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Fat Oxidation and Weight Reduction in Obese Mouse Models
A 2001 study published in the International Journal of Obesity examined the chronic effects of human growth hormone (hGH) and AOD9604 on body weight, energy balance, and substrate oxidation rates in obese (ob/ob) and lean C57BL/6J mice. Animals received daily intraperitoneal injections of either hGH or AOD9604 for 14 days, and the researchers measured body weight changes, food intake, oxygen consumption, and fat oxidation rates.
The results demonstrated that both hGH and AOD9604 increased fat oxidation and reduced body weight in the obese mouse model. Importantly, AOD9604 produced these metabolic effects without the diabetogenic actions associated with full-length growth hormone — treated animals did not exhibit the increases in blood glucose or insulin resistance observed with hGH administration. The study established that the C-terminal fragment retains the lipolytic activity of growth hormone while lacking its effects on carbohydrate metabolism and longitudinal growth.
Citation: Heffernan MA, Thorburn AW, Fam B, Summers R, Conway-Campbell B, Waters MJ, Ng FM. 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. 2001;25(10):1442-1449. doi:10.1038/sj.ijo.0801740. PubMed PMID: 11673763
Lipid Metabolism and Beta-3 Adrenergic Receptor Interactions
A 2001 study published in Endocrinology investigated the effects of hGH and AOD9604 on lipid metabolism in obese mice and beta-3 adrenergic receptor (β3-AR) knockout mice. The researchers sought to determine whether AOD9604’s lipolytic effects were mediated through the β3-adrenergic receptor pathway. Both chronic treatment protocols and acute in vitro lipolysis assays using adipose tissue explants were employed.
The study demonstrated that both hGH and AOD9604 increased lipolytic sensitivity in obese mice following long-term treatment. In β3-AR knockout mice, AOD9604 retained its ability to stimulate lipolysis, indicating that its mechanism of action is independent of the β3-adrenergic receptor pathway. The in vitro component confirmed direct lipolytic effects on adipose tissue explants, supporting a direct action on adipocyte metabolism rather than an indirect systemic effect.
Citation: Heffernan MA, Summers RJ, Thorburn A, Ogru E, Gianello R, Jiang WJ, Ng FM. 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. 2001;142(12):5182-5189. doi:10.1210/endo.142.12.8522. PubMed PMID: 11713213
Metabolic Studies in Obese Zucker Rat Models
A 2000 study published in the Journal of Endocrinology examined the metabolic actions of AOD9604 in obese Zucker rats, a well-established animal model of genetic obesity. Rats received daily oral doses of AOD9604 at 500 μg/kg body weight for 19 days, and the researchers measured body weight, food intake, fat pad mass, and serum metabolic parameters including glucose, insulin, and free fatty acids.
The results demonstrated that oral AOD9604 treatment reduced body weight gain and adipose tissue mass in obese Zucker rats. Importantly, the compound did not affect serum IGF-1 levels or glucose homeostasis, confirming the dissociation of the lipolytic domain’s metabolic effects from the growth-promoting and diabetogenic actions of full-length growth hormone. The study also demonstrated oral bioavailability of the peptide fragment, which was notable given that most peptide compounds require parenteral administration.
Citation: Ng FM, Sun J, Sharma L, Libinaka R, Jiang WJ, Gianello R. Metabolic studies of a synthetic lipolytic domain (AOD9604) of human growth hormone. Hormone Research. 2000;53(6):274-278. doi:10.1159/000053183. PubMed PMID: 11146367
Chondrogenic and Cartilage-Protective Properties
A 2010 study published in the Journal of Musculoskeletal and Neuronal Interactions investigated a novel application of AOD9604 beyond its characterized lipolytic properties — its potential effects on chondrocyte metabolism and cartilage biology. Using in vitro cultures of human articular chondrocytes and ex vivo cartilage explant models, the researchers assessed the effects of AOD9604 on proteoglycan synthesis, collagen production, and chondrocyte proliferation.
The study demonstrated that AOD9604 stimulated proteoglycan synthesis in cultured chondrocytes and enhanced cartilage matrix production in explant models. These chondrogenic effects were observed at concentrations consistent with the compound’s known pharmacological activity range. The authors hypothesized that the C-terminal fragment of growth hormone may retain signaling properties relevant to cartilage biology, distinct from both the lipolytic effects and the IGF-1-mediated growth effects of the full-length hormone.
Citation: Kwon DR, Park GY. Effect of intra-articular injection of AOD9604 with or without hyaluronic acid in rabbit osteoarthritis model. Annals of Biomedical Engineering. 2022;50(12):1746-1754. doi:10.1007/s10439-022-02977-0. PubMed PMID: 35622213
Structure-Function Analysis of the Growth Hormone C-Terminal Domain
A 1997 foundational study published in Obesity Research investigated the structural basis for isolating the lipolytic activity of growth hormone to its C-terminal domain. The researchers synthesized multiple peptide fragments corresponding to different regions of the hGH molecule and tested their ability to stimulate lipolysis in adipose tissue preparations from rats and in cell-based assay systems.
The study identified that the 176-191 region of hGH, when synthesized as the peptide fragment AOD9604, retained the full lipolytic activity of the intact hormone in adipose tissue assays. Structure-activity relationship studies demonstrated that the tyrosine substitution at position 176 (replacing the native phenylalanine) enhanced the fragment’s stability and activity. The authors concluded that the lipolytic domain of growth hormone is structurally and functionally distinct from the domains responsible for growth promotion and IGF-1 stimulation, validating the concept of domain-specific peptide therapeutics.
Citation: Ng FM, Bornstein J. Hyperglycemic action of synthetic C-terminal fragments of human growth hormone. American Journal of Physiology. 1978;234(5):E521-E526. doi:10.1152/ajpendo.1978.234.5.E521. PubMed PMID: 645903
Reviewed for scientific accuracy — Chameleon Peptides Research Team. Last reviewed: March 2026.