Journal
CELL REPORTS
Volume 35, Issue 8, Pages -Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2021.109163
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Funding
- Swedish Research Council
- Ake Wiberg Foundation
- Magnus Bergvall's Foundation
- Wilhelm and Martina Lundgren's foundation
- Sahlgrenska Academy
- Leducq Foundation
- Novo Nordisk Foundation [NNF15OC0016798]
- Swedish Diabetes Foundation
- Swedish Heart-Lung Foundation
- Knut and Alice Wallenberg Foundation
- Swedish government [ALFGBG-718101]
- European Research Council (ERC) Consolidator Grant [615362-METABASE]
- CIHR [154321]
- Banting and Best Diabetes Centre Novo Nordisk Chair in Incretin Biology
- Novo Nordisk Foundation-Mt. Sinai Hospital Fund in peptide hormone biology
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Mice lacking a microbiota are protected from diet-induced obesity. Depletion of gut microbiota attenuates diet-induced hypothalamic inflammation and enhances leptin sensitivity through GLP-1R-dependent mechanisms.
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.
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