AOD 9604: Lipid Metabolism Regulation & Osteoarthritis Protective Effects

AOD 9604, short for “Anti-Obesity Drug-9604,” is a synthetic analog of the human growth hormone’s lipolytic (fat-burning) region. Researchers isolated and modified a specific portion of hGH responsible for fat metabolism, hoping to create a targeted peptide that promotes weight loss without triggering the full spectrum of effects associated with growth hormone therapy. Unlike complete hGH, AOD 9604 generally does not raise levels of IGF-1 or significantly impact blood sugar regulation. Because of this, it has gained popularity as a possible alternative for individuals seeking fat reduction strategies with fewer systemic effects.

Effect of Intra-articular Injection of AOD 9604 with or without Hyaluronic Acid

Osteoarthritis (OA) is a degenerative joint disease that results from articular cartilage loss induced by complex interactions of genetic, metabolic, biochemical, and biomechanical factors with secondary components of inflammation. The role of NSAIDs in OA management is controversial because of its adverse side effects, as well as side effects on the cartilage. AOD 9604 is a new synthetic peptide fragment that comprises a modified 15 amino acid region of GH with a tyrosine component to help stabilize the molecule. Similar to GH, AOD 9604 aids weight reduction in rodent models of obesity and was originally developed for the treatment of obesity in humans. Additionally, it does not stimulate the production of IGF-1, has positive effects on the differentiation of adipose mesenchymal stem cells into bone, and was found to promote proteoglycan and collagen production in isolated bovine chondrocytes in an in vitro study by Metabolic Pharmaceuticals. Its positive effects include promoting the repair of bone and cartilage in cases of OA. The aim of this study was to investigate the protective effects of AOD9604 intra-articular injection on the cartilage in a collagenase-induced knee OA rabbit model. The efficacy of AOD 9604 combined with hyaluronic acid (HA) injection was also evaluated.[1]

In vitro studies by Metabolic Collaborators showed that AOD9604 enhances the differentiation of adipose mesenchymal stem cells into bone, promotes proteoglycan and collagen production in isolated bovine chondrocytes, and promotes differentiation of myoblasts into C2C12 cells. These effects induced by AOD 9604 are similar to those required for the repair of bone, cartilage, and muscle, all of which are affected in OA. To the best of our knowledge, no study has compared the effects of GH and HA intra-articular injections on OA. A previous study showed the effects of intra-articular GH injection on articulophyseal cartilage regeneration in the knees of rabbits. Our study showed that the groups that received AOD 9604 or HA injection had better outcomes in terms of morphological and histolopathological findings, as well as a lowered duration of lameness than the group that received saline injections, although there are no significant differences between the two groups. In addition, our study revealed that the groups that received combined injections of AOD9604 and HA showed better outcomes than the groups that received AOD9604 or HA alone. The apparently synergistic effect of combined injections is thought to indicate that intra-articular injection of HA may have a chondrocyte-protective role, and the AOD 9604 could help recapitulate the developmental cascades which regrows a segment of the articular cartilage in a joint.

Effects of Human GH and AOD 9604 on Lipid Metabolism

HUMAN GH (hGH) has profound lipolytic/antilipogenic actions in vivo, which result in decreased fat mass, increased lean mass, and weight loss. Studies in vitro and in vivo have indicated that this response is mediated in part by an increase inβ -adrenoceptor coupling efficiency, a reduction in Gi expression, increased activity of hormone sensitive lipase, and an inhibitory effect on the action of insulin. We have synthesized a fragment of hGH (AOD 9604) that contains a lipolytic domain that may be responsible for the lipolytic action of hGH. The parent molecule, AOD9401, induces lipolysis and antilipogenesis and fat oxidation in adipose tissue in vitro. In vivo, AOD9401 induces weight loss without affecting food intake as well as increasing lipolytic sensitivity and increasing fat oxidation with no adverse effects on insulin sensitivity. In this paper, we investigated whether the changes observed inβ 3-AR RNA expression in vitro also occur in an in vivo model. The in vivo model used was the obese (ob/ob) mouse model of obesity that has repressed levels of β3-ARs, which in part contributes to reduced lipolytic sensitivity. Lean C57BL/6J mice were used as a control. Following a 14-d chronic administration with AOD 9604 or hGH, adipose tissue weights were measured, and β3-AR mRNA expression was determined.[2]

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. The acute effect of AOD 9604 and BRL37344 (aβ 3-AR agonist) on energy expenditure and substrate oxidation rates in WT and KO mice was also assessed. KO animals had lower energy expenditure, lower fat oxidation, and increased glucose oxidation, compared with the WT controls (data not shown). Injection of WT mice with a single dose of BRL37344 or AOD9604 increased energy expenditure and fat oxidation and decreased glucose oxidation. These findings suggest that the acute effects of AOD 9604 are quite different from the chronic effects. Enhancedβ 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 AOD 9604 would permit enhanced lipolytic sensitivity.

References

[1]Kwon DR, Park GY. Effect of Intra-articular Injection of AOD9604 with or without Hyaluronic Acid in Rabbit Osteoarthritis Model. Ann Clin Lab Sci. 2015 Summer;45(4):426-32. PMID: 26275694.

[2]Heffernan M, 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 Dec;142(12):5182-9. doi: 10.1210/endo.142.12.8522. PMID: 11713213.

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