Mod GRF 1-29 & Ipamorelin Blend Actions on Adipose and Bone Cells

Mod GRF 1-29 (also referred to as CJC-1295 without DAC) and Ipamorelin are both synthetic peptides that have attracted scientific interest primarily because they have the potential to influence the growth hormone release mechanisms of pituitary gland cells under laboratory conditions. Mod GRF 1-29 is considered to be a modified analog of the growth hormone-releasing hormone (GHRH). GHRH is an endogenous hormone and an endogenous regulator of growth hormone synthesis.

The unmodified GRF 1-29 segment represents the smallest portion of the endogenous GHRH sequence that retains full biological activity in terms of stimulating growth hormone release. In the case of Mod GRF 1-29, research by Jetté et al. suggests that multiple amino acid substitutions are introduced to support the peptide’s stability against enzymatic degradation potentially:⁽¹⁾

• Position 2 (Alanine → D-Alanine): Introduces a D-form amino acid, which is less susceptible to standard enzymatic breakdown.
• Position 8 (Asparagine → Lysine): Alters the peptide’s charge profile, potentially strengthening its binding to GHRH receptors.
• Position 15 (Histidine → D-Phenylalanine): Incorporates another D-form amino acid to support stability and reduce enzymatic cleavage.
• Position 27 (Cysteine → N-Methylglycine): Further limits degradative enzymes from quickly dismantling the peptide.

Some researchers believe that these substitutions confer increased potency, receptor interaction efficiency, and an extended period during which the peptide might remain active in a controlled research setting. According to research by Johansen et al., Ipamorelin is another synthetic peptide studied for its interaction with growth hormone secretagogue receptors (GHS-Rs), the same receptors targeted by the endogenous ligand ghrelin. ⁽²⁾

Ghrelin, often referred to in other contexts as the “hunger hormone,” has a range of systemic actions, including stimulating growth hormone release. Raun et al. also reveals that Ipamorelin shares structural similarities with other synthetic secretagogues but appears to be more selective in its receptor activation compared to certain predecessors. (3) It may influence growth hormone synthesis without interacting with other pituitary hormones.

Figure 1: Mod GRF 1-29 chemical structure

Figure 2: Ipamorelin chemical structure

 

Research

Mod GRF 1-29 & Ipamorelin Actions on Somatotroph Cell Receptors

Mod GRF (1-29) and Ipamorelin both appear to interact with receptors on the anterior pituitary gland, particularly the somatotroph cells thought to be responsible for growth hormone synthesis. Mod GRF (1-29) is thought to selectively bind to GHRH receptors located on somatotroph cells and potentially induce a conformational change that initiates multiple intracellular signaling events.

Research by Zhou et al. suggests that a key element in this process involves the activation of G-proteins, which are closely associated with the inner surface of the cell membrane and activate downstream pathways leading to the production of secondary messengers such as cyclic adenosine monophosphate (cAMP) and inositol triphosphate (IP3). Elevated cAMP levels are believed to activate protein kinases—enzymes that phosphorylate target proteins. Among these targets are transcription factors that might translocate into the cell nucleus and influence gene expression for increased growth hormone synthesis. This may promote the accumulation of growth hormone-containing vesicles within somatotroph cells. IP3 may help liberate calcium ions (Ca²⁺) from internal cellular stores. Rising intracellular calcium levels may drive the fusion of growth hormone-containing vesicles with the plasma membrane, facilitating the release of growth hormone into the extracellular environment.

In contrast, Ipamorelin is generally regarded as a growth hormone secretagogue receptor (GHS-R) ligand. These are also referred to as ghrelin receptors. Upon binding to GHS-Rs, Ipamorelin may engage different signaling pathways. According to Jiménez-Reina et al., one important route involves the activation of phospholipase C (PLC). When stimulated, PLC may catalyze the production of two major second messengers: IP3 and diacylglycerol (DAG). IP3 encourages the release of Ca²⁺ from intracellular stores, increasing the cytosolic calcium concentration, while DAG activates protein kinase C (PKC). The rise in intracellular Ca²⁺, coupled with the activation of PKC, culminates in a series of events that support growth hormone-containing vesicle exocytosis.

Synergistic Potential of Mod GRF 1-29 & Ipamorelin

Studies indicate that both Mod GRF (1-29) and Ipamorelin may individually produce substantial increases in growth hormone secretion. According to an experiment by Khorram et al., Mod GRF (1-29), analogs have been observed to promote growth hormone output by approximately 70% to 107% over certain time frames in experimental settings. ⁽⁶⁾ Similarly, Gobburu et al. suggest that Ipamorelin may potentially upregulate growth hormone concentrations to around 80 mIU/L, representing roughly a 60-fold increase compared to placebo conditions in lab settings. ⁽⁷⁾ Mod GRF (1-29) and Ipamorelin, while both influencing growth hormone release, do so via distinct receptor pathways and intracellular mechanisms.

These differences in how each peptide may interact with pituitary cells have led some researchers to hypothesize that using both compounds simultaneously may yield synergistic actions on growth hormone secretion, surpassing what either might achieve alone. Sinha et al. have conducted a review of the literature and revealed that preliminary findings from studies looking at similar GHRH analogs and GHS-R agonists support this concept. In certain investigations, GHRH-like compounds and GHS-R activators were associated with apparent increases in pulsatile growth hormone secretion—20-fold and 47-fold above baseline, respectively. ⁽⁸⁾ Notably, when both agents were combined in laboratory settings, the outcome was apparently a 54-fold upregulation in pulsatile growth hormone output.

Mod GRF 1-29 & Ipamorelin Potential Actions on Adipose Cells

Research examining Mod GRF (1-29) and Ipamorelin suggests that both peptides may influence adipose tissue distribution, particularly through their association with growth hormone secretion. Growth hormone is recognized for its lipolytic actions, especially within visceral fat depots. Dehkhoda et al. have commented that “GH impacts adipose tissue in a depot-specific manner and influences other features of adipose tissue (for example, senescence, adipocyte subpopulations, and fibrosis), all of which [may] influence lipolysis.”⁽⁹⁾ This preference may arise from the higher density of growth hormone receptors found in visceral adipocytes compared to subcutaneous adipocytes. Once growth hormone binds to these receptors, it might activate enzymes such as hormone-sensitive lipase (HSL) and adipose triglyceride lipase (ATGL), which facilitate the breakdown of stored triglycerides into free fatty acids and glycerol. Additionally, by engaging signaling pathways such as JAK/STAT, growth hormone may drive the transcription of genes involved in lipid mobilization, thereby further promoting lipolysis and potentially reducing visceral fat stores.

By stimulating growth hormone release, both Mod GRF (1-29) and Ipamorelin may indirectly support a metabolic shift favoring the depletion of visceral fat. As the central fat depots are metabolized, a relative redistribution of adipose tissue from visceral to subcutaneous regions may occur, at least under experimental conditions. However, researchers such as Lall et al. suggest that Ipamorelin’s interaction with ghrelin receptors in the nervous system may also support hunger hormone signaling. ⁽¹⁰⁾ This increased hunger hormone signal may lead to greater caloric intake and may promote an accumulation of fat in subcutaneous regions instead. Because subcutaneous adipose tissue has a lower density of growth hormone receptors, it may not be as readily mobilized by growth hormone-induced lipolysis.

Mod GRF 1-29 & Ipamorelin Potential Actions on Bone Tissue Cells

Both Mod GRF (1-29) and Ipamorelin are posited to influence bone cells and bone-related tissues through pathways related to growth hormone secretion and local growth hormone signaling. Although the underlying mechanisms remain incompletely understood, studies on Ipamorelin suggest that via its impact on growth hormone levels, the peptide may then modulate osteoblast function and related progenitor cell activity. This modulation may lead to better-supported subperiosteal bone formation, resulting in a potential increase in bone dimensions without necessarily altering the intrinsic volumetric mineral density. Specifically, research by  Svensson et al. observed “that the increases in cortical and total BMC were due to an increased growth of the bones with increased bone dimensions, whereas the volumetric BMD was unchanged” when Ipamorelin was introduced to bone tissue in laboratory settings. ⁽¹¹⁾

Ipamorelin may also affect longitudinal bone growth, apparently by impacting the growth plate regions and thereby increasing the linear expansion of bone. ⁽¹²⁾ The potential actions of ipamorelin on bone cells and tissues in these controlled murine research models include increased deposition of mineral content and expanded cortical bone cross-sectional area, but seemingly not through altering the inherent mineral concentration of the bone matrix itself. Instead, the outcome is a possibly larger overall bone volume that maintains a stable intrinsic mineral composition. While the precise molecular intermediaries and signaling pathways remain to be clarified, ipamorelin’s influence on bone-associated endocrine loops (involving growth hormone and maybe local IGF-I) is plausibly central, potentially altering the balance between bone-forming and bone-remodeling processes at the tissue level.

 
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References:

1. Jetté L, Léger R, Thibaudeau K, Benquet C, Robitaille M, Pellerin I, Paradis V, van Wyk P, Pham K, Bridon DP. Human growth hormone-releasing factor (hGRF)1-29-albumin bioconjugates activate the GRF receptor on the anterior pituitary in rats: identification of CJC-1295 as a long-lasting GRF analog. Endocrinology. 2005 Jul;146(7):3052-8. doi: 10.1210/en.2004-1286. Epub 2005 Apr 7. PMID: 15817669.
2. Johansen PB, Nowak J, Skjaerbaek C, Flyvbjerg A, Andreassen TT, Wilken M, Orskov H. Ipamorelin, a new growth-hormone-releasing peptide, induces longitudinal bone growth in rats. Growth Horm IGF Res. 1999 Apr;9(2):106-13. doi: 10.1054/ghir.1999.9998. PMID: 10373343.
3. Raun K, Hansen BS, Johansen NL, Thøgersen H, Madsen K, Ankersen M, Andersen PH. Ipamorelin, the first selective growth hormone secretagogue. Eur J Endocrinol. 1998 Nov;139(5):552-61. doi: 10.1530/eje.0.1390552. PMID: 9849822.
4. Zhou F, Zhang H, Cong Z, Zhao LH, Zhou Q, Mao C, Cheng X, Shen DD, Cai X, Ma C, Wang Y, Dai A, Zhou Y, Sun W, Zhao F, Zhao S, Jiang H, Jiang Y, Yang D, Eric Xu H, Zhang Y, Wang MW. Structural basis for activation of the growth hormone-releasing hormone receptor. Nat Commun. 2020 Oct 15;11(1):5205. doi: 10.1038/s41467-020-18945-0. PMID: 33060564; PMCID: PMC7567103.
5. Jiménez-Reina L, Cañete R, de la Torre MJ, Bernal G. Influence of chronic treatment with the growth hormone secretagogue Ipamorelin, in young female rats: somatotroph response in vitro. Histol Histopathol. 2002;17(3):707-14. doi: 10.14670/HH-17.707. PMID: 12168778.
6. Khorram O, Laughlin GA, Yen SS. Endocrine and metabolic effects of long-term administration of [Nle27]growth hormone-releasing hormone-(1-29)-NH2 in age-advanced men and women. J Clin Endocrinol Metab. 1997 May;82(5):1472-9. doi: 10.1210/jcem.82.5.3943. PMID: 9141536.
7. Gobburu JV, Agersø H, Jusko WJ, Ynddal L. Pharmacokinetic-pharmacodynamic modeling of ipamorelin, a growth hormone releasing peptide, in human volunteers. Pharm Res. 1999 Sep;16(9):1412-6. doi: 10.1023/a:1018955126402. PMID: 10496658.
8. Sinha DK, Balasubramanian A, Tatem AJ, Rivera-Mirabal J, Yu J, Kovac J, Pastuszak AW, Lipshultz LI. Beyond the androgen receptor: the role of growth hormone secretagogues in the modern management of body composition in hypogonadal males. Transl Androl Urol. 2020 Mar;9(Suppl 2):S149-S159. doi: 10.21037/tau.2019.11.30. PMID: 32257855; PMCID: PMC7108996.
9. Dehkhoda F, Lee CMM, Medina J, Brooks AJ. The Growth Hormone Receptor: Mechanism of Receptor Activation, Cell Signaling, and Physiological Aspects. Front Endocrinol (Lausanne). 2018 Feb 13;9:35. doi: 10.3389/fendo.2018.00035. PMID: 29487568; PMCID: PMC5816795.
10. Lall S, Tung LY, Ohlsson C, Jansson JO, Dickson SL. Growth hormone (GH)-independent stimulation of adiposity by GH secretagogues. Biochem Biophys Res Commun. 2001 Jan 12;280(1):132-8. doi: 10.1006/bbrc.2000.4065. PMID: 11162489.
11. Svensson J, Lall S, Dickson SL, Bengtsson BA, Rømer J, Ahnfelt-Rønne I, Ohlsson C, Jansson JO. The GH secretagogues ipamorelin and GH-releasing peptide-6 increase bone mineral content in adult female rats. J Endocrinol. 2000 Jun;165(3):569-77. doi: 10.1677/joe.0.1650569. PMID: 10828840.
12. Johansen PB, Nowak J, Skjaerbaek C, Flyvbjerg A, Andreassen TT, Wilken M, Orskov H. Ipamorelin, a new growth-hormone-releasing peptide, induces longitudinal bone growth in rats. Growth Horm IGF Res. 1999 Apr;9(2):106-13. doi: 10.1054/ghir.1999.9998. PMID: 10373343.