Abstract
Uncertainty 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. We show that HFD-fed CNS-Gipr ko mice and humanized (h)GIPR knock-in mice with CNS-hGIPR deletion show improved body weight and glycemia, but these metabolic improvements vanish upon adult-onset Gipr deletion. In DIO mice, acute central administration of acyl-GIP increases cFos neuronal activity in the arcuate, dorsomedial, paraventricular and lateral hypothalamus and leads to improved body weight, food intake, and glycemia. Chronic administration of acyl-GIP improves body weight and food intake in wildtype 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 was extinguished in CNS-Gipr ko mice. Our data 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)
We show that mice with CNS deletion of murine (m)Gipr and humanized (h)glucose-dependent insulinotropic polypeptide receptor (GIPR) knockin mice with conditional CNS deletion of hGIPR phenocopy global germline Gipr KO mice with respect to lower body weight and improved glucose metabolism upon highfat diet (HFD) feeding
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
Summary
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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