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Sleeve Gastrectomy Improves High-Fat Diet-Associated Hepatic Steatosis Independent of the Glucagon-like-Petpide-1 Receptor in Rats. J Gastrointest Surg 2022 Aug;26(8):1607-1618



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BACKGROUND: The gastrointestinal hormone glucagon-like peptide-1 (GLP-1) is increased after sleeve gastrectomy (SG). Rat and clinical studies support, while mouse studies refute, a role for GLP-1R signaling after SG. Therefore, we developed a global GLP-1R knockout (KO) rat to test the hypothesis that a functional GLP-1R is critical to induce weight loss and metabolic disease improvement after SG.

METHODOLOGY: A 4A bp deletion was created in exon 2 of the GLP-1R gene on a Lewis strain background to create a global GLP-1R KO rat. KO and Lewis rats were placed on a high-fat or low-fat diet and phenotyped followed by SG or Sham surgery and assessed for the effect of GLP-1R KO on surgical and metabolic efficacy.

RESULTS: Loss of the GLP-1R created an obesity-prone rodent without changes in energy expenditure. Both male and female KO rats had significantly greater insulin concentrations after an oral glucose gavage, augmented by a high-fat diet, compared to Lewis rats despite similar glucose concentrations. GLP-1R KO caused hepatomegaly and increased triglyceride deposition compared to Lewis rats. We found no difference between SG GLP-1R KO and Lewis groups when considering efficacy on body weight, glucose tolerance, and a robustly preserved improvement in fatty liver disease.

CONCLUSIONS: Loss of the GLP-1R in rats resulted in increased adiposity, insulin resistance, and severe steatosis. A functional GLP-1R is not critical to the metabolic efficacy of SG in Lewis rats, similar to mouse studies, but importantly including steatosis, supporting a GLP-1R-independent mechanism for the improvement in fatty liver disease after SG.

Author List

Barron M, Hayes H, Fernando DG, Geurts AM, Kindel TL


Matthew R. Barron PhD Research Scientist I in the Surgery department at Medical College of Wisconsin
Aron Geurts PhD Professor in the Physiology department at Medical College of Wisconsin
Tammy Lyn Kindel MD, PhD Associate Professor in the Surgery department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Diet, High-Fat
Fatty Liver
Glucagon-Like Peptide Receptors
Glucagon-Like Peptide-1 Receptor
Rats, Inbred Lew