Alpha-cyclodextrin (α-CD) is a non-absorbable and soluble fiber that causes weight loss. We studied whether this is due to an effect on GLP-1 secretion. In GLUTag cells, α-CD increased GLP-1 secretion up to 170% via adenylyl cyclase, phospholipase C, and L-type calcium channels dependent processes. In rat isolated colon perfusions, luminal α-CD increased GLP-1 secretion with 20%. In lean mice, once daily α-CD versus saline caused weight loss and lowered the peak in glucose after an oral glucose tolerance test (OGTT). In obese mice, α-CD added to high-fat diet caused weight loss similar to the control group (receiving cellulose). However, compared to cellulose, the α-CD group ate less. During an OGTT, no differences were observed in glucose, insulin and GLP-1. Thus, α-CD increases GLP-1 secretion in a dose-dependent manner and could be a safe and easy addition to food products to help reduce body weight.