Glucose-Dependent Insulinotropic Polypeptide Receptor-Expressing Cells in the Hypothalamus Regulate Food Intake

Ambiguity regarding the role of glucose-dependent insulinotropic polypeptide (GIP) in obesity arises from conflicting reports asserting that both GIP receptor (GIPR) agonism and antagonism are effective strategies for inhibiting weight gain. To enable identification and manipulation of Gipr-expressi...

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Bibliographic Details
Published in:	Cell metabolism Vol. 30; no. 5; pp. 987 - 996.e6
Main Authors:	Adriaenssens, Alice E, Biggs, Emma K, Darwish, Tamana, Tadross, John, Sukthankar, Tanmay, Girish, Milind, Polex-Wolf, Joseph, Lam, Brain Y, Zvetkova, Ilona, Pan, Warren, Chiarugi, Davide, Yeo, Giles S H, Blouet, Clemence, Gribble, Fiona M, Reimann, Frank
Format:	Journal Article
Language:	English
Published:	United States Cell Press 05-11-2019
Subjects:	Aged, 80 and over Animals Eating - drug effects Eating - physiology Female Gastric Inhibitory Polypeptide - metabolism Gene Knock-In Techniques Glucagon-Like Peptide 1 - metabolism Glucagon-Like Peptide-1 Receptor - agonists Glucagon-Like Peptide-1 Receptor - metabolism Humans Hypothalamus - cytology Mice Mice, Inbred C57BL Mice, Transgenic Neurons - metabolism Obesity - drug therapy Receptors, Gastrointestinal Hormone - agonists Receptors, Gastrointestinal Hormone - genetics Receptors, Gastrointestinal Hormone - metabolism glucose-dependent insulinotropic polypeptide receptor glucose-dependent insulinotropic polypeptide hypothalamus food intake
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Summary:	Ambiguity regarding the role of glucose-dependent insulinotropic polypeptide (GIP) in obesity arises from conflicting reports asserting that both GIP receptor (GIPR) agonism and antagonism are effective strategies for inhibiting weight gain. To enable identification and manipulation of Gipr-expressing (Gipr) cells, we created Gipr-Cre knockin mice. As GIPR-agonists have recently been reported to suppress food intake, we aimed to identify central mediators of this effect. Gipr cells were identified in the arcuate, dorsomedial, and paraventricular nuclei of the hypothalamus, as confirmed by RNAscope in mouse and human. Single-cell RNA-seq identified clusters of hypothalamic Gipr cells exhibiting transcriptomic signatures for vascular, glial, and neuronal cells, the latter expressing somatostatin but little pro-opiomelanocortin or agouti-related peptide. Activation of G -DREADDs in hypothalamic Gipr cells suppressed food intake in vivo, which was not obviously additive with concomitant GLP1R activation. These data identify hypothalamic GIPR as a target for the regulation of energy balance.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Lead Contact Senior author
ISSN:	1550-4131 1932-7420
DOI:	10.1016/j.cmet.2019.07.013