Kirk Habegger, Ph.D. A new research study led by UAB Comprehensive Diabetes Center scientist Kirk Habegger, Ph.D., shows that cholesterol-lowering drugs enhance weight loss facilitated by glucagon receptor agonist obesity drugs.

Habegger is a professor in the UAB Department of Medicine Division of Endocrinology, Diabetes and Metabolism and also a scientist in the UAB Nutrition Obesity Research Center who studies how glucagon signaling works in the body with a special emphasis on weight loss and glucose metabolism.

Glucagon is a hormone in the pancreas that regulates blood glucose and lipid metabolism. Glucagon receptor agonists are drugs that stimulate the glucagon receptor, which increases energy expenditure and suppresses appetite, leading to weight loss. Manipulating glucagon receptor activity has been a key addition to the recent breakthrough GLP-1/GIP therapies for Type 2 diabetes and now obesity.

Habegger said his latest study, in collaboration with researchers at Eli Lilly and Company and Indianna University, is to his knowledge the first investigation of how bile acid-binding cholesterol drugs affect the weight loss stimulated by glucagon receptor agonist drugs.

Their work, “Bile Acid Binding Resins Improve Glucagon Receptor Agonist-Mediated Weight Loss in Diet-Induced Obese Mice,” was published in Obesity, the official peer-reviewed journal of The Obesity Society.

Bile acids are made from cholesterol and help the body digest and absorb dietary fat and fat-soluble nutrients. In previous studies, Habegger and his team found that glucagon-receptor agonism regulates bile acid metabolism and promotes weight loss in obese mice via the farnesoid X receptor (FXR) in the liver. The FXR acts as a sensor for bile acids and functions as a key regulator of bile acid homeostasis, lipid metabolism, inflammation, and glucose metabolism.

Habegger therefore hypothesized that bile acid signaling contributes to glucagon-receptor-stimulated weight loss.

To test this hypothesis, researchers designed an experiment to see how sequestering bile acids would affect weight loss. They used bile-acid binding resins colesevelam (Colsv) and cholestyramine (Cstyr) to prevent intestinal bile acid reuptake. Colsv and Cstyr are lipid-lowering drugs used to lower cholesterol levels in the bloodstream.

Diet-induced obese mice were administered the glucagon receptor agonist IUB288 or isotonic saline with and without Colsv and Cstyr daily for 14 days. The results were not what researchers expected.

“We really wanted to test if the bile acids were acting as signals downstream of glucagon receptor signaling. We thought that by sequestering the bile acids, we would inhibit at least part of the glucagon program,” Habegger said. “We hypothesized that this (bile acid sequestration) might inhibit glucagon receptor stimulated weight loss effects. We saw the exact opposite. We increased the amount of weight lost in response to the same dose of glucagon receptor agonist.”

Habegger said future studies will investigate if the mechanism driving the enhanced weight loss is glucagon-specific—since glucagon regulates bile acids—or if this is a universal effect that could be potentially used to enhance current and future weight loss therapies.

“Together, these studies suggest that bile acid resins enhance the antiobesity effect of glucagon agonism in diet-induced obese mice, representing a novel antiobesity strategy,” Habegger said.

Other study authors from the Habegger Lab include Teayoun Kim, Ph.D., Huixian Hong, M.D., Ph.D., Shelly Nason, Ph.D., Khadija Seck, Jessica Antipenko, and Natalie Presedo.

This study was supported by grants from the National Institute of Health, the Lilly Research Award Program, and the American Heart Association.

Read the full paper in Obesity.