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Preclinical Trial of Gastric Injection of Botulinum Toxin Type a As Weight-Loss-Surgery
Helene Johannessen*1, Magnus K. Olsen1, Nikki Cassie2, Perry Barrett2, Jens F. Rehfeld3, Jens J. Holst4, Baard Kulseng5,1, Chun-Mei Zhao1, Duan Chen1,5
1Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway; 2Rowett Institute of Nutrition and Health, University of Aberdeen, Aberdeen, United Kingdom; 3Department of Clinical Biochemistry, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark; 4The NNF Center for Basic Metabolic Research, Department of Biomedical Sciences, Panum Institute, University of Copenhagen, Copenhagen, Denmark; 5Department of Surgery, St. Olav's University Hospital, Trondheim, Norway
Background/aim: Recently, a clinical trial enrolling 60 obese patients failed to show that gastric injection of botulinum neurotoxin type -A (Botox) promotes body weight (BW) loss. The aim of this study was to verify the effectiveness and the underlying mechanism of gastric injection of Botox as weight-loss-surgery (WLS).
Methods: 102 male rats (42 normal rats at 500 g BW and 60 high-fat-diet-induced obese rats at 700-800 g BW) were subjected to Botox injection, vehicle injection, or sleeve gastrectomy (SG) followed by Botox injection. Rats on high-fat-diet were continuously fed the high-fat-diet after Botox injection or surgery. Botox was injected at a dose of 20 U/rat into the subserosa layer of pyloric antrum or the remaining antrum post SG, and Botox injection was repeated when rats regained BW. Measurements included BW development, food intake, eating behavior and metabolic parameters (monitored by Comprehensive Laboratory Animal Monitoring System, CLAMS), fasting blood glucose levels, gastric emptying rate (acetaminophen absorption test), gut hormones (RIA), and expression of genes encoding orexigenic and anorexigenic neuropeptides in the hypothalamus (in situ hybridization).
Results: There were no mortality, adverse effects and pathological changes in rats subjected to Botox injection. Botox injection reduced BW by 14% in normal rats and 25% in obese rats compared to values before Botox injection (p<0.001). Rats started to regain BW after 3 and 4 weeks in normal and obese rats, respectively. The 2nd Botox injection caused a total BW loss of 18% in normal rats and 32% in obese rats (p<0.001). SG reduced BW by 10% (p>0.05). Additional Botox injection led to BW loss of 22% (p<0.01). Botox injection increased satiety ratio (min/g), leading to reduced food intake (g/day), and increased energy expenditure (kcal/h/100g BW). Botox injection reduced fasting blood glucose levels, while gastric emptying rate was unchanged (measured at 3 days, 1, 2 or 3 weeks after Botox injection) in either normal or obese rats. Gene expression in hypothalamus and plasma levels of gut hormones were unchanged at 48 hours after Botox injection. However, 8 weeks after Botox injection, the gene expression for neuropeptide Y and agouti-related peptide was increased, while pro-opiomelanocortin was decreased in arcuate nucleus in hypothalamus, and plasma levels of cholecystokinin, gastrin, and peptide YY, but not glucagon, glucagon-like peptide-1, were reduced, suggesting compensatory changes in the gut hormones-hypothalamus pathway.
Conclusions: This preclinical trial demonstrates the safety and efficacy of gastric injection of Botox as WLS when it is performed alone or in combination with SG. Botox reduced food intake and increased energy expenditure, independently of the gastric emptying rate and of the hypothalamus-gut hormone pathway.
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