Abstract
SummaryAmbiguity 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 Gq-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.
Highlights
Glucose-dependent insulinotropic polypeptide (GIP) is a gut hormone released from enteroendocrine cells in the duodenum and jejunum (Buchan et al, 1978; Buffa et al, 1975) within minutes of ingesting a meal (Elliott et al, 1993)
Gipr null offspring were protected against body weight gain when subjected to a high-fat diet (HFD) for 17 weeks and had significantly lower percent fat mass compared with Gipr-Cre heterozygous and wild-type (WT) littermates (Figures S1A and S1B), supporting previous results from another Gipr knock-out (KO) model (Miyawaki et al, 2002)
By crossing Gipr-Cre mice with ROSA26-EYFP reporter mice (GiprEYFP), we identified Gipr cells in target tissues
Summary
Glucose-dependent insulinotropic polypeptide (GIP) is a gut hormone released from enteroendocrine cells in the duodenum and jejunum (Buchan et al, 1978; Buffa et al, 1975) within minutes of ingesting a meal (Elliott et al, 1993). GIPR activation stimulates insulin release in pancreatic beta cells (Dupre et al, 1973), and together with its sister incretin, glucagonlike peptide-1 (GLP-1), GIP is an important glucostat to keep post-prandial blood glucose levels in check. It is GLP-1, that has enjoyed the therapeutic limelight in efforts to design more effective type 2 diabetes treatments. Initial interest in GIP-based therapies waned following studies showing that the insulinotropic properties of GIP are attenuated in patients with type 2 diabetes (Nauck et al, 1993). The complex relationship between GIP and adiposity has further obscured our understanding of GIP’s therapeutic potential
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