AOD-9604 Peptide (5MG)

This 2001 study in Endocrinology (Heffernan et al., Monash University) compared AOD9604 with full-length GH (hGH) in mice. The researchers asked whether either compound changed body weight, fat-tissue mass and expression of the β3-adrenergic receptor (β3-AR), the main receptor that drives fat breakdown in rodent fat cells.

They used three mouse models: genetically obese (ob/ob) mice, lean C57BL/6J mice, and β3-AR knockout mice. They also measured short-term energy expenditure and fuel use after a single dose.

Scope: This was a mouse study with small groups. It did not test AOD9604 in people.

• Citation: Heffernan M, Summers RJ, Thorburn A, et al. Endocrinology. 2001;142(12):5182–5189.
• Animals: Lean C57BL/6J and obese (ob/ob) mice, plus β3-AR knockout and wild-type mice (males)
• Experiments: 14-day daily treatment (lean and ob/ob), 28-day daily treatment (knockout and wild-type), and a 30-minute calorimetry study after one dose
• Administration in the study: Intraperitoneal
• Comparison groups: Saline, full-length hGH, and a β3-AR agonist (BRL37344) in the acute study
• Group sizes: 3 to 6 mice per group

Growth hormone affects fat metabolism, but it also influences growth, insulin action and other processes. Earlier laboratory work suggested that the C-terminal region of hGH carries much of its fat-metabolizing activity. AOD9604 was made to study that region in isolation.

Before this paper, the same group had reported that AOD9604 and hGH increased β3-AR expression in mouse and cell lines. This study tested whether the same change occurs in living mice, and whether the β3-AR is needed for the effects on fat tissue.

14-day study (lean versus obese mice): Lean C57BL/6J and ob/ob mice (12 weeks old, n = 6 per group) received saline, AOD9604 (250 µg/kg/day) or hGH (1 mg/kg/day) intraperitoneally once daily. Researchers recorded body weight and food intake every second day, then weighed white (epididymal) and brown (interscapular) fat and measured β3-AR mRNA.

28-day study (β3-AR knockout mice): Male β3-AR knockout mice and wild-type controls (n = 3–5 per group) received the same daily treatments for 28 days. Researchers measured body weight, food intake, fat-pad weights and plasma glycerol, a marker of fat breakdown.

Acute calorimetry study: Wild-type and knockout mice (n = 3 per treatment) received a single dose of saline, AOD9604 (2 mg/kg) or the β3-AR agonist BRL37344 (250 µg/kg). Energy expenditure, fat oxidation and glucose oxidation were measured for 30 minutes.

The amounts above are reported only to describe the published mouse methods.

Obese (ob/ob) mice: Over 14 days, both AOD9604 and hGH were associated with lower body weight, and food intake did not change. Epididymal white fat mass was 28% lower with AOD9604 and 40% lower with hGH than with saline.

Lean mice: The pattern was different. Neither compound changed white fat mass. hGH increased body-weight gain, and AOD9604 increased body weight only on the final day.

Brown fat: Brown adipose tissue mass decreased with treatment in both lean and obese mice.

β3-AR expression: Untreated ob/ob mice had lower β3-AR mRNA in fat than lean mice. In white fat, both compounds raised β3-AR mRNA in obese mice only, which matched the drop in white fat mass. In brown fat, β3-AR mRNA rose in both lean and obese mice.

In the 28-day study, AOD9604 and hGH increased body weight in lean wild-type mice, similar to the lean mice in the 14-day study. Neither compound changed body weight in β3-AR knockout mice.

Neither compound changed white fat mass in either genotype. In wild-type mice, brown fat mass fell by 20% with AOD9604 and 31% with hGH. This did not happen in knockout mice.

Plasma glycerol rose with both compounds in wild-type mice. In knockout mice, AOD9604 had no effect on glycerol, and the rise with hGH was much smaller than in wild-type mice. The authors concluded that the β3-AR is needed for the longer-term fat-tissue effects of both compounds.

In wild-type mice, a single dose of AOD9604 or BRL37344 increased fat oxidation and energy expenditure and lowered glucose oxidation within 30 minutes. The effect plateaued about 18 minutes after dosing.

In β3-AR knockout mice, AOD9604 still increased fat oxidation and energy expenditure, but BRL37344 did not. The response to AOD9604 in knockout mice was smaller and shorter, and glucose oxidation did not fall. This suggested that AOD9604's short-term effect does not depend directly on the β3-AR.

The authors proposed a two-part explanation:

• Neither AOD9604 nor hGH acts directly on the β3-AR. In earlier ligand-binding studies, AOD9604 did not bind this receptor.
• With repeated treatment, both compounds increased β3-AR expression in fat tissue. This may increase sensitivity to fat-breakdown signals, especially where β3-AR levels are low, as in ob/ob mice.

The short-term effect on fat oxidation in knockout mice points to at least one additional pathway that this study did not identify.

• Groups were very small (3–6 mice), and the knockout study used 3–5 mice per group.
• Effects depended on the mouse model. Obese ob/ob mice lost fat mass, while lean mice did not, and lean mice gained some body weight.
• ob/ob mice lack leptin, which makes them a specific genetic model rather than a general model of diet-related weight gain.
• The study measured fat-pad weights, mRNA and short-term calorimetry. It did not measure long-term outcomes.
• Mouse findings do not establish effects, safety or dosing in other species, including people.

In Heffernan et al. (2001), 14 days of AOD9604 or hGH was associated with lower body weight and white fat mass in obese ob/ob mice without a change in food intake, alongside increased β3-AR expression in fat. Lean mice did not show the same reduction. Knockout experiments indicated that the β3-AR is needed for the longer-term fat-tissue effects, while a short-term rise in fat oxidation after AOD9604 also occurred without the receptor.

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