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Botulinum neurotoxin (available commercially as BOTOX®) has been used successfully for treatment of several neuromuscular disorders including blepharospasm, dystonia, spasticity, and cerebral palsy in children. Our data demonstrate that injection of BOTOX® into the proximal intestinal wall of diet-induced obese (DIO) mice induces weight loss and reduces food intake. This was associated with amelioration of hyperglycemia, hyperlipidemia, and significant improvement of glucose tolerance without alteration of energy expenditure. We also observed accelerated gastrointestinal transit and significant reductions in glucose and lipid absorption which may account at least, in part to the observed weight loss and robust metabolic benefits, although possible systemic effects occurring as a consequence of central and/or peripheral signaling cannot be ignored. The observed metabolic benefits were found to be largely independent of weight loss as demonstrated by pair-feeding experiments. Effects lasted until about 8 weeks, for as long as the half-life of Botox as reported in prior rodent studies. These results have valuable clinical implications. If the observed effects are translatable in humans this approach could lay the foundation for therapeutic approaches geared toward robust and sustained weight loss, mimicking some of the benefits of bariatric surgeries without its cost and complications.