The effects of genetic GRF knock-out on the growth and body composition of mice (KO) compared with that of normal healthy controls. From Sun LY, Spong A, Swindell WR, et al., Growth hormone-releasing hormone disruption extends lifespan and regulates response to caloric restriction in mice. eLife. 2013;2:e01098, reproduced under the terms of the Creative Commons Attribution License

176-191 is the common term for a fragment of human growth hormone (hGH). It is often regarded as a mimic of the C-terminus of hGH; in other words, it is a peptide made up of the last 16 amino acids found in the sequence of the hormone. This region of hGH has been linked to the reduction of fat and fat tissue in mammals, by promoting lipolysis and inhibiting lipogenesis¹. However, this fragment of hGH has also been associated with the inhibition of insulin, and thus increased risks of hyperglycaemia². These effects may be related to amino acids 178 to 190 in the hGH sequence². Conversely, the amino-terminus of hGH has been found to have a significant effect on glucose breakdown mediated by insulin in healthy rats³. Animal studies investigating the properties of a 177-191 fragment have found that this peptide may disrupt the regulation of glycogen synthase in vivo⁴. This may lead to altered levels of circulating glucose. When the 176th amino acid is added to this fragment, however, it becomes an analog of the growth-hormone releasing factor (GRF). This peptide, as the name suggests, plays a role in the regulation of GH release, and is also known as growth hormone releasing hormone (GHRH)⁵.

GRF has demonstrated the ability to significantly increase plasma GH levels and growth, as observed in young female buffalo treated with this peptide, compared to controls⁶. Other researchers have claimed that chronic GRF administration also resulted in significant increases in the concentrations of luteinizing hormone (LH) and progesterone in similar animals⁶. GRF may also be associated with reductions in dyslipidemia (impaired lipid metabolism leading to the increased accumulation of body fat)⁷. Based on findings such as these, some scientists argue that GRF analogs may be useful in the promotion of body weight and improved body composition in livestock and other commercially-viable animals⁸.

Other functions of 176-191

GRF and its analogs are associated with the release of GH, and possibly IGsF, in many animals⁹. The release of GRF is historically associated with the hypothalamus, but has been detected in other sources, including the gonads and placenta⁹. As a result, some researchers propose that it has a role in fetal development⁹. GRF is also found in leukocytes⁹. Therefore, it may also have a role in the immune response and/or the regulation of the immune system. 

GRF and Neurons 

GRF is released by a population of neurons in the hypothalamus and anterior pituitary of many animals¹⁰. Therefore, it can also be categorized as a neuropeptide, or a protein fragment that may also act as a neurotransmitter or other type of mediator between nerve cells. A recent imaging study using rat brains found that up to 30% of the GRF neurons in this region could take up radiolabeled estradiol¹⁰. This indicates that estradiol may have a role in stimulating GRF release, and thus in the control of GH production in turn. These findings may also further clarify the as-yet uncertain role of estradiol in the central nervous system. GRF and similar peptides may also alleviate the effects of hypoxia in murine CNS studies¹¹.

References:

1. Wu Z, Ng FM. Antilipogenic action of synthetic C-terminal sequence 177-191 of human growth hormone. Biochemistry and molecular biology international. 1993;30(1):187-196.

2. Wade JD, Ng FM, Bornstein J, Pullin CO, Pearce JS. Effect of C-terminal chain shortening on the insulin-antagonistic activity of human growth hormone 177--191. Acta endocrinologica. 1982;101(1):10-14.

3. Mondon CE, Reaven GM, Ling N, Lewis UJ, Frigeri LG. Amino-terminal peptide of growth hormone enhances insulin action in normal rats. Endocrinology. 1988;123(2):827-833.

4. Macaulay SL, Armstrong JM, Bornstein J. Regulation of glycogen synthase activity in muscle by a C-terminal part sequence of human growth hormone. Archives of biochemistry and biophysics. 1983;224(1):365-371.

5. Mangili A, Falutz J, Mamputu J-C, Stepanians M, Hayward B. Predictors of Treatment Response to Tesamorelin, a Growth Hormone-Releasing Factor Analog, in HIV-Infected Patients with Excess Abdominal Fat. PLoS ONE. 2015;10(10):e0140358.

6. Haldar A, Prakash BS. Effects of growth hormone-releasing factor on growth hormone response, growth and feed conversion efficiency in buffalo heifers (Bubalus bubalis). Veterinary journal (London, England : 1997). 2007;174(2):384-389.

7. Hu M, Tomlinson B. Growth hormone-releasing factor agonists for the treatment of HIV-associated lipodystrophy. Current opinion in investigational drugs (London, England : 2000). 2010;11(10):1143-1150.

8. Sun LY, Spong A, Swindell WR, et al. Growth hormone-releasing hormone disruption extends lifespan and regulates response to caloric restriction in mice. eLife. 2013;2:e01098.

9. Campbell RM, Scanes CG. Evolution of the growth hormone-releasing factor (GRF) family of peptides. Growth regulation. 1992;2(4):175-191.

10. Shirasu K, Stumpf WE, Sar M. Evidence for direct action of estradiol on growth hormone-releasing factor (GRF) in rat hypothalamus: localization of [3H]estradiol in GRF neurons. Endocrinology. 1990;127(1):344-349.

11. Nair D, Ramesh V, Li RC, Schally AV, Gozal D. Growth hormone releasing hormone (GHRH) signaling modulates intermittent hypoxia-induced oxidative stress and cognitive deficits in mouse. Journal of neurochemistry. 2013;127(4):531-540.