The glucose-dependent insulinotropic polypeptide (GIP) regulates body weight and food intake via CNS-GIPR signaling

Qian Zhang,Robert Augustin,Richard D Dimarchi,Konxhe Kulaj,Annette Feuchtinger,Matthias H Tschöp,Mostafa Bakhti,Stephan Herzig,Brian Finan,Heiko Lickert,Daniel J Drucker,Christian Wolfrum,Patrick J Knerr,Emilija Malogajski,Gustav Colldén,Gerald Grandl,Kerstin Stemmer,Challa Tenagne Delessa,Stephanie A Mowery,Andreas Blutke,Beata Legutko,Susanne Keipert,Ciro Salinno,Dominik Lutter,Martin Jastroch,Maximilian Kleinert,Laura Sehrer,Gerd Luippold,Alexandra Harger,Marta Tarquis-Medina ,Cristina García Cáceres ,Cassie Holleman ,Susanna M Hofmann ,Xue Li ,Diego Pérez-Tilve ,Timo Müller

doi:10.1016/j.cmet.2021.01.015

Abstract

SummaryUncertainty exists as to whether the glucose-dependent insulinotropic polypeptide receptor (GIPR) should be activated or inhibited for the treatment of obesity. Gipr was recently demonstrated in hypothalamic feeding centers, but the physiological relevance of CNS Gipr remains unknown. Here we show that HFD-fed CNS-Gipr KO mice and humanized (h)GIPR knockin mice with CNS-hGIPR deletion show decreased body weight and improved glucose metabolism. In DIO mice, acute central and peripheral administration of acyl-GIP increases cFos neuronal activity in hypothalamic feeding centers, and this coincides with decreased body weight and food intake and improved glucose handling. Chronic central and peripheral administration of acyl-GIP lowers body weight and food intake in wild-type mice, but shows blunted/absent efficacy in CNS-Gipr KO mice. Also, the superior metabolic effect of GLP-1/GIP co-agonism relative to GLP-1 is extinguished in CNS-Gipr KO mice. Our data hence establish a key role of CNS Gipr for control of energy metabolism.

Highlights

The glucose-dependent insulinotropic polypeptide (GIP) regulates blood glucose via its insulinotropic and glucagonotropic action on the pancreas (Christensen et al, 2011; Finan et al, 2016)
Consistent with localization of Gipr in hypothalamic nuclei linked to control of appetite (Adriaenssens et al, 2019), we show that acute central and peripheral administration of fatty acyl-GIP increases cFOS neuronal activity in key hypothalamic feeding centers and that this coincides acutely and chronically with decreased body weight, food intake, and blood glucose
Mice with CNS-specific deletion of mGipr are protected from diet-induced obesity and glucose intolerance To evaluate the role of CNS Gipr signaling for systemic energy metabolism control, we generated mice in which mGipr is deleted in the CNS by crossing mGiprflx/flx mice (Ussher et al, 2018) with mice that express the cre recombinase under control of the nestin promoter

Summary

Introduction

The glucose-dependent insulinotropic polypeptide (GIP) regulates blood glucose via its insulinotropic and glucagonotropic action on the pancreas (Christensen et al, 2011; Finan et al, 2016). GIP activates lipoprotein lipase (Eckel et al, 1979; Kim et al, 2007, 2010), stimulates uptake of fatty acids and glucose (Beck and Max, 1986; Hauner et al, 1988), and promotes lipid synthesis in cultured adipocytes (Hauner et al, 1988) These data align with studies in humans, in which GIP is shown to promote lipid storage by increasing adipose tissue blood flow and triglyceride uptake (Asmar et al, 2017). It was shown that GIPR antagonizing antibodies improve body weight and glucose control in mice and non-human primates (Killion et al, 2018) and enhance the anorectic effect of leptin in HFDfed mice (Kaneko et al, 2019). There is considerable uncertainty as to how GIPR agonism versus antagonism improves energy metabolism

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