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Mice lacking a microbiota are protected from diet-induced obesity. Previous studies have shown that feeding a Western diet causes hypothalamic inflammation, which in turn can lead to leptin resistance and weight gain. Here, we show that wild-type (WT) mice with depleted gut microbiota, i.e., germ-free (GF) and antibiotic-treated mice, have elevated levels of glucagon-like peptide-1 (GLP-1), are protected against diet-induced hypothalamic inflammation, and have enhanced leptin sensitivity when fed a Western diet. Using GLP-1 receptor (GLP-1R)-deficient mice and pharmacological inhibition of the GLP-1R in WT mice, we demonstrate that intact GLP-1R signaling is required for preventing hypothalamic inflammation and enhancing leptin sensitivity. Furthermore, we show that astrocytes express the GLP-1R, and deletion of the receptor in glial fibrillary acidic protein (GFAP)-expressing cells diminished the antibiotic-induced protection against diet-induced hypothalamic inflammation. Collectively, our results suggest that depletion of the gut microbiota attenuates diet-induced hypothalamic inflammation and enhances leptin sensitivity via GLP-1R-dependent mechanisms., Competing Interests: Declaration of interests D.J.D. has served as an advisor or consultant or speaker within the past 12 months to Forkhead Biotherapeutics, Intarcia Therapeutics, Kallyope, Eli Lilly, Merck Research Laboratories, Novo Nordisk Inc., and Pfizer Inc. Neither D.J.D. nor his family members hold stock in these companies. GLP-2 is the subject of a patent license agreement between Shire Inc. and the University of Toronto, Toronto General Hospital (UHN), and D.J.D. R.J.S. has research support from Ethicon Endo-Surgery/Johnson & Johnson, Novo Nordisk, Zafgen, Kallyope, Astra Zeneca, and Pfizer. He has been a consultant or part of a Scientific Advisory Board for Ethicon Endo-Surgery/Johnson & Johnson, Novo Nordisk, Janssen/Johnson & Johnson, Sanofi, Kallyope, Scohia, Ironwood Pharma, and GuidePoint Consultants. In addition, R.J.S. holds equity in Zafgen and Redesign Health., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)