hypothalamic
NPY neurons, we investigated by which mechanism a synthetic ghrelin receptor
agonist, GHRP-2, would generate a positive energy balance in NPY-deficient
[Npy(-/-) mice] and wild-type controls. A dose-dependent increase in body weight
and food intake was observed during daily sc injections with GHRP-2. Pre- and
posttreatment analysis of body composition indicated increased fat mass and bone
mass but not lean mass. Respiratory quotient was increased in GHRP-2-treated
mice, indicating preservation of fat. Hypothalamic mRNA levels of agouti-
related protein (AGRP), an orexigenic melanocortin receptor antagonist,
increased after GHRP-2 treatment. Competitive blockade of AGRP action by
melanocortin-receptor agonist MT-II prevented GHRP-induced weight gain in
Npy(-/-) mice. In conclusion, chronic peripheral treatment with a ghrelin
receptor agonist induced a positive energy balance leading to fat gain in the
absence of NPY. These effects could be mediated in part by AGRP. To date, there
are few therapeutics that can produce a positive energy balance. Ghrelin
receptor agonists offer a treatment option for syndromes like anorexia nervosa,
cancer cachexia, or AIDS wasting.