Effects of novel vaccines on weight loss in diet-induced-obese (DIO) mice

Abstract

The purpose of the study was to test the therapeutic effects of novel vaccines for reducing weight gain and increasing weight loss in diet induced obesity (DIO) model. Male C57BL/6 J mice, fed a 60% Kcal fat diet for 8 weeks prior to the start of the study, were vaccinated via the intraperitoneal route with two formulations (JH17 & JH18) of chimeric-somatostatin vaccines at 1 and 22 days of the study. Control mice were injected with PBS. All mice continued to be feed the 60% Kcal fat diet for the 6 week study. Body weights were measured two times a week and food intake was measured weekly. At week 6, mice were euthanized and a terminal bleed was made and antibody levels to somatostatin and levels of insulin-like growth factor 1 (IGF-1) were determined. Vaccination with both vaccine formulations induced a statistically significant body weight change over the study period, as compared with PBS controls. Percentage of baseline body weight was also significantly affected by vaccination during the study period. Vaccinates finished the study at 104% and 107% of baseline weight, JH17 & JH18 respectively, while untreated controls reached 115% of baseline weight. Food intake per mouse was similar in all mouse groups during the entire study. Control mice did not demonstrate any antibody titers to somatostatin, while all vaccinated mice had measurable antibody responses (> 1:500,000 titer). IGF-1 levels were not statistically significant among the groups, but were elevated in the JH18 vaccinates (mean 440.4 ng/mL) when compared with PBS controls (mean 365.6 ng/mL). Vaccination with either JH17 or JH18 chimeric –somatostatin vaccines produced a statistically significant weight loss as compared with PBS controls (P < 0.0001), even though the DIO mice with continually fed a 60% Kcal fat diet. The weight loss/lower weight gain observations were even more significant, as all mice consumed similar amounts of food for the entire study. The presence of high levels of anti-somatostatin antibodies at 6 weeks was correlative with the weight observations and confirmed the success of vaccination.

Reduced brain somatostatin in mood disorders: a common pathophysiological substrate and drug target?

“…An example is SOM230, which interacts with Sst 1,2,3,5 and particularly potent at Sst 5 compared with LAR-OCT; (2) Chimeric somatostatin/dopamine molecule (Saveanu et al, 2002; Pivonello et al, 2005): a somatostatin and dopamine hybrid agonist, based on reports that dopamine and somatostatin receptors can hetero-oligomerize to enhance functional responses (Rocheville et al, 2000). An example is BIM-23A760, which accelerates the suppression of growth hormone and adrenocorticotropic hormone by the interaction with Sst 2 and Drd2 simultaneously; (3) Chimeric-somatostatin vaccinations (Haffer, 2012): a fusion protein expressing chloramphenicol acetyl transferase protein and somatostatin. Two somatostatin vaccinations, JH17 and JH18, can effectively reduce weight gain and reduce final body weight percentage of normal, non-obese mice and mice with diet-induced obesity via the intra-peritoneal route; (4) Non-peptide antagonists, such as SRA880 (Sst 1 selective), ACQ090 (Sst 3 selective) and Sst 4 selective β peptide agonists (Rivier et al, 2003; Hoyer et al, 2004).…”

Significant obesity-associated gene expression changes occur in the stomach but not intestines in obese mice

“…). Vaccines that induced high levels of antisomatostatin antibodies significantly reduced weight gain in HFD mice (Haffer ). Therefore, the increased somatostatin production may be the key connection between gastric acid secretion and obesity but more animal and human studies are needed to verify this hypothesis.…”

“…Although somatostatin analogs were proposed as a treatment for obesity, somatostatin actually reduced postprandial sensations after a satiating meal in obese individuals (Cremonini et al 2005). Vaccines that induced high levels of antisomatostatin antibodies significantly reduced weight gain in HFD mice (Haffer 2012). Therefore, the increased somatostatin production may be the key connection between gastric acid secretion and obesity but more animal and human studies are needed to verify this hypothesis.…”

Role of Somatostatin in the Regulation of Central and Peripheral Factors of Satiety and Obesity

“…Synthetic analogues are structurally similar to natural SST and are currently used in the treatment of several pathological conditions including acromegaly and neuroendocrine tumours and have potential clinical applications in the management of inflammation and nociception, obesity, and diabetic complications [9][10][11][12][13]. In addition to SST analogues, SST vaccinations, namely JH17 and JH18, using intraperitoneal route of administration have been reported in reduction of weight gain and body weight percentage of normal, non-obese mice and mice with diet-induced obesity [14].…”